On June 5, 2017 Seattle Genetics, Inc. (NASDAQ: SGEN) and Astellas reported updated phase 1 data for enfortumab vedotin (ASG-22ME) studied as monotherapy treatment for metastatic urothelial cancer (mUC) in an oral presentation at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 52nd Annual Meeting in Chicago (Press release, Seattle Genetics, JUN 5, 2017, View Source [SID1234519431]). Enfortumab vedotin is an investigational antibody-drug conjugate (ADC) that targets Nectin-4, a cell surface protein expressed in multiple solid tumors including mUC, ovarian cancer, and non-small cell lung cancer (NSCLC). Based on the data from the ongoing phase 1 clinical trial, the companies this year plan to initiate a registrational monotherapy phase 2 trial for locally advanced or mUC patients who have been previously treated with checkpoint inhibitor (CPI) therapy. A trial evaluating enfortumab vedotin in combination with CPIs is also planned for later this year as part of a broad clinical development program.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Patients with metastatic urothelial cancer typically have a five-year survival rate of just five percent and are in urgent need of new treatment options. Despite recent clinical advances, up to 80 percent of patients fail to respond to checkpoint inhibitors, or CPIs, and there are no approved therapeutic options for use after CPI failure," said Daniel P. Petrylak, M.D., Ph.D., Yale Cancer Center and presenter of the phase 1 data at ASCO (Free ASCO Whitepaper). "The objective response rates observed in our phase 1 analysis of enfortumab vedotin show the potential benefit of this agent for patients with metastatic urothelial cancer, particularly those who have failed CPI therapy. Enfortumab vedotin was generally well-tolerated, and the most common adverse events were nausea, itching, fatigue and diarrhea."

"Our updated enfortumab vedotin monotherapy phase 1 data at ASCO (Free ASCO Whitepaper) continue to show encouraging antitumor activity and a well-tolerated safety profile in patients with heavily pretreated metastatic urothelial cancer. We plan to initiate this year a pivotal phase 2 study in the CPI-pretreated setting with the intent of pursuing accelerated approval from the FDA," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Enfortumab vedotin is our first late-stage clinical program for solid tumors, and these data demonstrate the potential for antibody-drug conjugates to provide therapeutic benefit across a wide array of cancers."

"We are encouraged by the data we’ve seen so far in the enfortumab vedotin clinical trials," said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas. "We’re pleased to be moving forward the enfortumab vedotin development program in support of patients who may benefit from this new potential treatment option."

The following updated results from the ongoing phase 1 study evaluating enfortumab vedotin as a monotherapy for mUC were presented by Dr. Petrylak on Monday, June 5:

A Phase I Study of Enfortumab Vedotin (ASG-22CE; ASG-22ME): Updated Analysis of Patients with Metastatic Urothelial Cancer (Abstract #106, oral presentation on Monday, June 5 at 9:45 a.m. CT)

The ongoing trial is evaluating the safety and anti-tumor activity of enfortumab vedotin at escalating doses of 0.5 to 1.25 milligrams per kilogram (mg/kg) weekly for three of every four week cycles. Data were reported from 81 patients diagnosed with mUC and a median age of 67 years. Of these patients, 37 (46 percent) were previously treated with CPIs and 77 (95 percent) had undergone treatment with a platinum-based chemotherapy. Ninety-seven percent of patient screening samples showed Nectin-4 expression, the majority of which were at a high level. All response rates include confirmed and unconfirmed responses, as assessed by the investigator. The recommended phase 2 dose (RP2D) has been established at 1.25 mg/kg. Key findings include:

Of the 71 patients evaluated for response, 29 patients (41 percent) had an objective response, including three (four percent) complete responses and 26 (37 percent) partial responses. Disease control was achieved in 51 patients (72 percent), defined as the sum of patients achieving complete responses, partial responses or stable disease. The preliminary estimate of median duration of response for all patients was 24 weeks.
In 30 patients treated at the RP2D level, 16 patients (53 percent) had an objective response, including one (three percent) complete response and 15 (50 percent) partial responses. Disease control was achieved for 22 patients (73 percent).
Of the 32 patients previously treated with CPIs and evaluated for response, 14 patients (44 percent) had an objective response, including one complete response (three percent) and 13 (41 percent) partial responses. At the RP2D, eight out of 17 CPI-treated patients (47 percent) achieved a partial response, and disease control occurred in 13 patients (77 percent).
Of the 19 patients with liver metastases, nine (47 percent) had an objective response, including one (five percent) complete response and eight (42 percent) partial responses. Disease control was achieved for 13 patients (68 percent).
The most common treatment-related adverse events of any grade occurring in 10 percent or more of patients were nausea (36 percent), pruritus (31 percent), fatigue (30 percent) and diarrhea (28 percent). The most common Grade 3 or 4 adverse events occurring in five percent or more of patients, regardless of attribution, were urinary tract infections, hypophosphatemia, hyponatremia and anemia.
These results support further development of enfortumab vedotin as monotherapy and in combination with other therapies for patients with mUC. Enrollment is ongoing at the RP2D in patients with mUC who have been previously treated with CPIs.
More information about this clinical trial (NCT02091999), including enrolling centers, is available by visiting www.clinicaltrials.gov.

