BioNTech and DualityBio Initiate Pivotal Phase 3 Trial Of Antibody-Drug Conjugate Candidate BNT323/DB-1303 in Metastatic Breast Cancer

On January 22, 2024 BioNTech SE (Nasdaq: BNTX, "BioNTech") and Duality Biologics (Suzhou) Co., Ltd. ("DualityBio") reported that the first patient with metastatic breast cancer has been treated in a pivotal Phase 3 trial evaluating the efficacy and safety of the next-generation antibody-drug conjugate ("ADC") candidate BNT323/DB-1303 targeting the Human Epidermal Growth Factor Receptor 2 ("HER2"), a cancer cell surface protein (Press release, BioNTech, JAN 22, 2024, View Source [SID1234639405]).

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Breast cancer is the most commonly diagnosed cancer worldwide and the leading cause of death from malignant tumors in women globally.1,2 The breast cancer subtype, which is defined by the expression of hormone receptors ("hormone receptor-positive", "HR+") and a low expression level of the HER2 protein ("HER2-low") on the cancer cell surface, accounts for approximately 40 % to 45 % of patients in advanced, metastatic disease stage.3 HER2 has been shown to be a suitable target structure for the treatment of breast cancers with intermediate and high HER2 expression.4 HER2-directed therapies have been ineffective in the past in patients with tumors with low expression levels of the protein.5 Recent studies have indicated that next-generation ADCs may have the potential to transfer the impact of HER2-directed therapies to HER2-low tumors.6

The global, multi-center, open-label, randomized Phase 3 trial (NCT06018337) will assess the efficacy and safety of BNT323/DB-1303 compared to standard-of-care single-agent chemotherapy in chemotherapy-naïve patients with HR+ and HER2-low metastatic breast cancer that have progressed on hormone therapy. The trial is expected to enroll 532 patients at more than 223 clinical sites worldwide, initially in China, followed by sites in the United States, Europe, and additional regions. The study’s primary endpoint is progression-free survival. Secondary endpoints include overall survival, objective response rate, duration of response, and safety.

"For patients with advanced HR+/HER2-low breast cancers who progressed after primary therapy, single-agent palliative chemotherapy is the most common regimen to control the disease and reduce mortality. BNT323/DB-1303 has been designed with the aim to combine the selectivity of antibodies with the cancer cell-killing properties of chemotherapy, thereby aiming to minimize the toxicity of the chemotherapeutic agents for patients," said Prof. Özlem Türeci, M.D., Chief Medical Officer and Co-Founder at BioNTech. "Our objective is to further expand the impact of HER2-targeted ADC therapies to chemotherapy naïve patients in metastatic disease stage who express HER2 at low levels at earliest possible treatment lines, seeking to extend the therapeutic window and improve outcomes for these patients."

"The initiation of the Phase 3 trial marks an important step in the development of our next-generation ADC candidate with the first indication progressing into pivotal evaluation," said Vivian Gu, M.D., Chief Medical Officer at DualityBio. "Results from our Phase 1/2 clinical study indicate a robust mechanism of action of BNT323/DB-1303 and have demonstrated preliminary efficacy and a manageable safety profile. We look forward to further advancing this differentiated ADC candidate."

The Phase 3 trial is based on positive safety and efficacy data from a Phase 1/2 study (NCT05150691) with BNT323/DB-1303 in patients with advanced/metastatic solid tumors. Data presented at ASCO (Free ASCO Whitepaper) 2023 demonstrated encouraging anti-tumor activity in heavily pretreated patients with HER2-low breast cancer with an objective response rate of 38.5% and a disease control rate of 84.6%. BNT323/DB-1303 was well tolerated with a manageable safety profile across all evaluated patients with advanced/metastatic solid tumors.

The milestone is in furtherance of BioNTech and DualityBio’s strategic objective to advance the product candidate into late-stage development in multiple high unmet medical need cancer indications. The Phase 3 trial initiation marks a major landmark in BioNTech’s and DualityBio’s strategic collaboration initiated in April 2023. The collaboration aims to accelerate the development of differentiated antibody-drug conjugate therapeutics for solid tumors. BioNTech will hold commercial rights globally (excluding Mainland China, Hong Kong Special Administrative Region, and Macau Special Administrative Region), while DualityBio will retain commercial rights for Mainland China, Hong Kong Special Administrative Region, and Macau Special Administrative Region.

Further information for media: Fact Sheet about BNT323/DB-1303

About BNT323/DB-1303
BNT323/DB-1303 is a third-generation topoisomerase-1 inhibitor-based ADC targeting HER2 which was built from DualityBio’s proprietary Duality Immune Toxin Antibody Conjugates ("DITAC") platform. HER2 is a surface-expressed protein on solid tumors and has been linked to the aggressive growth and spread of cancer cells, making it a potential target for innovative cancer therapeutics. The candidate has exhibited antitumor activity in both HER2-positive and HER2-low tumor models as well as in several solid tumor indications, including patients with breast, gastric, endometrial, biliary tract cancers, and other advanced solid tumors. Preclinical data and preliminary clinical data for BNT323/DB-1303 indicate its potential to target HER2 receptors on solid tumors irrespective of expression level with a manageable safety profile and a potentially expanded therapeutic window. BNT323/DB-1303 is currently being evaluated in an ongoing Phase 1/2 study (NCT05150691) in patients with advanced/metastatic solid tumors and in a pivotal Phase 3 study (NCT06018337) in patients with Hormone Receptor-positive ("HR+") and Human Epidermal Growth Factor Receptor 2 ("HER2")-low, metastatic breast cancer that have progressed on hormone and/or cyclin-dependent kinase 4/6 ("CDK4/6") therapy. The BNT323/DB-1303 program received the Fast Track designation and Breakthrough Therapy designation from the U.S. Food and Drug Administration ("FDA") for the treatment of endometrial cancer in 2023.

