On March 1, 2021 Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688), an innovative commercial-stage biopharmaceutical company, reported financial results for the second half and full year of 2020, along with corporate updates (Press release, Zai Laboratory, MAR 1, 2021, View Source [SID1234575858]).

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"2020 was another year of great accomplishment for Zai Lab," said Dr. Samantha Du, Founder, Chairperson and Chief Executive Officer of Zai Lab. "We successfully launched ZEJULA for both second-line and first-line ovarian cancer and Optune for glioblastoma in China. We submitted NDAs and were granted priority reviews by China’s National Medical Products Administration (NMPA) for both QINLOCK for advanced gastrointestinal stromal tumors (GIST) and NUZYRA for community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in China. We continued to expand our pipeline by forming new strategic partnerships with four companies for five compounds that we believe can address significant unmet medical needs. We and our partners continued to execute in clinical development, and we now have 21 product candidates, including 17 in clinical development, 11 in late-stage development and five that have been approved in the United States. Our pipeline of internally developed products with global rights grew to seven, including three in global clinical development.

"Looking ahead to 2021, we expect to receive approval for and launch QINLOCK and NUZYRA in China, bringing our total number of commercial products to four. In addition, ZEJULA for second-line ovarian cancer has been included in the National Reimbursement Drug List (NRDL), and we expect this will drive strong volume growth for the product this year and beyond. We also plan to submit regulatory filings for Tumor Treating Fields in mesothelioma and for MARGENZA in HER2-positive breast cancer in China in 2021. We expect to hold regulatory discussions with the NMPA regarding a potential accelerated regulatory pathway for efgartigimod, which has already been filed by our partner argenx for generalized myasthenia gravis in the United States. And we expect to obtain new clinical data for many products and product candidates.

"We are focused on building disease strongholds in China in three therapeutic areas — oncology, autoimmune disorders and infectious diseases. Within oncology, we have focused on five cancer franchises that account for over half of all new cancer patients in China. These cancer franchises include lung cancer and gastric cancer, where we have a world-class portfolio of product candidates, as well as women’s cancer, brain cancer and hematology. We plan to continue to expand this product pipeline both vertically within these areas of focus and horizontally into new therapeutic areas of significant unmet medical need.

"Over the next three years, our mission is to become a leading global biopharmaceutical company. In addition to seeking to deliver a steady stream of approvals and launches in China from our existing pipeline and forming new strategic collaborations and transformative partnerships, we aim to discover and develop innovative medicines. To accomplish our mission, we will continue to build upon our current scale, which currently consists of nearly 1,200 employees across eight operational locations around the world. While the challenges of COVID-19 continue for all of us, we at Zai Lab remain committed to extending our track record of execution in pursuit of our overall goal of improving human health globally."

Recent Product Highlights and Anticipated Milestones

Oncology

ZEJULA (niraparib)

ZEJULA is an oral, once-daily small-molecule poly ADP-ribose polymerase (PARP) 1/2 inhibitor. It is the only PARP inhibitor approved in the United States, the European Union and China as a monotherapy for patients with advanced ovarian cancer, regardless of their biomarker status.

Second-half 2020 Accomplishments

In December 2020, we announced that ZEJULA was included in the NRDL released by China’s National Healthcare Security Administration.

In September 2020, the NMPA approved the supplemental New Drug Application (sNDA) for ZEJULA as a maintenance treatment for adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.

In September 2020, we announced detailed positive results from the NORA study, the Phase 3 randomized, double-blind, placebo-controlled study of ZEJULA as a maintenance therapy in patients in China with recurrent ovarian cancer. The NORA study demonstrated a significant progression-free survival (PFS) benefit for ZEJULA, regardless of biomarker status, with an improved safety profile when given in an individualized starting dose regimen.

Since its commercial launch in January 2020 in China, ZEJULA has been listed in 67 commercial health insurance plans and 44 supplemental insurance plans initiated by provincial or municipal governments.
Anticipated 2021 Zai Milestones

Complete enrollment of the Phase 1b study of ZEJULA in combination with tebotelimab (PD-1 x LAG-3) in gastric cancer.

Announce topline results of the China Phase 3 PRIME study of ZEJULA in patients with first-line ovarian cancer in the second half.

Submit the sNDA for late-line ovarian cancer treatment in the second half.
Continue to explore additional indications and combination opportunities.
Tumor Treating Fields

Tumor Treating Fields is a cancer therapy that uses electric fields tuned to specific frequencies to disrupt cell division, inhibiting tumor growth and potentially causing cancer cell death.

Second-half 2020 Accomplishments

In August 2020, we launched Optune LuaTM for the treatment of malignant pleural mesothelioma (MPM) in Hong Kong.