About Urothelial Cancer

Urothelial cancer is most commonly found in the bladder (90 percent). According to the American Cancer Society, approximately 79,000 people in the U.S. will be diagnosed with bladder cancer during 2017 and almost 17,000 will die from the disease. Outcomes are poor for patients diagnosed with metastatic disease, with a five-year survival rate of five percent.

About Enfortumab Vedotin

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary, industry-leading linker technology. Enfortumab vedotin is the first and only agent to target Nectin-4, a cell adhesion molecule identified as an ADC target by Agensys (an affiliate of Astellas), which is expressed on many solid tumors.

Nectin-4 is highly expressed in urothelial cancers, particularly in bladder cancer. Preclinical data demonstrate that enfortumab vedotin binds to Nectin-4 on cancer cells and releases the cell-killing agent into these target cells upon internalization.

On June 5, 2017 BeiGene, Ltd. (NASDAQ:BGNE), a clinical-stage biopharmaceutical company developing innovative molecularly targeted and immuno-oncology drugs for the treatment of cancer, reported initial data from the dose escalation portion of the Phase 1 trial of anti-PD-1 antibody BGB-A317 in combination with PARP inhibitor BGB-290 in patients with advanced solid tumors at the 2017 American Society for Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL (Press release, BeiGene, JUN 5, 2017, View Source [SID1234519430]). The data are being presented in a poster session and are scheduled to be further reviewed during a poster discussion session. The preliminary data suggest that the combination of BGB-A317 and BGB-290 is generally well-tolerated and shows anti-tumor activity in multiple solid tumors.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Based on the preliminary Phase 1 data, the combination of BGB-A317 and BGB-290 appears feasible and leads to tumor regression in a variety of malignancies. The observed activity was not restricted to patients with a known germline BRCA mutation," commented Michael Friedlander, MRCP, FRACP, PhD, Prince of Wales Hospital, Australia and coordinating principal investigator of the study.

"The evaluation of this combination is supported by published literature demonstrating that damage to DNA can induce an immune response. We believe that this is the largest body of clinical data published to date on the combination of a PD-1 antibody and a PARP inhibitor, and it is also the first published dataset from our internal combination trials. We look forward to further exploring the combination’s clinical activity and tolerability in multiple dose expansion cohorts of patients with specific tumor types," commented Amy Peterson, MD, Chief Medical Officer, Immuno-oncology at BeiGene.

Trial Design

The multicenter, open-label Phase 1/1b study is evaluating the combined use of BGB-A317 and BGB-290. The dose escalation phase is designed to establish the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose, evaluate the pharmacokinetics (PK) of the drug combination, and assess the immunogenicity of BGB-A317. The dose expansion phase is designed to further evaluate the tolerability and activity of the combination in patients with advanced solid tumors likely to harbor DNA damage repair deficiencies or who may be susceptible to treatment either with a PARP inhibitor or with PD-1 blockade.

Summary of Preliminary Results

At the data cut-off of March 31, 2017, 43 patients were enrolled in the dose-escalation portion of the trial. Cohorts of six to 12 patients each received treatments at five planned dose levels (DLs). BGB-A317 was administered at 2 mg/kg every three weeks (Q3W) with BGB-290 at 20, 40, or 60 mg twice daily (BID) in DLs 1, 2, and 3, respectively. BGB-A317 was also administered at a fixed dose of 200 mg Q3W with BGB-290 at 40 or 60 mg BID in DLs 4 and 5, respectively. Duration of treatment was greater than 200 days for 10 patients, and a total of seven patients remained on treatment as of the data cut-off.