Opdivo® (nivolumab) in Combination with CABOMETYX® (cabozantinib) Demonstrates Long-Term Survival Benefits After Four Years of Follow-Up in the CheckMate -9ER Trial in First-Line Advanced Renal Cell Carcinoma

On January 22, 2024 Bristol Myers Squibb (NYSE: BMY) and Exelixis, Inc. (NASDAQ: EXEL) reported four-year follow-up results from the CheckMate -9ER trial evaluating Opdivo (nivolumab) in combination with CABOMETYX (cabozantinib) vs. sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC) (Press release, Exelixis, JAN 22, 2024, View Source [SID1234639406]). Results continued to show superior progression-free survival (PFS) and objective response rates (ORR) in patients treated with Opdivoplus CABOMETYXover sunitinib, regardless of risk classification based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) scores. Superior overall survival (OS) was also observed in patients treated with the combination. These updated results, including data showing health-related quality-of-life benefits with Opdivo in combination with CABOMETYX vs. sunitinib, will be featured in an oral presentation (Abstract #362) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2024 Genitourinary Cancers Symposium from January 25-27, 2024.

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"Renal cell carcinoma can be very challenging to treat and patients who are diagnosed with advanced disease or develop metastasis often face poor outcomes," said Maria Teresa Bourlon, Urologic Oncology Clinic, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico. "These updated results from the CheckMate -9ER trial continue to support the role of nivolumab in combination with cabozantinib as an important first-line treatment option for this devastating disease, demonstrating durable efficacy across its multiple study endpoints, including a 23% reduction in the risk of death."

At a median follow-up of 55.6 months (48.1 months minimum), all patients randomized to the Opdivo plus CABOMETYX treatment arm (n=323) continued to experience benefits over those who received sunitinib (n=328) across efficacy endpoints:

PFS (primary endpoint): PFS continued to favor Opdivo plus CABOMETYX, with median PFS nearly doubled with the combination regimen at 16.4 months vs. 8.4 months with sunitinib (Hazard Ratio [HR] 0.58; 95% Confidence Interval [CI]: 0.49 to 0.70).
OS (secondary endpoint): Treatment with Opdivo in combination with CABOMETYX elicited durable survival benefit over sunitinib, with a median OS of 46.5 months compared to 36.0 months with sunitinib (HR 0.77; 95% CI: 0.63 to 0.95).
ORR (secondary endpoint): The combination regimen showed durable response improvements, doubling the ORR compared to sunitinib (55.7% vs. 27.7%, respectively).
Complete response (CR): Patients who received Opdivo plus CABOMETYX continued to show CR benefit, with triple the number of patients achieving CR vs. sunitinib (13.6% vs. 4.6%).
Duration of response (DOR): Opdivo plus CABOMETYX was associated with a longer median DOR of 22.0 months vs. 15.2 months in the sunitinib group.
Safety: No new safety concerns were identified in this follow-up analysis. Among all treated patients, any-grade treatment-related adverse events (TRAEs) occurred in 97.5% in the Opdivo plus CABOMETYX group compared to 93.1% in the sunitinib group. Grade ≥3 TRAEs occurred in 67.5% of Opdivo plus CABOMETYX-treated patients vs. 55.3% in sunitinib-treated patients.
Additionally, in exploratory analyses, durable and clinically meaningful benefits were observed in patient subgroups across risk groups, including within the favorable-risk and intermediate- and poor-risk groups:

OS: Among patients with intermediate-/poor-risk, median OS was 43.9 months for those treated with Opdivo plus CABOMETYX vs. 29.3 months with sunitinib (HR 0.73; 95% CI: 0.58 to 0.91). In patients with favorable risk, median OS was similar across treatment arms at 52.9 months with the combination regimen and 58.9 months with sunitinib (HR 1.10; 95% CI: 0.69 to 1.75).
PFS: PFS was improved with the combination regimen in patients with intermediate-/poor-risk with a median PFS of 15.4 months compared to 7.1 months with sunitinib (HR 0.56; 95% CI: 0.45 to 0.68), as well as in those with favorable risk at 21.4 months vs. 12.8 months (HR 0.69; 95% CI: 0.48 to 1.00).
ORR: In patients with intermediate-/ poor-risk, ORR was more than doubled at 52.6% with Opdivo and CABOMETYX vs. 23.0% with sunitinib. In those with favorable risk, ORR was 66.2% vs. 44.4%, respectively.
CR: Among those with intermediate-/poor-risk profiles, the number of patients who achieved CR more than tripled (12.9% vs. 3.5%) with the combination regimen compared to sunitinib. In those with favorable risk profiles, the number of patients who achieved CR was doubled (16.2% vs. 8.3%) with the combination regimen.
DOR: Median DOR was also improved with Opdivo and CABOMETYX across both groups. Among the intermediate- and poor-risk group, those treated with the combination regimen had a median DOR of 23.1 months vs. 13.8 months with sunitinib. Among the favorable risk group, median DOR was 18.7 months vs. 17.8 months, respectively.
"There has been an ongoing need for therapeutic options that can provide patients with previously untreated advanced or metastatic renal cell carcinoma with the potential for disease control and extended survival. By combining the power of these two unique modalities, we established a new standard of care with Opdivo and CABOMETYX, building on our commitment to improving outcomes for patients with advanced cancers, including but not limited to genitourinary cancers," said Dana Walker, M.D., M.S.C.E., vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. "Now, after more than four years of follow up, the data continue to underscore the value of Opdivo-based combinations in the GU cancer treatment paradigm with the potential to help patients diagnosed with advanced RCC live longer, regardless of risk classification."