Since its launch in June 2020, Optune has been listed in 10 supplemental insurance plans and is the first innovative medical device supported by commercial health insurance in China.
Anticipated 2021 Zai Milestones

Submit a Marketing Authorization Application (MAA) for MPM.

Join the global Phase 3 pivotal LUNAR trial in non-small cell lung cancer (NSCLC), the Phase 3 pivotal PANOVA-3 trial in locally advanced pancreatic cancer, the Phase 3 pivotal INNOVATE-3 trial in recurrent ovarian cancer and the Phase 3 pivotal METIS trial in brain metastases from non-small cell lung cancer.

Complete enrollment of the Phase 2 pilot trial in first-line gastric adenocarcinoma.
Anticipated 2021 Partner Milestones

Obtain final data from the Phase 2 HEPANOVA trial in advanced liver cancer in the first half.

Complete the interim analysis of the Phase 3 pivotal INNOVATE-3 trial in recurrent ovarian cancer in the second half.

Complete the interim analysis of the Phase 3 pivotal LUNAR trial in NSCLC in the second half.
QINLOCK (ripretinib)

QINLOCK is a switch-control tyrosine kinase inhibitor engineered to broadly inhibit KIT- and PDGFRα-mutated kinases. It is the only therapeutic approved in the United States for advanced GIST patients who have received prior treatment with three or more kinase inhibitors in the all-comer setting.

Second-half 2020 and 2021 Accomplishments

In March 2021, the Hong Kong Department of Health approved QINLOCK in Hong Kong for the treatment of adult patients with advanced GIST who have received prior treatment with imatinib, sunitinib, and regorafenib.

In December 2020, we announced dosing of the first patient with QINLOCK in Greater China for the second-line GIST registrational bridging study.

In August 2020, the NMPA granted priority review for the New Drug Application (NDA) for QINLOCK for the treatment of fourth-line GIST.

In July 2020, the NMPA accepted the NDA submission of QINLOCK for the treatment of fourth-line GIST.
Anticipated 2021 Zai Milestone

Potential NMPA approval and commercial launch of QINLOCK for the treatment of fourth-line GIST in the first half.
Anticipated 2021 Partner Milestone

Obtain topline data from the INTRIGUE Phase 3 study of QINLOCK in patients with second-line GIST in the second half.
Odronextamab

Odronextamab is a bispecific monoclonal antibody designed to trigger tumor killing by linking and activating a cytotoxic T-cell (binding to CD3) to a lymphoma cell (binding to CD20).

Anticipated 2021 Zai Milestone

Enroll the first patient in Greater China in the global Phase 2 potentially pivotal program in the first half, subject to feedback from the U.S. Food and Drug Administration (FDA).
Anticipated 2021 Partner Milestones

Complete enrollment of the Phase 2 potentially pivotal program in B-cell non-Hodgkin lymphoma (B-NHL).

Initiate confirmatory OLYMPIA Phase 3 trials in combination with chemotherapy in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and explore other combination opportunities.

Initiate development of a subcutaneous formulation.
Repotrectinib

Repotrectinib is a next-generation tyrosine kinase inhibitor (TKI) designed to effectively target ROS1 and TRK A/B/C, with the potential to treat TKI-naïve or TKI-pretreated patients.

Anticipated 2021 Zai Milestone

Enroll the first patient in Greater China in the global TRIDENT-1 Phase 2 registrational study in the first half.
Anticipated 2021 Partner Milestones

Plan to discuss the regulatory path of repotrectinib in patients with TKI-naïve ROS1-positive NSCLC with the FDA in the first half.

Initiate a Phase 2 combination study in KRAS-mutant NSCLC.

Provide clinical data updates from cohorts of the ongoing TRIDENT-1 study in the second half.
MARGENZA (Margetuximab)

MARGENZA is an Fc-optimized monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2).

Second-half 2020 Accomplishments

In December 2020, our partner MacroGenics announced that the FDA approved MARGENZA, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

In October 2020, we announced dosing of the first patient in Greater China in the global MAHOGANY study evaluating margetuximab as an investigational agent in combination with a checkpoint inhibitor, with or without chemotherapy, as a potential first-line treatment for patients with HER2-positive gastric cancer or gastroesophageal junction (GEJ) cancer.
Anticipated 2021 Zai Milestone

Submit an NDA for pretreated metastatic HER2-positive breast cancer.
Anticipated 2021 Partner Milestones

Obtain initial data from Module A of the MAHOGANY study.

Complete the final overall survival (OS) analysis of the SOPHIA study, a randomized, open-label Phase 3 study evaluating margetuximab plus chemotherapy compared to trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer who have previously been treated with HER2-targeted therapies.
Bemarituzumab

Bemarituzumab is a first-in-class antibody that is being developed in gastric and GEJ cancer as a targeted therapy for tumors that overexpress FGFR2b.