The safety analysis suggested that the combination of BGB-A317 and BGB-290 was generally well-tolerated in patients with advanced solid tumors. Dose-limiting toxicities occurred in three patients; these included one patient with grade 2 nausea at DL4, one patient with grade 2 nausea and grade 2 vomiting at DL5, and one patient with grade 4 autoimmune hepatitis at DL5. DL4 was determined to be the MTD. Grade 3 or 4 adverse events (AEs) assessed by the investigator to be related to BGB-A317 and reported in more than one patient included autoimmune hepatitis / hepatitis (12%) and elevated alanine aminotransferase (ALT) (5%). Grade 3 or 4 AEs assessed by the investigator to be related to BGB-290 and reported in more than one patient included anemia (14%), as well as elevated ALT, elevated aspartate aminotransferase (AST), fatigue, and nausea (5% each). Suspected immune-related AEs (irAEs) of any grade regardless of causality occurred in 17 patients (40%); those reported in at least two patients included elevated ALT/AST or gamma-glutamyltransferase (GGT), autoimmune hepatitis, diarrhea, hypothyroidism, and hyperthyroidism. Grade 3-4 liver-related events regardless of causality were reported in eight patients, including five patients with hepatitis and three patients with ALT and/or AST elevations. Together, liver-related AEs of any grade regardless of causality were observed in 12 patients; all events were reversible with or without corticosteroid treatment. Treatment with both agents was discontinued by 33 patients for reasons including disease progression (26 patients), AEs (seven patients), and / or consent withdrawal (two patients). There were no fatal adverse events.

Co-administration of BGB-A317 with BGB-290 did not have a significant impact on the pharmacokinetic profile of either compound. In 29 patients with ovarian or fallopian tube cancer, best responses included one confirmed complete response (CR), two confirmed partial responses (PRs), five unconfirmed partial responses (PRs), and seven cases of stable disease (SD). In two patients with breast cancer, best responses included one confirmed PR. In three patients with pancreatic cancer, best responses included one unconfirmed PR and two cases of SD. The one patient with uterine cancer had a best response of an unconfirmed PR. SD was observed in one of three patients with prostate cancer and the one patient with bile duct cancer. Additional tumor types enrolled in the study include bladder, cervical, lung, and peripheral nerve sheath cancer, with one patient each.

The trial will further evaluate the combination’s activity in expansion cohorts of patients with ovarian, triple-negative breast, castration-resistant prostate, small cell lung, gastric / gastro-esophageal junction, urothelial, and pancreatic cancers.

About BGB-A317

BGB-A317 is an investigational humanized monoclonal antibody that belongs to a class of immuno-oncology agents known as immune checkpoint inhibitors. It is designed to bind to PD-1, a cell surface receptor that plays an important role in downregulating the immune system by preventing the activation of T-cells. BGB-A317 has high affinity and specificity for PD-1, and we believe it is differentiated from the currently approved PD-1 antibodies, as the ability to bind to Fc gamma receptors has been specifically engineered out. BGB-A317 is being developed as a monotherapy and in combination with other therapies for the treatment of various cancers.

About BGB-290

BGB-290 is a potent and highly selective investigational inhibitor of PARP1 and PARP2 that has been engineered to facilitate unique properties such as brain penetration and PARP–DNA complex trapping for improved cytotoxicity via cell‑cycle arrest and apoptosis. BGB-290 is being developed as a monotherapy and in combination with other therapies for the treatment of several cancers, including ovarian cancer, prostate cancer, breast cancer, glioblastoma multiforme, small cell lung cancer, and gastric cancer.

On June 5, 2017 Lion Biotechnologies, Inc. (NASDAQ: LBIO), a biotechnology company developing novel cancer immunotherapies based on tumor-infiltrating lymphocyte (TIL) technology, reported a poster presentation of additional data from 16 patients enrolled in the first cohort of its ongoing Phase 2 study of LN-144 for the treatment of metastatic melanoma at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Lion Biotechnologies, JUN 5, 2017, View Source [SID1234519429]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"The data presented today demonstrate that we can manufacture TIL at our central GMP facilities and treat a patient population with a high unmet need at multiple clinical sites," said Dr. Maria Fardis, PhD, MBA, Chief Executive Officer of Lion Biotechnologies. "These initial data show clinically-meaningful outcomes, as assessed both by ORR and DCR, in a heavily pre-treated patient group, all of which had received prior anti-PD-1 and over 80% with prior anti-CTLA-4 checkpoint inhibitors."