"These results from CheckMate -9ER provide hope that patients with previously untreated advanced kidney cancer may experience a long-term survival benefit. We are pleased to see that the combination of CABOMETYX and Opdivo continues to demonstrate durable and clinically meaningful efficacy after four years of follow-up in this patient population across risk groups, reinforcing the value of this regimen as a standard of care in this setting," said Amy Peterson, M.D., executive vice president, product development & medical affairs, and chief medical officer, Exelixis. "It is also encouraging that CABOMETYX in combination with Opdivo demonstrated superior PFS and OS benefits in patients who had disease burdens in often challenging-to-treat areas, including bone, liver and lung metastases. The totality of these encouraging findings, achieved in partnership with Bristol Myers Squibb, underscore our commitment to collaborating with the scientific community to advance treatment regimens for patients with advanced cancers."

Bristol Myers Squibb and Exelixis thank the patients and investigators involved in the CheckMate -9ER clinical trial.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized, multi-national Phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). A total of 651 patients (23% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1≥1%) were randomized to receive Opdivo plus CABOMETYX (n=323) vs. sunitinib (n=328). The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS) and objective response rate (ORR). The primary efficacy analysis is comparing the doublet combination vs. sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by Exelixis, Inc., Ipsen Pharma SAS and Takeda Pharmaceutical Company Limited.

About Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 431,000 new cases and 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. At diagnosis, up to 30% of patients present with advanced or metastatic RCC.

Eight-Year Data for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Continue to Demonstrate Longest Survival Benefit vs. Sunitinib Reported in Patients with Previously Untreated Advanced or Metastatic Renal Cell Carcinoma

On January 22, 2024 Bristol-Myers Squibb reported that Opdivo (nivolumab) plus Yervoy (ipilimumab) continued to demonstrate long-term survival results in the Phase 3 CheckMate -214 trial, reducing the risk of death by 28% in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC) vs. sunitinib after eight years, regardless of International Metastatic RCC Database Consortium (IMDC) risk group (Press release, Bristol-Myers Squibb, JAN 22, 2024, View Source [SID1234646263]). Patients treated with Opdivo plus Yervoy maintained superior survival and more durable response benefits compared to those who received sunitinib in both patients with intermediate- and poor-risk prognostic factors and across all randomized patients. These data will be presented in an oral presentation (Abstract #363) during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2024 Genitourinary Cancers Symposium from January 25-27, 2024.

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Among intermediate- and poor-risk patients (n=847), Opdivo plus Yervoy (n=425) maintained efficacy after eight years (99.1 months median), with improvements seen in overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and duration of response (DOR) over sunitinib:

OS: Median OS was 46.7 months for intermediate- and poor-risk patients treated with Opdivo plus Yervoy vs. 26.0 months with sunitinib (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI]: 0.59 to 0.81). The 90-month landmark OS rates were 32.9% vs. 22.0%, respectively.
DOR: Median DOR was 82.8 months for patients treated with Opdivo plus Yervoy compared to 19.8 months with sunitinib.
PFS: Median PFS by independent radiology review committee (IRRC) was 12.4 months with Opdivo plus Yervoy vs. 8.5 months with sunitinib (HR 0.73; 95% CI: 0.61 to 0.87), tripling the 90-month landmark PFS rate at 25.4% vs. 8.5%, respectively.
ORR: ORR benefits were maintained with Opdivo plus Yervoy compared to sunitinib (42% vs. 27%). In addition, four times more patients treated with the combination achieved complete responses (CR) than with sunitinib (12% vs. 3%).
Additionally, in the intent-to-treat (ITT) population (n=1,096), Opdivo plus Yervoy (n=550) demonstrated long-term benefits across endpoints:

OS: Among all randomized patients treated with Opdivo plus Yervoy, median OS was 52.7 months vs. 37.8 months with sunitinib (HR 0.72; 95% CI: 0.62 to 0.83).
DOR: For patients treated with Opdivo plus Yervoy, median DOR was 76.2 months compared to 25.1 months with sunitinib.
PFS: Median PFS by IRRC was 12.4 months with Opdivo plus Yervoy and 12.3 months with sunitinib (HR 0.88; 95% CI: 0.75 to 1.03)
ORR: ORR was better with Opdivo plus Yervoy compared to sunitinib (39% vs. 33%), and four times more patients treated with the combination achieved CR (12% vs. 3%).
"It is incredible to see that after eight years in the CheckMate -214 trial, which represents the longest reported follow up of any Phase 3 trial of a checkpoint inhibitor combination therapy in advanced renal cell carcinoma, the combination of nivolumab and ipilimumab continues to provide superior survival and durable responses for these patients," said Nizar Tannir, M.D., F.A.C.P., professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas, MD Anderson Cancer Center. "Not only are we seeing sustained benefits over sunitinib in the primary endpoint population of intermediate- and poor-risk patients, but also within the key secondary endpoint intent-to-treat population, which goes to show that this dual immunotherapy combination can potentially help patients achieve positive long-term outcomes, regardless of IMDC risk."

The safety profile of Opdivo plus Yervoy was manageable using established treatment algorithms, and no new safety signals emerged with extended follow-up.