Second-half 2020 Accomplishment

In November 2020, our partner Five Prime Therapeutics announced positive topline results from the global, randomized, double-blind, placebo-controlled Phase 2 FIGHT trial. All three efficacy endpoints in the FIGHT trial – PFS, OS and objective response rate (ORR) – achieved pre-specified statistical significance in the bemarituzumab arm compared to the placebo arm. The trial results were later presented at the 2021 ASCO (Free ASCO Whitepaper) Gastrointestinal Cancers Virtual Annual Symposium (ASCO GI) in January 2021.
Anticipated 2021 Zai Milestone

Initiate a pivotal Phase 3 trial in gastric cancer with our partner Five Prime Therapeutics.
Anticipated 2021 Partner Milestone

Initiate a pivotal Phase 3 trial in gastric cancer and clinical development in other FGFR2b+ cancers.
CLN-081

CLN-081 is an orally available, small-molecule, next-generation, irreversible epidermal growth factor receptor (EGFR) inhibitor designed to selectively target cells expressing mutant EGFR variants, including EGFR exon 20 insertions.

Anticipated 2021 Zai Milestone

Enroll the first patient in Greater China in the global potentially pivotal study in the second half.
Anticipated 2021 Partner Milestone

Provide a clinical data update from the Phase 1/2a global study.
TPX-0022

TPX-0022 is an orally bioavailable, multi-targeted kinase inhibitor with a novel three-dimensional macrocyclic structure that inhibits the MET, CSF1R (colony stimulating factor 1 receptor) and SRC kinases.

Anticipated 2021 Partner Milestone

Provide updated data from the Phase 1 SHIELD-1 study and initiate the Phase 2 portion of the SHIELD-1 study pending FDA feedback in the second half.
Tebotelimab

Tebotelimab is an investigational, first-in-class, bispecific, tetravalent DART molecule targeting PD-1 and LAG-3.

Second-half 2020 Accomplishments

In November 2020, our partner MacroGenics presented Phase 1 clinical data for tebotelimab in combination with margetuximab in advanced HER2-positive neoplasms at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) annual meeting.

In December 2020, our partner MacroGenics presented Phase 1 cohort data in relapsed or refractory DLBCL at the ASH (Free ASH Whitepaper) Annual Meeting and Exposition.
Anticipated 2021 Zai Milestones

Make go/no-go decision on tebotelimab in combination with brivanib for hepatocellular carcinoma based on the Phase 1/2 proof-of-concept trial.
Anticipated 2021 Partner Milestone

Provide a clinical update, including future development plans.
Retifanlimab

Retifanlimab is an investigational monoclonal antibody that inhibits PD-1.

Second-half 2020 Accomplishments

In October 2020, we announced dosing of the first patient in Greater China in the global Phase 3 study evaluating retifanlimab in combination with platinum-based chemotherapy in patients with first-line metastatic NSCLC.

In October 2020, we announced dosing of the first patient in Greater China in the global potentially registrational study of retifanlimab in patients with previously treated microsatellite-instability-high endometrial cancer.
2021 Partner Accomplishment

In January 2021, our partner Incyte announced that FDA had accepted for Priority Review its Biologics License Application (BLA) for retifanlimab in patients with pretreated advanced squamous cell anal cancer (SCAC), with a PDUFA date of July 25, 2021.
Autoimmune Diseases

Efgartigimod

Efgartigimod is an antibody fragment designed to reduce disease-causing immunoglobulin G (IgG) antibodies and block the IgG recycling process. Efgartigimod binds to the neonatal Fc receptor (FcRn), which is widely expressed throughout the body and plays a central role in rescuing IgG antibodies from degradation.

Anticipated 2021 Zai Milestones

Discuss with the NMPA the potential accelerated regulatory pathway for efgartigimod in generalized myasthenia gravis (gMG).

Continue to explore and advance additional indications in coordination with argenx.
Anticipated 2021 Partner Milestones

Potential FDA approval and global commercial launch of efgartigimod for the treatment of patients with gMG.

Continue enrollment of the registrational ADHERE trial in chronic inflammatory demyelinating polyneuropathy (CIDP).

Initiate clinical trials in fifth and sixth indications.
Infectious Disease

NUZYRA (Omadacycline)

NUZYRA is a once-daily oral and intravenous antibiotic for the treatment of adults with CABP and ABSSSI.

Anticipated 2021 Zai Milestone

Potential NMPA approval and commercial launch of NUZYRA for the treatment of CABP and ABSSSI.
Sulbactam-Durlobactam (SUL-DUR)

Sulbactam-Durlobactam is a beta-lactam/beta-lactamase inhibitor combination that provides unique activity against Acinetobacter organisms, including carbapenem-resistant strains.