This Phase 2, multicenter, three-cohort study is designed to assess the safety and efficacy of LN-144 for treatment of patients with metastatic melanoma. Cohorts one and two will now enroll up to 30 patients each and cohort three is a re-treatment cohort for a second LN-144 infusion in up to ten patients. The first two cohorts are evaluating two different manufacturing processes for LN-144. Patients in cohort one are receiving fresh, non-cryopreserved TIL and cohort two patients are receiving product manufactured through a more streamlined and rapid three-week procedure yielding a cryopreserved product.

In the poster presentation entitled, "Efficacy of Single Administration of Tumor Infiltrating Lymphocytes (TIL) in Heavily Pre-treated Metastatic Melanoma Patients Following Checkpoint Therapy," Amod Sarnaik, MD, a surgical oncologist in the Department of Cutaneous Oncology at Moffitt Cancer Center and a member of the Immunology Program provided updated data from 16 patients in cohort one who were infused as of April 24, 2017. These advanced metastatic melanoma patients were a median age of 55 and were highly refractory to multiple prior lines of therapy with significant tumor burden at baseline. All had prior anti-PD-1 therapy, 88 percent had anti-CTLA4 therapy and 64 percent had received three or more prior therapies. The results show:

Of the evaluable patients, a 29 percent objective response rate was reported including one complete response (CR) continuing beyond 15 months post-administration of a single TIL treatment
77 percent of patients had reduction in target tumor size
Mean time to first response of 1.6 months, with the CR developing at 6 months
Responses were observed in patients with tumors carrying wild type or BRAF mutations
The protocol allows for administration of up to 6 doses of IL-2. The median number of IL-2 administrations was six.
Additionally, the protocol for this study was amended to both increase the sample size for the study as well as further define the patient population to patients with unresectable or metastatic melanoma who have progressed after immune checkpoint inhibition therapy (e.g., anti-PD-1), and if BRAF mutation-positive, after BRAF targeted therapy.

On June 5, 2017 VBL Therapeutics (Nasdaq:VBLT), reported the presentation of new data demonstrating that treatment with VB-111 (ofranergene obadenovec) induced durable tumor regression and attenuation of tumor growth in patients with recurrent glioblastoma (rGBM) (Press release, VBL Therapeutics, JUN 5, 2017, View Source [SID1234519427]). Data from the company’s prior Phase 2 study in rGBM, will be presented today at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) annual meeting, taking place in Chicago. They will be presented by Andrew Brenner, MD, PhD, the principal investigator of the Phase 2 study and associate professor in medicine, neurology and neurosurgery at the Cancer Therapy and Research Center (CTRC), University of Texas Health Science Center San Antonio.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

VBL’s Phase 2 multi-center study for VB-111 was designed to determine the safety, tolerability and efficacy of VB-111 in patients with rGBM. A total of 46 patients were enrolled in two sequential cohorts. In the first cohort, patients were treated with VB-111 as monotherapy for a median of only one dose and, upon disease progression, switched to Avastin (bevacizumab) alone as standard of care (Limited Exposure cohort). This cohort behaved like an Avastin historical control with a median Overall Survival (mOS) of 8 months.

In the second cohort, patients continued to receive treatment with VB-111 after progression, in combination with Avastin as the standard of care (Treatment Through Progression cohort). This cohort received in median 4 doses of VB-111, about 8 months of treatment.

VBL previously reported that the study met the primary endpoint of statistically-significant increase in median overall survival, with 59 weeks in patients treated continuously with VB-111, compared to 32 weeks in patients with only one dose (in median) of VB-111 (p=0.048), both groups having received Avastin upon progression after a short course of VB-111. 12-Month overall survival was 57% in the VB-111 continuous exposure cohort, compared with only 24% in historical pooled Avastin trials (p=0.03), consistent with data indicating that Avastin monotherapy does not improve OS in rGBM patients.

To further understand the why treatment with VB-111 was associated with prolonged survival, VBL analyzed the tumor growth kinetics in all rGBM patients who participated in the VB-111 Phase 2 trial. These new data demonstrate that tumor growth kinetics was significantly attenuated upon longer treatment with VB-111.