"The updated data from CheckMate -214 with Opdivo plus Yervoy in advanced or metastatic renal cell carcinoma to be presented at ASCO (Free ASCO Whitepaper) GU speak to our long-standing leadership with immunotherapy not only in genitourinary cancers, but across multiple tumor types. These extended results further exemplify to the scientific community the potential that we have long recognized for immunotherapy to transform treatment paradigms in oncology," said Dana Walker, M.D., M.S.C.E., vice president, global program lead, gastrointestinal and genitourinary cancers, Bristol Myers Squibb. "We are proud to see the eight-year results, the longest survival benefit vs. sunitinib seen in any Phase 3 trial in this patient population, point toward sustained overall survival with this first-line dual immunotherapy approach and reinforce its role as the current standard of care in this setting."

Bristol Myers Squibb thanks the patients and investigators involved in the CheckMate -214 clinical trial.

About CheckMate -214
CheckMate -214 is a Phase 3, randomized, open-label study evaluating the combination of Opdivo plus Yervoy versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC). Patients in the combination group (n=550) received Opdivo 3 mg/kg plus Yervoy 1 mg/kg every three weeks for four doses followed by Opdivo 3 mg/kg every two weeks. Patients in the comparator group (n=546) received sunitinib 50 mg once daily for four weeks, followed by two weeks off before continuation of treatment. Patients were treated until progression or unacceptable toxic effects for up to two years. The primary endpoints of the trial are overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in an intermediate- to poor-risk patient population (approximately 75% of patients). ORR was assessed by independent radiology review committee (IRRC).

About Renal Cell Carcinoma
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, accounting for more than 431,000 new cases and 179,000 deaths worldwide each year. RCC is approximately twice as common in men as in women, with the highest rates of the disease in North America and Europe. At diagnosis, up to 30% of patients present with advanced or metastatic RCC.

Bristol Myers Squibb: Creating a Better Future for People with Cancer
Bristol Myers Squibb is inspired by a single vision — transforming patients’ lives through science. The goal of the company’s cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine and, through innovative digital platforms, are turning data into insights that sharpen their focus. Deep understanding of causal human biology, cutting-edge capabilities and differentiated research platforms uniquely position the company to approach cancer from every angle.

Cancer can have a relentless grasp on many parts of a patient’s life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. As a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

About Opdivo
Opdivo is a programmed death-1 (PD-1) immune checkpoint inhibitor that is designed to uniquely harness the body’s own immune system to help restore anti-tumor immune response. By harnessing the body’s own immune system to fight cancer, Opdivo has become an important treatment option across multiple cancers.

Opdivo’s leading global development program is based on Bristol Myers Squibb’s scientific expertise in the field of Immuno-Oncology, and includes a broad range of clinical trials across all phases, including Phase 3, in a variety of tumor types. To date, the Opdivo clinical development program has treated more than 35,000 patients. The Opdivo trials have contributed to gaining a deeper understanding of the potential role of biomarkers in patient care, particularly regarding how patients may benefit from Opdivo across the continuum of PD-L1 expression.

In July 2014, Opdivo was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. Opdivo is currently approved in more than 65 countries, including the United States, the European Union, Japan and China. In September 2015, the Company’s Opdivo and Yervoy combination regimen was the first Immuno-Oncology to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries, including the United States and the European Union.

About Yervoy
Yervoy is a recombinant, human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). CTLA-4 is a negative regulator of T-cell activity. Yervoy binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor immune response. On March 25, 2011, the U.S. Food and Drug Administration (FDA) approved Yervoy 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. Yervoy is approved for unresectable or metastatic melanoma in more than 50 countries. There is a broad, ongoing development program in place for Yervoy spanning multiple tumor types.

INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma.

OPDIVO is indicated for the adjuvant treatment of adult and pediatric patients 12 years and older with completely resected Stage IIB, Stage IIC, Stage III, or Stage IV melanoma.

OPDIVO (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors ≥4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

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

OPDIVO (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall 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.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum- containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune- mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. 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 OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, 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 immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune- mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune- mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) 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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4 ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. 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 clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (48/666) of patients, including Grade 4 (0.3%), Grade 3 (2.5%), and Grade 2 (4.1%). In patients receiving OPDIVO and cabozantinib, adrenal insufficiency occurred in 4.7% (15/320) of patients, including Grade 3 (2.2%) and Grade 2 (1.9%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%).

In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypophysitis occurred in 4.4% (29/666) of patients, including Grade 4 (0.3%), Grade 3 (2.4%), and Grade 2 (0.9%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, thyroiditis occurred in 2.7% (22/666) of patients, including Grade 3 (4.5%) and Grade 2 (2.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hyperthyroidism occurred in 12% (80/666) of patients, including Grade 3 (0.6%) and Grade 2 (4.5%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, hypothyroidism occurred in 18% (122/666) of patients, including Grade 3 (0.6%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis. In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/666) of patients, including Grade 4 (0.6%), Grade 3 (0.3%), and Grade 2 (0.9%).

Immune-Mediated Nephritis with Renal Dysfunction

OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated nephritis with renal dysfunction occurred in 4.1% (27/666) of patients, including Grade 4 (0.6%), Grade 3 (1.1%), and Grade 2 (2.2%).

Immune-Mediated Dermatologic Adverse Reactions

OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated rash occurred in 16% (108/666) of patients, including Grade 3 (3.5%) and Grade 2 (4.2%).