Anticipated 2021 Zai Milestone

Complete enrollment of patients in Greater China in the global Phase 3 ATTACK trial.
Internal Programs with Global Rights

ZL-2309 (CDC7)

ZL-2309 is an orally active, selective and ATP-competitive cell division cycle 7 (CDC7) kinase inhibitor.

Anticipated 2021 Zai Milestone

Initiate a biomarker-driven POC study in selected tumors.
ZL-1201 (CD47)

ZL-1201 is a humanized, IgG4 monoclonal antibody, engineered to reduce effector function, that specifically targets CD47. Its therapeutic potential will be assessed in both solid tumors and hematological malignancies, in both monotherapy and combination opportunities.

In June 2020, first-in-human dosing was achieved in the Phase 1 study.
ZL-1102 (IL-17)

ZL-1102 is a novel human nanobody targeting IL-17 with high affinity and avidity. Unlike other anti-IL-17 products, ZL-1102 is being developed as a topical treatment for chronic plaque psoriasis (CPP).

In July 2020, first-in-human dosing was achieved in the Phase 1 study.
Business Development

Second-half 2020 and Early 2021 Accomplishments

In January 2021, we expanded the collaboration with Turning Point Therapeutics with an exclusive license agreement for the development and commercialization of TPX-0022 in Greater China.

In January 2021, we announced an exclusive license agreement with argenx for the development and commercialization of efgartigimod in Greater China.

In December 2020, we announced an exclusive license agreement for the development, manufacturing and commercialization of CLN-081 in Greater China.

In July 2020, we announced an exclusive license agreement with Turning Point Therapeutics for the development and commercialization of repotrectinib in Greater China.
Anticipated 2021 Zai Milestone

Continue to pursue bolt-on and transformational business development opportunities.
Corporate Updates

Zai Lab continues to build its presence and capabilities in the United States in discovery, clinical development, business development and legal teams. The research center in the San Francisco Bay Area and the Cambridge office have been expanded.

Zai Lab continues to enhance R&D and other operational capabilities with a new campus under development in Suzhou, China.

Zai Lab continues to expand and hire talented professionals. As of January 31, 2021, Zai Lab employed 1,194 full-time employees, including 450 and 592 employees engaged in R&D and commercial activities, respectively.

Zai Lab appointed several executives with extensive global experience, including Alan Sandler, M.D., as President and Head of Global Development, Oncology; Ty Edmondson as Chief Legal Officer; and Ann Beasley as Chief Compliance Officer.
In September 2020, Zai Lab achieved a secondary listing on the Main Board of the Stock Exchange of Hong Kong, with total proceeds, before deducting underwriting discounts and commissions and other offering expenses, of approximately HK$6.83 billion ($881 million).

Zai Lab has been added to the Hang Seng Composite MidCap Index as of December 7, 2020.
Full-Year 2020 Financial Results

Revenues for the full year of 2020 were $49.0 million, compared to $13.0 million in 2019. Revenues for the period were comprised of $32.1 million in sales of ZEJULA, compared to $6.6 million in 2019; and $16.4 million in sales of Optune, compared to $6.4 million in 2019.

R&D expenses were $222.7 million for 2020, compared to $142.2 million for 2019. The increase in R&D expenses was primarily attributable to the upfront and milestone payments for licensing agreements, ongoing and newly initiated late-stage clinical trials, payroll and payroll-related expenses from increased R&D headcount and expansion of research efforts to support internal development programs.

Selling, General & Administrative expenses were $111.3 million for 2020, compared to $70.2 million for 2019. The increase was primarily due to payroll and payroll-related expenses from increased commercial headcount and related costs as Zai Lab continued to expand its commercial operations in China.

For the full year of 2020, Zai Lab reported a net loss of $268.9 million, or a loss per share attributable to common stockholders of $3.46, compared to a net loss of $195.1 million, or a loss per share attributable to common stockholders of $3.03, for the full year of 2019.

As of December 31, 2020, cash and cash equivalents, short-term investments and restricted cash totaled $1,187.5 million compared to $276.4 million as of December 31, 2019.
Conference Call and Webcast Information

Zai Lab will host a live conference call and webcast on March 1, 2021 at 8:00 a.m. ET. Listeners may access the live webcast by visiting the Company’s website at View Source Participants must register in advance of the conference call. Details are as follows:

Registration Link: View Source

Conference ID: 3008148
All participants must use the link provided above to complete the online registration process in advance of the conference call. Upon registering, each participant will receive a dial-in number, a Direct Event passcode and a unique access PIN, which can be used to join the conference call.