Whereas brief exposure to VB-111 was associated with tumor progression in most patients, longer exposure to VB-111 (median= 4, mean=4.7 doses) led to attenuation of tumor growth kinetics (median % increase (MPI) per 30 days: 0.6 vs 14.1, p=0.0032). Furthermore, tumor regression was more frequent upon longer exposure to VB-111; only 16% of patients with limited exposure to VB-111 had tumors shrink below baseline dimensions during the first 100 days, compared to 61% of patients who continued to receive VB-111 through progression (p=0.002; McNemar’s test). Except for longer treatment with VB-111 leading to favorable OS, there was no evidence for difference between the two cohorts in any of the criteria tested, including patient characteristics, initial tumor growth kinetics, and Avastin treatment of both groups.

Overall, VBL’s Phase 2 data point to a favorable anti-tumor effect of VB-111 in rGBM, in terms of both regression rate and overall survival following treatment through progression, compared to both brief exposure to VB-111 with subsequent Avastin monotherapy and to historical data of Avastin monotherapy. Notably, responses were seen even with VB-111 monotherapy, including a patient who remains in complete remission after over 3 years.

"The new analysis supports the benefit of continuous exposure to VB-111 in combination with Avastin, on both inhibition of tumor growth and survival in rGBM patients," said Dr. Andrew Brenner, CTRC, University of Texas Health Science Center San Antonio, principal investigator in the VB-111 Phase 2 study.

Yael Cohen, MD, Vice President of Clinical Development at VBL Therapeutics, said, "We are encouraged by these Phase 2 results in rGBM, which also are consistent with the findings from our trials of VB-111 in ovarian cancer and thyroid cancer. The current data support the design of our ongoing Phase 3 GLOBE study in rGBM."

VBL’s pivotal Phase 3 GLOBE study in rGBM, comparing VB-111 in combination with Avastin to Avastin alone, is currently being conducted in the US, Canada and Israel. Enrollment in the study, 256 patients in total, was completed in December 2016, five months ahead of schedule. The study is proceeding under a Special Protocol Assessment (SPA) granted by the U.S. Food and Drug Administration (FDA), with full endorsement by the Canadian Brain Tumor Consortium (CBTC). The company expects an interim analysis of the GLOBE trial to occur in the third quarter of 2017, with top-line results from the full dataset expected in early 2018.

The new Phase 2 data will be presented in a poster session at ASCO (Free ASCO Whitepaper) today at 1:15 PM – 4:45 PM CDT, Hall A, poster board # 297. The poster will be also available on the company’s website, at ir.vblrx.com.

About Ofranergene Obadenovec (VB-111)
Ofranergene obadenovec is a unique biologic agent that uses a dual mechanism to target solid tumors. Based on a non-integrating, non-replicating, Adeno 5 vector, ofranergene obadenovec utilizes VBL’s proprietary Vascular Targeting System (VTS) to target the tumor vasculature for cancer therapy. Unlike anti-VEGF or TKIs, ofranergene obadenovec does not aim to block a specific pro-angiogenic pathway; instead, it uses an angiogenesis-specific sensor (VBL’s PPE-1-3x proprietary promoter) to specifically induce cell death in angiogenic endothelial cells in the tumor milieu. This mechanism retains activity regardless of baseline tumor mutations or the identity of the pro-angiogenic factors secreted by the tumor and shows activity even after failure of prior treatment with other anti-angiogenics. Moreover, ofranergene obadenovec induces specific anti-tumor immune response, which is accompanied by recruitment of CD8 T-cells and apoptosis of tumor cells.

Ofranergene obadenovec completed a Phase 2 study in rGBM, which showed a statistically significant improvement in overall survival in patients treated with ofranergene obadenovec through progression, compared to either patients treated with ofranergene obadenovec followed by bevacizumab alone, or to historical bevacizumab data. In a Phase 2 trial for recurrent platinum-resistant ovarian cancer, ofranergene obadenovec demonstrated a statistically significant increase in overall survival and 60% durable response rate (as measured by reduction in CA-125), approximately twice the historical response with bevacizumab plus chemotherapy in ovarian cancer. In a Phase 2 study in recurrent, iodine-resistant differentiated thyroid cancer, ofranergene obadenovec met the primary endpoint demonstrating disease stabilization with a positive safety profile, along with a dose-response and evidence of an overall survival benefit. Ofranergene obadenovec has received Fast Track Designation for recurrent glioblastoma in the U.S. and orphan drug status for glioblastoma in both the U.S. and EU.

Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported updated overall survival (OS) findings from KEYNOTE-024, the phase 3 study evaluating KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, as a monotherapy compared to platinum-containing chemotherapy in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors express high levels of PD-L1 (tumor proportion score [TPS] of 50 percent or more). The study included patients with squamous and non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations and demonstrated a reduction in the risk of death by 37 percent for KEYTRUDA compared to chemotherapy based on 19 months of median follow-up (HR, 0.63 [95% CI, 0.46-0.88]; p = 0.003). Additionally, in an exploratory analysis, progression-free survival 2 (PFS2) – a clinical endpoint used to assess the impact of next-line treatment on disease control – was substantially improved for patients in the KEYTRUDA group compared to the chemotherapy group. These data are being presented in an oral session at the 2017 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on Tuesday, June 6, from 9:45 – 9:57 a.m. CDT (Location: Hall D1) (Abstract #9000).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

With approximately eight additional months of follow-up, data showed continued OS benefit with KEYTRUDA over chemotherapy in the first-line treatment of patients with advanced NSCLC whose tumors expressed high levels of PD-L1 – showing an 18-month OS rate of 61.2 percent in the KEYTRUDA group compared to 43.0 percent in the chemotherapy group; the 12-month OS rate was 70.3 percent in the KEYTRUDA group compared to 54.8 percent in the chemotherapy group.

For PFS2, findings based on 19 months of median follow-up showed a 46 percent reduction in the risk of progression after the start of the second-line regimen or death in patients initially randomized to KEYTRUDA compared to patients initially randomized to chemotherapy (HR, 0.54 [95% CI, 0.40-0.72]; p < 0.001]).

"From the start of the KEYTRUDA program in non-small cell lung cancer, one of our goals has been to demonstrate the value of KEYTRUDA monotherapy in appropriate patient populations," said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. "With updated data from KEYNOTE-024, as well as from other studies in our clinical development program, we are establishing the role of KEYTRUDA in the treatment of advanced non-small cell lung cancer."

Merck has a robust clinical development program for KEYTRUDA in lung cancer, with multiple registration-enabling studies currently underway. The KEYTRUDA clinical development program includes more than 30 tumor types in more than 500 clinical trials, including more than 300 trials that combine KEYTRUDA with other cancer treatments.

"These results from additional follow-up in KEYNOTE-024 – including improved overall survival despite significant crossover – give us further confidence in KEYTRUDA as a first-line treatment for patients with non-small cell lung cancer whose tumors express high levels of PD-L1," said Prof. Martin Reck, head of the department of thoracic oncology, LungenClinic Grosshansdorf, Germany.

Key Findings from the KEYNOTE-024 Study

KEYNOTE-024 is a randomized, phase 3 study of 305 patients with metastatic NSCLC who were assigned either KEYTRUDA (pembrolizumab) as monotherapy (n=154) or standard of care platinum-based chemotherapy (n=151). Enrollment criteria included: having no prior systemic chemotherapy treatment for their advanced disease, tumors without an EGFR sensitizing mutation or ALK translocation, and tumors expressing high levels of PD-L1 (TPS of 50 percent or more) as determined by a central laboratory using the Dako PD-L1 IHC 22C3 PharmDx test, from Agilent Technologies. The primary endpoint was progression-free survival (PFS) and the key secondary endpoint was OS. Other secondary endpoints include overall response rate (ORR) and safety. Exploratory endpoints include PFS2 and duration of response.

Data presented at ASCO (Free ASCO Whitepaper) are based on a median follow-up of 19.1 months (range: 14.3-27.6) and include findings from 79 patients who crossed over from the chemotherapy arm to receive KEYTRUDA, per study protocol, and 12 patients who received anti-PD-1 therapy outside of study crossover. Results show that KEYTRUDA maintained an OS benefit over chemotherapy in patients whose tumors expressed high levels of PD-L1 (TPS of 50 percent or more), with a 37 percent reduction in the risk of death (HR, 0.63 [95% CI, 0.46-0.88]; p = 0.003). The 12-month OS rate was 70.3 percent in the KEYTRUDA group compared to 54.8 percent in the chemotherapy group; at 18 months, the OS rate was 61.2 percent in the KEYTRUDA group compared to 43.0 percent in the chemotherapy group. The median OS had not yet been reached in the KEYTRUDA group (95% CI, 19.4-NE), compared to 14.5 months in the chemotherapy group (95% CI, 9.8-19.6).