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 OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. 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; 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, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR 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, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions

OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion- related reactions occurred in 2.5% (10/407) of patients. In HCC patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 8% (4/49) of patients. In RCC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of patients. In MSI-H/dMMR mCRC patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, infusion-related reactions occurred in 4.2% (5/119) of patients. In MPM patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, infusion-related reactions occurred in 12% (37/300) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone

In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation

There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions

In Checkmate 037, serious adverse reactions occurred in 41% of patients receiving OPDIVO (n=268). Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse drug reactions reported in 2% to <5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. In Checkmate 066, serious adverse reactions occurred in 36% of patients receiving OPDIVO (n=206). Grade 3 and 4 adverse reactions occurred in 41% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of patients receiving OPDIVO were gamma-glutamyltransferase increase (3.9%) and diarrhea (3.4%). In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%). In Checkmate 238, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=452). Grade 3 or 4 adverse reactions occurred in 25% of OPDIVO-treated patients (n=452). The most frequent Grade 3 and 4 adverse reactions reported in ≥2% of OPDIVO-treated patients were diarrhea and increased lipase and amylase. In Checkmate 816, serious adverse reactions occurred in 30% of patients (n=176) who were treated with OPDIVO in combination with platinum-doublet chemotherapy. Serious adverse reactions in >2% included pneumonia and vomiting. No fatal adverse reactions occurred in patients who received OPDIVO in combination with platinum-doublet chemotherapy. In Checkmate 227, serious adverse reactions occurred in 58% of patients (n=576). The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. In Checkmate 9LA, serious adverse reactions occurred in 57% of patients (n=358). The most frequent (>2%) serious adverse reactions were pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Fatal adverse reactions occurred in 7 (2%) patients, and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia. In Checkmate 017 and 057, serious adverse reactions occurred in 46% of patients receiving OPDIVO (n=418). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, pulmonary embolism, dyspnea, pyrexia, pleural effusion, pneumonitis, and respiratory failure. In Checkmate 057, fatal adverse reactions occurred; these included events of infection (7 patients, including one case of Pneumocystis jirovecii pneumonia), pulmonary embolism (4 patients), and limbic encephalitis (1 patient). In Checkmate 743, serious adverse reactions occurred in 54% of patients receiving OPDIVO plus YERVOY. The most frequent serious adverse reactions reported in ≥2% of patients were pneumonia, pyrexia, diarrhea, pneumonitis, pleural effusion, dyspnea, acute kidney injury, infusion-related reaction, musculoskeletal pain, and pulmonary embolism. Fatal adverse reactions occurred in 4 (1.3%) patients and included pneumonitis, acute heart failure, sepsis, and encephalitis. In Checkmate 214, serious adverse reactions occurred in 59% of patients receiving OPDIVO plus YERVOY (n=547). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pyrexia, pneumonia, pneumonitis, hypophysitis, acute kidney injury, dyspnea, adrenal insufficiency, and colitis. In Checkmate 9ER, serious adverse reactions occurred in 48% of patients receiving OPDIVO and cabozantinib (n=320). The most frequent serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia. Fatal intestinal perforations occurred in 3 (0.9%) patients. In Checkmate 025, serious adverse reactions occurred in 47% of patients receiving OPDIVO (n=406). The most frequent serious adverse reactions reported in ≥2% of patients were acute kidney injury, pleural effusion, pneumonia, diarrhea, and hypercalcemia. In Checkmate 205 and 039, adverse reactions leading to discontinuation occurred in 7% and dose delays due to adverse reactions occurred in 34% of patients (n=266). Serious adverse reactions occurred in 26% of patients. The most frequent serious adverse reactions reported in ≥1% of patients were pneumonia, infusion-related reaction, pyrexia, colitis or diarrhea, pleural effusion, pneumonitis, and rash. Eleven patients died from causes other than disease progression: 3 from adverse reactions within 30 days of the last OPDIVO dose, 2 from infection 8 to 9 months after completing OPDIVO, and 6 from complications of allogeneic HSCT. In Checkmate 141, serious adverse reactions occurred in 49% of patients receiving OPDIVO (n=236). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis. In Checkmate 275, serious adverse reactions occurred in 54% of patients receiving OPDIVO (n=270). The most frequent serious adverse reactions reported in ≥2% of patients receiving OPDIVO were urinary tract infection, sepsis, diarrhea, small intestine obstruction, and general physical health deterioration. In Checkmate 274, serious adverse reactions occurred in 30% of patients receiving OPDIVO (n=351). The most frequent serious adverse reaction reported in ≥2% of patients receiving OPDIVO was urinary tract infection. Fatal adverse reactions occurred in 1% of patients; these included events of pneumonitis (0.6%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), serious adverse reactions occurred in 47% of patients. The most frequent serious adverse reactions reported in ≥2% of patients were colitis/diarrhea, hepatic events, abdominal pain, acute kidney injury, pyrexia, and dehydration. In Checkmate 040, serious adverse reactions occurred in 59% of patients receiving OPDIVO with YERVOY (n=49). Serious adverse reactions reported in ≥4% of patients were pyrexia, diarrhea, anemia, increased AST, adrenal insufficiency, ascites, esophageal varices hemorrhage, hyponatremia, increased blood bilirubin, and pneumonitis. In Attraction-3, serious adverse reactions occurred in 38% of patients receiving OPDIVO (n=209). Serious adverse reactions reported in ≥2% of patients who received OPDIVO were pneumonia, esophageal fistula, interstitial lung disease, and pyrexia. The following fatal adverse reactions occurred in patients who received OPDIVO: interstitial lung disease or pneumonitis (1.4%), pneumonia (1.0%), septic shock (0.5%), esophageal fistula (0.5%), gastrointestinal hemorrhage (0.5%), pulmonary embolism (0.5%), and sudden death (0.5%). In Checkmate 577, serious adverse reactions occurred in 33% of patients receiving OPDIVO (n=532). A serious adverse reaction reported in ≥2% of patients who received OPDIVO was pneumonitis. A fatal reaction of myocardial infarction occurred in one patient who received OPDIVO. In Checkmate 648, serious adverse reactions occurred in 62% of patients receiving OPDIVO in combination with chemotherapy (n=310). The most frequent serious adverse reactions reported in ≥2% of patients who received OPDIVO with chemotherapy were pneumonia (11%), dysphagia (7%), esophageal stenosis (2.9%), acute kidney injury (2.9%), and pyrexia (2.3%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with chemotherapy; these included pneumonitis, pneumatosis intestinalis, pneumonia, and acute kidney injury. In Checkmate 648, serious adverse reactions occurred in 69% of patients receiving OPDIVO in combination with YERVOY (n=322). The most frequent serious adverse reactions reported in ≥2% who received OPDIVO in combination with YERVOY were pneumonia (10%), pyrexia (4.3%), pneumonitis (4.0%), aspiration pneumonia (3.7%), dysphagia (3.7%), hepatic function abnormal (2.8%), decreased appetite (2.8%), adrenal insufficiency (2.5%), and dehydration (2.5%). Fatal adverse reactions occurred in 5 (1.6%) patients who received OPDIVO in combination with YERVOY; these included pneumonitis, interstitial lung disease, pulmonary embolism, and acute respiratory distress syndrome. In Checkmate 649, serious adverse reactions occurred in 52% of patients treated with OPDIVO in combination with chemotherapy (n=782). The most frequent serious adverse reactions reported in ≥2% of patients treated with OPDIVO in combination with chemotherapy were vomiting (3.7%), pneumonia (3.6%), anemia (3.6%), pyrexia (2.8%), diarrhea (2.7%), febrile neutropenia (2.6%), and pneumonitis (2.4%). Fatal adverse reactions occurred in 16 (2.0%) patients who were treated with OPDIVO in combination with chemotherapy; these included pneumonitis (4 patients), febrile neutropenia (2 patients), stroke (2 patients), gastrointestinal toxicity, intestinal mucositis, septic shock, pneumonia, infection, gastrointestinal bleeding, mesenteric vessel thrombosis, and disseminated intravascular coagulation. In Checkmate 76K, serious adverse reactions occurred in 18% of patients receiving OPDIVO (n=524). Adverse reactions which resulted in permanent discontinuation of OPDIVO in >1% of patients included arthralgia (1.7%), rash (1.7%), and diarrhea (1.1%). A fatal adverse reaction occurred in 1 (0.2%) patient (heart failure and acute kidney injury). The most frequent Grade 3-4 lab abnormalities reported in ≥1% of OPDIVO-treated patients were increased lipase (2.9%), increased AST (2.2%), increased ALT (2.1%), lymphopenia (1.1%), and decreased potassium (1.0%).