A replay will be available shortly after the call and can be accessed by visiting the Company’s website at View Source

On March 1, 2021 Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported that it will report its fourth quarter and full year 2020 financial and operating results on Thursday, March 11, 2021, following the close of the U.S. financial markets (Press release, Lineage Cell Therapeutics, MAR 1, 2021, View Source [SID1234575813]). Lineage management will also host a conference call and webcast on Thursday, March 11, 2021, at 4:30 p.m. Eastern Time/1:30 p.m. Pacific Time to discuss its fourth quarter and full year 2020 financial and operating results and to provide a business update.

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Interested parties may access the conference call by dialing (866) 888-8633 from the U.S. and Canada and (636) 812-6629 from elsewhere outside the U.S. and Canada and should request the "Lineage Cell Therapeutics Call". A live webcast of the conference call will be available online in the Investors section of Lineage’s website. A replay of the webcast will be available on Lineage’s website for 30 days and a telephone replay will be available through March 19, 2021, by dialing (855) 859-2056 from the U.S. and Canada and (404) 537-3406 from elsewhere outside the U.S. and Canada and entering conference ID number 4176568.

On March 1, 2021 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported the company is voluntarily withdrawing the U.S. indication for KEYTRUDA (pembrolizumab) for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy (Press release, Merck & Co, MAR 1, 2021, View Source [SID1234575841]). The withdrawal of this indication was done in consultation with the U.S. Food and Drug Administration (FDA), and Merck is working to complete this process over the coming weeks. This decision does not affect other indications for KEYTRUDA, Merck’s anti-PD-1 therapy.

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This accelerated approval for KEYTRUDA was granted in June 2019 based on tumor response rate and durability of response data from KEYNOTE-158 (cohort G) and KEYNOTE-028 (cohort C1). Continued approval for this indication was contingent upon completion of the post-marketing requirement establishing superiority of KEYTRUDA as determined by overall survival (OS). As announced in Jan. 2020, KEYNOTE-604, the confirmatory Phase 3 trial for this indication, met one of its dual primary endpoints of progression-free survival but did not reach statistical significance for the other primary endpoint of OS.

Merck’s consultation with the FDA on this withdrawal is part of an industry-wide evaluation of indications based on accelerated approvals that have not yet met their post-marketing requirements. Merck is notifying health care professionals about this withdrawal. Patients being treated with KEYTRUDA for their metastatic SCLC should discuss their care with their health care provider.

"The accelerated pathways created by the FDA have been integral to the remarkable progress in oncology care over the past five years and have helped many cancer patients with advanced disease, including small cell lung cancer, access new treatments," said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. "KEYTRUDA remains a foundational treatment for certain patients with metastatic non-small cell lung cancer. We will continue to rigorously evaluate the benefits of KEYTRUDA in small cell lung cancer and other types of cancer, in pursuit of Merck’s mission to save and improve lives."

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,300 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least 1 other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS ≥10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1). All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti–PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other anti–PD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after anti–PD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between anti–PD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using anti–PD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an anti–PD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients with advanced NSCLC; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-204, KEYTRUDA was discontinued due to adverse reactions in 14% of 148 patients with cHL. Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA; those ≥1% were pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis. Three patients died from causes other than disease progression: 2 from complications after allogeneic HSCT and 1 from unknown cause. The most common adverse reactions (≥20%) were upper respiratory tract infection (41%), musculoskeletal pain (32%), diarrhea (22%), and pyrexia, fatigue, rash, and cough (20% each).

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% were pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression: 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

In KEYNOTE-057, KEYTRUDA was discontinued due to adverse reactions in 11% of 148 patients with high-risk NMIBC. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.4%). Serious adverse reactions occurred in 28% of patients; those ≥2% were pneumonia (3%), cardiac ischemia (2%), colitis (2%), pulmonary embolism (2%), sepsis (2%), and urinary tract infection (2%). The most common adverse reactions (≥20%) were fatigue (29%), diarrhea (24%), and rash (24%).

Adverse reactions occurring in patients with MSI-H or dMMR CRC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with hepatocellular carcinoma (HCC) were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3-4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3-4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent (≥1%) were hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%); the most common were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). The most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Adverse reactions occurring in patients with TMB-H cancer were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

Adverse reactions occurring in patients with cSCC were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-355, when KEYTRUDA and chemotherapy (paclitaxel, paclitaxel protein-bound, or gemcitabine and carboplatin) were administered to patients with locally recurrent unresectable or metastatic TNBC (n=596) who had not been previously treated with chemotherapy in the metastatic setting, fatal adverse reactions occurred in 2.5% of patients, including cardio-respiratory arrest (0.7%) and septic shock (0.3%). Serious adverse reactions occurred in 30% of patients receiving KEYTRUDA in combination with chemotherapy, the most common were: pneumonia (2.9%), anemia (2.2%), and thrombocytopenia (2%). KEYTRUDA was discontinued in 11% of patients due to adverse reactions. The most common adverse reactions resulting in permanent discontinuation (≥1%) were increased ALT (2.2%), increased AST (1.5%), and pneumonitis (1.2%). The most common adverse reactions (≥20%) in patients receiving KEYTRUDA in combination with chemotherapy were: fatigue (48%), nausea (44%), alopecia (34%), diarrhea and constipation (28% each), vomiting and rash (26% each), cough (23%), decreased appetite (21%), and headache (20%).