In an exploratory analysis of PFS2 – a clinical endpoint used to assess the impact of next-line treatment on disease control – findings showed a 46 percent reduction in the risk of progression after initiation of the second-line regimen or death in patients initially randomized to KEYTRUDA compared to patients initially randomized to chemotherapy (HR, 0.54 [95% CI, 0.40-0.72]; p < 0.001]). The 12-month PFS2 rate was 59.7 percent in the KEYTRUDA group and 38.5 percent in the chemotherapy group; the 18-month PFS2 rate was 51.0 percent in the KEYTRUDA group and 24.6 percent in the chemotherapy group. The median PFS2 was 18.3 months in the KEYTRUDA group (95% CI, 12.7-NE) compared to 8.4 months in the chemotherapy group (95% CI, 6.8-9.8).

A safety analysis was not performed for this data set.

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon, breast and prostate cancers combined. The two main types of lung cancer are non-small cell and small cell. NSCLC is the most common type of lung cancer, accounting for about 85 percent of all cases. The five-year survival rate for patients suffering from highly advanced, metastatic (Stage IV) lung cancers is estimated to be two percent.

About KEYTRUDA (pembrolizumab) Injection

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.

Studies of KEYTRUDA – from the largest immuno-oncology program in the industry with more than 500 trials – include a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand factors that predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including the exploration of several different biomarkers across a broad range of tumors.

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single-dose vial.

KEYTRUDA (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [tumor proportion score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is also 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.

KEYTRUDA, in combination with pemetrexed and carboplatin, is indicated for the first-line treatment of patients with metastatic nonsquamous NSCLC. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for pemetrexed and carboplatin.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. 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. In HNSCC, KEYTRUDA (pembrolizumab) is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after three or more prior lines 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 the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. 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 the confirmatory trials.

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

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) 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.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Selected Important Safety Information for KEYTRUDA (pembrolizumab)

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 94 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%) pneumonitis, and occurred more frequently in patients with a history of prior thoracic radiation (6.9%) compared to those without (2.9%). Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 48 (1.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%) colitis. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 19 (0.7%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%) hepatitis. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

KEYTRUDA can cause hypophysitis. Hypophysitis occurred in 17 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%) hypophysitis. Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3 or 4 hypophysitis.

KEYTRUDA (pembrolizumab) can cause thyroid disorders, including hyperthyroidism, hypothyroidism, and thyroiditis. Hyperthyroidism occurred in 96 (3.4%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.8%) and 3 (0.1%) hyperthyroidism. Hypothyroidism occurred in 237 (8.5%) of 2799 patients receiving KEYTRUDA, including Grade 2 (6.2%) and 3 (0.1%) hypothyroidism. Thyroiditis occurred in 16 (0.6%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.3%) thyroiditis. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism.

KEYTRUDA can cause type 1 diabetes mellitus, including diabetic ketoacidosis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 9 (0.3%) of 2799 patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

KEYTRUDA can cause other clinically important immune-mediated adverse reactions. These immune-mediated reactions may occur in any organ system. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), exfoliative dermatitis, bullous pemphigoid, rash (1.4%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, and partial seizures arising in a patient with inflammatory foci in brain parenchyma. In addition, myelitis and myocarditis were reported in other clinical trials, including classical Hodgkin lymphoma, and postmarketing use.

Solid organ transplant rejection has been reported in postmarketing use of KEYTRUDA (pembrolizumab). Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment with KEYTRUDA vs the risk of possible organ rejection in these patients.

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 6 (0.2%) of 2799 patients. Monitor patients for signs and symptoms of infusion-related reactions, including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after being treated with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after treatment with KEYTRUDA on any trial, 6 patients (26%) developed graft-versus-host-disease (GVHD), one of which was fatal, and 2 patients (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning, one of which was fatal. Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. These complications may occur despite intervening therapy between PD-1 blockade and allogeneic HSCT. Follow patients closely for early evidence of transplant-related complications such as hyperacute GVHD, severe (Grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic VOD, and other immune-mediated adverse reactions, and intervene promptly.

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of KEYTRUDA.

KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC. The most common adverse event resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%). The most common adverse reactions (occurring in at least 20% of patients and at a higher incidence than with docetaxel) were decreased appetite (25% vs 23%), dyspnea (23% vs 20%), and nausea (20% vs 18%).

It is not known whether KEYTRUDA (pembrolizumab) is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA and for 4 months after the final dose.

Our Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.

As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 500 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic candidates with the potential to improve the treatment of advanced cancers.

For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

– See more at: View Source