Common Adverse Reactions

In Checkmate 037, the most common adverse reaction (≥20%) reported with OPDIVO (n=268) was rash (21%). In Checkmate 066, the most common adverse reactions (≥20%) reported with OPDIVO (n=206) vs dacarbazine (n=205) were fatigue (49% vs 39%), musculoskeletal pain (32% vs 25%), rash (28% vs 12%), and pruritus (23% vs 12%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%). In Checkmate 238, the most common adverse reactions (≥20%) reported in OPDIVO-treated patients (n=452) vs ipilimumab-treated patients (n=453) were fatigue (57% vs 55%), diarrhea (37% vs 55%), rash (35% vs 47%), musculoskeletal pain (32% vs 27%), pruritus (28% vs 37%), headache (23% vs 31%), nausea (23% vs 28%), upper respiratory infection (22% vs 15%), and abdominal pain (21% vs 23%). The most common immune-mediated adverse reactions were rash (16%), diarrhea/colitis (6%), and hepatitis (3%). In Checkmate 816, the most common (>20%) adverse reactions in the OPDIVO plus chemotherapy arm (n=176) were nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%). In Checkmate 227, the most common (≥20%) adverse reactions were fatigue (44%), rash (34%), decreased appetite (31%), musculoskeletal pain (27%), diarrhea/colitis (26%), dyspnea (26%), cough (23%), hepatitis (21%), nausea (21%), and pruritus (21%). In Checkmate 9LA, the most common (>20%) adverse reactions were fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhea (31%), rash (30%), decreased appetite (28%), constipation (21%), and pruritus (21%). In Checkmate 017 and 057, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=418) were fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. In Checkmate 743, the most common adverse reactions (≥20%) in patients receiving OPDIVO plus YERVOY were fatigue (43%), musculoskeletal pain (38%), rash (34%), diarrhea (32%), dyspnea (27%), nausea (24%), decreased appetite (24%), cough (23%), and pruritus (21%). In Checkmate 214, the most common adverse reactions (≥20%) reported in patients treated with OPDIVO plus YERVOY (n=547) were fatigue (58%), rash (39%), diarrhea (38%), musculoskeletal pain (37%), pruritus (33%), nausea (30%), cough (28%), pyrexia (25%), arthralgia (23%), decreased appetite (21%), dyspnea (20%), and vomiting (20%). In Checkmate 9ER, the most common adverse reactions (≥20%) in patients receiving OPDIVO and cabozantinib (n=320) were diarrhea (64%), fatigue (51%), hepatotoxicity (44%), palmar-plantar erythrodysaesthesia syndrome (40%), stomatitis (37%), rash (36%), hypertension (36%), hypothyroidism (34%), musculoskeletal pain (33%), decreased appetite (28%), nausea (27%), dysgeusia (24%), abdominal pain (22%), cough (20%) and upper respiratory tract infection (20%). In Checkmate 025, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=406) vs everolimus (n=397) were fatigue (56% vs 57%), cough (34% vs 38%), nausea (28% vs 29%), rash (28% vs 36%), dyspnea (27% vs 31%), diarrhea (25% vs 32%), constipation (23% vs 18%), decreased appetite (23% vs 30%), back pain (21% vs 16%), and arthralgia (20% vs 14%). In Checkmate 205 and 039, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=266) were upper respiratory tract infection (44%), fatigue (39%), cough (36%), diarrhea (33%), pyrexia (29%), musculoskeletal pain (26%), rash (24%), nausea (20%) and pruritus (20%). In Checkmate 141, the most common adverse reactions (≥10%) in patients receiving OPDIVO (n=236) were cough (14%) and dyspnea (14%) at a higher incidence than investigator’s choice. In Checkmate 275, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=270) were fatigue (46%), musculoskeletal pain (30%), nausea (22%), and decreased appetite (22%). In Checkmate 274, the most common adverse reactions (≥20%) reported in patients receiving OPDIVO (n=351) were rash (36%), fatigue (36%), diarrhea (30%), pruritus (30%), musculoskeletal pain (28%), and urinary tract infection (22%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO as a single agent (n=74), the most common adverse reactions (≥20%) were fatigue (54%), diarrhea (43%), abdominal pain (34%), nausea (34%), vomiting (28%), musculoskeletal pain (28%), cough (26%), pyrexia (24%), rash (23%), constipation (20%), and upper respiratory tract infection (20%). In Checkmate 142 in MSI-H/dMMR mCRC patients receiving OPDIVO with YERVOY (n=119), the most common adverse reactions (≥20%) were fatigue (49%), diarrhea (45%), pyrexia (36%), musculoskeletal pain (36%), abdominal pain (30%), pruritus (28%), nausea (26%), rash (25%), decreased appetite (20%), and vomiting (20%). In Checkmate 040, the most common adverse reactions (≥20%) in patients receiving OPDIVO with YERVOY (n=49), were rash (53%), pruritus (53%), musculoskeletal pain (41%), diarrhea (39%), cough (37%), decreased appetite (35%), fatigue (27%), pyrexia (27%), abdominal pain (22%), headache (22%), nausea (20%), dizziness (20%), hypothyroidism (20%), and weight decreased (20%). In Attraction-3, the most common adverse reactions (≥20%) in OPDIVO-treated patients (n=209) were rash (22%) and decreased appetite (21%). In Checkmate 577, the most common adverse reactions (≥20%) in patients receiving OPDIVO (n=532) were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%). In Checkmate 648, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=310) were nausea (65%), decreased appetite (51%), fatigue (47%), constipation (44%), stomatitis (44%), diarrhea (29%), and vomiting (23%). In Checkmate 648, the most common adverse reactions reported in ≥20% of patients treated with OPDIVO in combination with YERVOY were rash (31%), fatigue (28%), pyrexia (23%), nausea (22%), diarrhea (22%), and constipation (20%). In Checkmate 649, the most common adverse reactions (≥20%) in patients treated with OPDIVO in combination with chemotherapy (n=782) were peripheral neuropathy (53%), nausea (48%), fatigue (44%), diarrhea (39%), vomiting (31%), decreased appetite (29%), abdominal pain (27%), constipation (25%), and musculoskeletal pain (20%). In Checkmate 76K, the most common adverse reactions (≥20%) reported with OPDIVO (n=524) were fatigue (36%), musculoskeletal pain (30%), rash (28%), diarrhea (23%) and pruritis (20%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

Clinical Trials and Patient Populations

Checkmate 227–previously untreated metastatic non-small cell lung cancer, in combination with YERVOY; Checkmate 9LA–previously untreated recurrent or metastatic non–small cell lung cancer in combination with YERVOY and 2 cycles of platinum–doublet chemotherapy by histology; Checkmate 649–previously untreated advanced or metastatic gastric cancer, gastroesophageal junction and esophageal adenocarcinoma; Checkmate 577–adjuvant treatment of esophageal or gastroesophageal junction cancer; Checkmate 238–adjuvant treatment of patients with completely resected Stage III or Stage IV melanoma; Checkmate 76K–adjuvant treatment of patients 12 years of age and older with completely resected Stage IIB or Stage IIC melanoma; Checkmate 274–adjuvant treatment of urothelial carcinoma; Checkmate 275–previously treated advanced or metastatic urothelial carcinoma; Checkmate 142–MSI–H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Checkmate 142–MSI–H or dMMR metastatic colorectal cancer, as a single agent or in combination with YERVOY; Attraction–3–esophageal squamous cell carcinoma; Checkmate 648—previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma; Checkmate 648–previously untreated, unresectable advanced recurrent or metastatic esophageal squamous cell carcinoma; Checkmate 040–hepatocellular carcinoma, in combination with YERVOY; Checkmate 743–previously untreated unresectable malignant pleural mesothelioma, in combination with YERVOY; Checkmate 037–previously treated metastatic melanoma; Checkmate 066–previously untreated metastatic melanoma; Checkmate 067–previously untreated metastatic melanoma, as a single agent or in combination with YERVOY; Checkmate 017–second–line treatment of metastatic squamous non–small cell lung cancer; Checkmate 057–second–line treatment of metastatic non–squamous non–small cell lung cancer; Checkmate 816–neoadjuvant non–small cell lung cancer, in combination with platinum–doublet chemotherapy; Checkmate 141–recurrent or metastatic squamous cell carcinoma of the head and neck; Checkmate 025–previously treated renal cell carcinoma; Checkmate 214–previously untreated renal cell carcinoma, in combination with YERVOY; Checkmate 9ER–previously untreated renal cell carcinoma, in combination with cabozantinib; Checkmate 205/039–classical Hodgkin lymphoma.