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

In KEYNOTE-051, 161 pediatric patients (62 pediatric patients aged 6 months to younger than 12 years and 99 pediatric patients aged 12 years to 17 years) were administered KEYTRUDA 2 mg/kg every 3 weeks. The median duration of exposure was 2.1 months (range: 1 day to 24 months).

Adverse reactions that occurred at a ≥10% higher rate in pediatric patients when compared to adults were pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On March 1, 2021 Athenex, Inc., (NASDAQ: ATNX), a global biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies for the treatment of cancer and related conditions, reported a corporate and financial update for the fourth quarter and full year ended December 31, 2020 (Press release, Athenex, MAR 1, 2021, View Source [SID1234575859]).

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Oral Paclitaxel Plus Encequidar Update

As announced by Athenex in a separate press release this morning, the U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) for the Company’s New Drug Application (NDA) for oral paclitaxel and encequidar for the treatment of metastatic breast cancer. In the CRL, the FDA expressed the following:

Concerns about safety risks associated with increase in neutropenia-related sequelae
Concerns regarding the primary endpoint assessment conducted by the Blinded Independent Central Review (BICR)
Recommendation that Athenex conduct a new clinical trial in a patient population with metastatic breast cancer representative of the population in the U.S.
"We are surprised and disappointed by the FDA’s decision to issue a complete response letter for oral paclitaxel and encequidar," said Johnson Lau, Chief Executive Officer of Athenex. "Based on the clinical benefits demonstrated by the Phase III trial results, we are committed to exploring our available options to obtain approval for oral paclitaxel and encequidar. Additionally, we will undertake a thorough review of our organization to best position ourselves to create value for all stakeholders as we move forward."

Fourth Quarter 2020 and Recent Business Updates

Clinical Programs:

Oral Paclitaxel Plus Encequidar for Metastatic Breast Cancer

Athenex received a Complete Response Letter from the FDA for the NDA for oral paclitaxel for metastatic breast cancer
On December 9, 2020, the Company presented four abstracts associated with oral paclitaxel plus encequidar for the treatment of metastatic breast cancer and angiosarcoma at the 2020 San Antonio Breast Cancer Symposium
Klisyri for Actinic Keratosis

On December 14, 2020, the U.S. Food and Drug Administration (FDA) approved Klisyri (tirbanibulin), 1% for the treatment of actinic keratosis of the face or scalp
In February 2021, the New England Journal of Medicine published Phase 3 trial results on the efficacy and safety of tirbanibulin ointment for the topical treatment of actinic keratosis of the face or scalp
Almirall, S.A. (BLM: ALM), Athenex’s U.S. partner, launched Klisyri in the U.S. on February 18, 2021
Commercial Business:

Product sales growth in the fourth quarter were primarily driven by sales of specialty pharmaceutical products used to treat patients hospitalized with COVID-19
Athenex Pharmaceutical Division (APD) currently markets a total of 34 products with 63 SKUs
Athenex Pharma Solutions (APS) currently markets 6 products with 19 SKUs
Key Anticipated Future Milestones

Request a meeting with the FDA to discuss and align on next steps to obtain approval for oral paclitaxel plus encequidar in metastatic breast cancer
Identify and undertake appropriate adjustments for the company pending the outcome of the FDA meeting
Begin expansion portion of the oral paclitaxel plus pembrolizumab Phase I trial
Present the oral paclitaxel plus pembrolizumab Phase I trial data at a medical conference in 2021
Anticipate EMA approval of Klisyri in 2021
TCR-T NY-ESO-1 IRB approval and initiate P1 trial enrollment in 1H 2021
Anticipate results from the I-SPY 2 trial of oral paclitaxel plus anti PD-1 in 2022
Fourth Quarter and Full Year 2020 Financial Highlights

Product sales for the three months ended December 31, 2020 were $21.8 million, up from $14.1 million for the three months ended December 31, 2019, which represents a 54% increase. Product sales for the full year in 2020 were $105.3 million, up from $80.5 million for the full year in 2019, which represents a 31% increase. The increase was primarily driven by the impact of the global health pandemic which led to the increased demand for COVID-19 related drugs, and the launch of additional products, resulting in a significant increase in specialty product sales. The product sales increase was partially offset by a decrease in API and 503B products sales, which was attributable to the reduced production and external sales of API, and the discontinued vasopressin sales.

Collaboration and license revenue for the three months and year ended December 31, 2020 were $28 thousand and $39.1 million, respectively, compared to $20.3 million and $20.7 million, respectively, for the same periods in 2019. The collaboration and license revenue recognized in the full year of 2020 was primarily attributable to the 2019 Xiangxue License Agreement, while the revenue in the full year of 2019 was primarily attributable to a milestone achieved pursuant to the license agreement entered with Almirall in December 2017.

Total revenues for the three months and year ended December 31, 2020 were $21.8 million and $144.4 million, respectively, compared to $34.4 million and $101.2 million, respectively, for the same periods in 2019.

Cost of sales totaled $18.3 million for the three months ended December 31, 2020, an increase of 16%, as compared to $15.7 million for the three months ended December 31, 2019. Cost of sales totaled $95.4 million for the full year in 2020, an increase of 37%, as compared to $69.6 million for the full year in 2019. The increase in cost of specialty product sales was generally in-line with the increase in revenue, and we continued to incur fixed costs despite decreased production at our API and 503B facilities. in the fourth quarter, the increase in product sales outpaced that of cost of sales, primarily as a result of an uptake in the blended product margin of our specialty product portfolio.

Research & Development (R&D) expenses totaled $18.3 million for the three months ended December 31, 2020, a decrease of 16%, as compared to $21.8 million for the three months ended December 31, 2019. R&D expenses totaled $75.9 million for the full year in 2020, a decrease of 10%, as compared to $84.4 million for the full year in 2019. This was primarily attributable to a decrease in clinical operations expenses, drug development costs for specialty products and certain licensing costs. The decrease in R&D expenses in the full year of 2020 was partially offset by an increase in medical affairs expenses related to preparing our proprietary drugs for commercialization, API development costs, and expenses related to the expansion of our R&D teams in Latin America and Taiwan.

Selling, General & Administrative (SG&A) expenses totaled $31.4 million for the three months ended December 31, 2020, an increase of 73%, as compared to $18.1 million for the three months ended December 31, 2019. SG&A expenses totaled $96.9 million for the full year in 2020, an increase of 45%, as compared to $66.7 million for the full year in 2019. This was primarily attributable to an increase in commercial preparations costs associated with the possible approval of Oral Paclitaxel, expanded work forces at our manufacturing facilities and an increase in general and administrative costs related to professional service fees, IT costs, insurance and other operational costs. In addition, in the three months ended December 31, 2020, we recorded a provision for a potential credit loss of $8.9 million related to an outstanding balance due from Xiangxue and associated expenses resulting from currency conversion. This provision is related to the license revenue we recognized in the third quarter of 2020. As of February 28, 2021, we have received $1.5 million from Xiangxue.

Interest expense totaled $4.4 million and $1.7 million for the three months ended December 31, 2020 and 2019, respectively. Interest expense totaled $11.2 million and $7.0 million for the full year in 2020 and 2019, respectively. In June 2020, we refinanced the $50 million long-term debt with Perceptive, with an up to $225 million long-term credit facility with Oaktree. In the three months ended December 31, 2020, we received net proceeds of $24.25 million from the Oaktree facility upon achievement of the tirbanibulin FDA approval milestone. As of December 31, 2020, we had drawn down $150 million, out of the $225 million Oaktree facility.

We recognized a $7.2 million loss on the extinguishment of debt related to the termination of the senior secured loan agreement with Perceptive and a $3.0 million loss on the partial extinguishment of debt related to the assignment of a portion of the senior secured loan from Oaktree’s co-investors to Sagard during the year ended December 31, 2020. We did not incur expenses of similar nature in 2019.

For the full year in 2020, we incurred income tax expense of $4.1 million, compared to $0.9 million for the same period in 2019. The increase was primarily attributable to foreign income tax withholdings on our revenue earned under our out-license arrangements.

Net losses attributable to Athenex for the three months and year ended December 31, 2020 were $49.5 million and $146.2 million, respectively, or ($0.53) and ($1.72) per diluted share, respectively, as compared to a net loss of $21.7 million and $123.7 million, or ($0.28) and ($1.67) per diluted share, for the same periods in 2019. Excluding the credit loss provision of $8.9 million during the three months ended December 31, 2020, net loss attributable to Athenex for the quarter was $40.6 million or ($0.43) per diluted share. Excluding the one-time debt extinguishment expenses of $10.3 million and the $8.9 million credit loss provision during the year ended December 31, 2020, net loss attributable to Athenex for the full year in 2020 was $127.0 million, or ($1.49) per diluted share.

As of December 31, 2020, the Company had cash, cash equivalents and restricted cash of $86.1 million and short-term investments of $138.6 million.

2021 Financial Guidance

In terms of product sales guidance, the Company is limiting financial guidance to only the existing product portfolio, which excludes any proprietary products, until meaningful sales data from the proprietary product Klisyri becomes available. In 2020, the Company recorded a significant amount of revenues from international customers as a result of the global pandemic. However, the Company does not see these revenues as recurring in nature, while it has been continuing to expand its product portfolio. The Company currently expects its product sales in 2021, excluding any royalties from Klisyri, to be in line with 2020 levels.

The Company expects that its cash, cash equivalents, restricted cash, and short-term investments as of December 31, 2020, will enable it to meet its current operational liquidity needs and fund operations into the second quarter of 2022. The Company’s estimates are based on relevant conditions that are known and reasonably knowable at the date of these consolidated financial statements being available for issuance, and are subject to change due to changes in business, industry or macroeconomic conditions. The cash runway described above does not reflect additional funding available through the existing Senior Credit Agreement with Oaktree, or the Revenue Interest Financing Agreement with Sagard.

Conference Call and Webcast Information

Athenex will host a conference call and live audio webcast today, Monday, March 1, 2021, before the market open, at 8:00 am Eastern Time to discuss the financial results and provide a business update.

To participate in the call, dial (877) 407-0784 (domestic) or (201) 689-8560 (international) fifteen minutes before the conference call begins and reference the conference passcode 13715950. The live conference call and replay can also be accessed by audio webcast here and also on the Investor Relations section of the Company’s website, located at View Source

On March 1, 2021 Cancer Research UK and Teon Therapeutics, Inc. (Teon) today (Monday 1 March) reported that they have signed a collaboration agreement to progress the early phase clinical development of Teon’s first-in-class small molecule adenosine A2B receptor antagonist, TT-702 (Press release, Teon Therapeutics, MAR 1, 2021, View Source [SID1234575900]).

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Cancer Research UK is the world’s leading cancer charity dedicated to saving lives. Teon is a biopharmaceutical company that is developing a focused portfolio of small molecules that modulate metabolic signalling pathways in the tumour microenvironment.

Under the terms of the clinical development partnership, Cancer Research UK will sponsor the first-in-human Phase I/II clinical trial of TT-702, which will be led by a team at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust.

TT-702 targets cancer’s ability to evade the human immune response, enabling the immune system to expose and then destroy cancer cells. The hope is that TT-702 could be used to treat patients with advanced hard-to-treat solid tumours, including metastatic castrate-resistant prostate cancer, which is an aggressive form of cancer which has progressed despite surgery and hormone therapy.

Cancer Research UK’s Centre for Drug Development will work closely with Teon throughout the collaboration and share clinical insights as they emerge to help guide TT-702’s future development strategy.

Teon retains the rights to further develop and commercialise TT-702 and will receive the results of the clinical trial from Cancer Research UK in return for undisclosed success-based milestone and royalty payments.

TT-702 is an adenosine receptor antagonist and specifically targets the A2B receptor, which is over expressed on various types of tumour cells and immune cells*.

High levels of adenosine in the tumour microenvironment activate the A2B receptor, triggering tumour cells to grow and suppress T-cells, allowing the cancer cells to avoid immune detection.

TT-702 prevents the A2B receptor being activated by high levels of adenosine, which prevents cancer cell growth and enhances the anti-tumour immune response.

The Centre for Drug Development, Teon, and a team of clinical investigators led by Professor Johann de Bono are currently preparing to open a first-in-human clinical trial in the second half of 2021.

The researchers will test the safety and efficacy of TT-702 in multiple cancer indications, including hard-to-treat prostate cancer and triple negative breast cancer. TT-702 will be evaluated as both a monotherapy and in combination with anti-PD1 immunotherapy or hormonal therapy.

Dr Nigel Blackburn, Cancer Research UK’s director of drug development, said: "We are delighted to be working with Teon to advance TT-702 into human trials, and the drug makes an exciting addition to our growing portfolio of innovative anti-cancer agents. Finding new ways to target difficult-to-treat cancers remains a research priority for Cancer Research UK, and despite the challenges from the COVID-19 pandemic, we are continuing to leverage new partnerships like Teon, so we can bring potentially life-saving treatments closer to patients who need them."

Ken Horne, president and chief operating officer at Teon Therapeutics, said: "The partnership with the Centre for Drug Development provides an ideal route for Teon to pursue early-phase clinical development of TT-702, and leverage the incredible resources that Cancer Research UK brings. We are very excited to collaborate with a world-class investigator like Professor de Bono, thanks to the Centre for Drug Development".

Professor Johann de Bono, Professor of Experimental Cancer Medicine at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, said: "We are excited to begin clinical trials of this new anti-cancer drug in several types of cancer. This new agent targets the evasive strategies cancer takes against the human immune response, exposing cancer cells to the immune system for destruction."