About the Bristol Myers Squibb and Ono Pharmaceutical Collaboration
In 2011, through a collaboration agreement with Ono Pharmaceutical Co., Bristol Myers Squibb expanded its territorial rights to develop and commercialize Opdivo globally, except in Japan, South Korea and Taiwan, where Ono had retained all rights to the compound at the time. On July 23, 2014, Ono and Bristol Myers Squibb further expanded the companies’ strategic collaboration agreement to jointly develop and commercialize multiple immunotherapies – as single agents and combination regimens – for patients with cancer in Japan, South Korea and Taiwan.

Latest Phase III trial data investigating Cabometyx® in combination with immunotherapy to be presented at ASCO GU 2024

On January 22, 2024 Ipsen (Euronext: IPN; ADR: IPSEY) reported new data to be presented for Cabometyx (cabozantinib) in combination with immunotherapy across indications at the upcoming American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Symposium (ASCO GU) taking place on 25-27 January 2024 in San Francisco, U.S (Press release, Ipsen, JAN 22, 2024, View Source [SID1234639407]).

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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

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Detailed top-line results from the Phase III CONTACT-02 trial of the combination of Cabometyx and atezolizumab versus a second novel hormone therapy (NHT) in people living with metastatic castration-resistant prostate cancer (mCRPC) and measurable extra-pelvic soft tissue disease who have progressed on one prior NHT, are to be presented as an oral presentation (Abstract #18).

With a median follow-up of 14.3 months, data from the primary analysis of progression-free survival (PFS) from the CONTACT-02 trial demonstrated a statistically significant PFS benefit for the combination of Cabometyx and atezolizumab of 6.3 months versus 4.2 months for a second NHT (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.50-0.84; p=0.0007). At an interim analysis for the other primary endpoint of overall survival (OS), the data demonstrated a trend toward improvement for the combination, however, these data were immature, and the trial will continue to the next planned analysis, anticipated in 2024. Safety for the combination appeared to be consistent with the known safety profiles of the individual medicines, and no new safety signals were identified.

Prostate cancer is the second most common cancer in men1 and for those living with advanced metastatic castration-resistant disease, the prognosis is poor, with an estimated survival of 1-2 years2.

"At the advanced metastatic castration-resistant stage of disease, the prognosis is poor, with a median survival of two years and limited available treatment options," said Stéphane Oudard, Professor of Oncology and Chief of the Oncology Clinical and Translational Research Unit at Georges Pompidou Hospital in Paris, France. "These results from the CONTACT-02 trial represent a positive step in the context of the current treatment landscape, contributing the first positive Phase III data of its kind for the benefit of patients, as we await further data from the overall survival analysis."

Also, four-year extended follow-up data from the landmark Phase III CheckMate -9ER trial investigating the combination of Cabometyx and nivolumab versus sunitinib in people living with previously untreated advanced renal cell carcinoma (aRCC) will be presented (Abstract #362).

With a median follow-up of 55.6 months for OS, the combination of Cabometyx and nivolumab demonstrated a sustained and clinically meaningful OS benefit versus sunitinib, with an absolute median OS gain of 10.5 months (46.5 months for the combination vs 36.0 months for sunitinib, HR 0.77, 95% CI: 0.63-0.95). Additionally, median PFS remained almost double that for the combination versus sunitinib, at 16.4 vs 8.4 months respectively (HR 0.58, 95% CI: 0.49-0.70). The safety profile was consistent with the known safety profiles of the individual medicines, and no new safety signals were identified.

Renal cell carcinoma is the most common form of kidney cancer3, 4 and for the 30% of people diagnosed with an advanced form of the disease, the 5-year survival rate is low at 12%, with no identified cure for this disease.5,6

"Data from our ongoing trials continue to reinforce the value of Cabometyx for patients across a number of challenging tumor types," said Christelle Huguet, EVP and Head of Research and Development, Ipsen. "In combination with immunotherapy, Cabometyx is delivering long-term survival benefits today for people living with renal cell carcinoma worldwide, while also showcasing future potential in metastatic castration-resistant prostate cancer, an area of significant unmet need where no other trials of this modality have proven successful in recent decades."

Additionally, health-related quality of life (HRQoL) data from a modelling analysis based on the CheckMate 9ER trial explored the link between HRQoL and clinical outcomes at a median follow-up of 32.9 months (Abstract #384). These data provide further patient-focused context to the benefits of the combination of Cabometyx and nivolumab, whilst also reinforcing the association of the combination with an increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration.

Dianthus Therapeutics Announces $230 Million Private Placement

On January 22, 2024 Dianthus Therapeutics, Inc. ("Dianthus" or the "Company") (NASDAQ: DNTH), a clinical-stage biotechnology company dedicated to advancing the next generation of antibody complement therapeutics to treat severe autoimmune diseases, reported that it has entered into a securities purchase agreement for a private investment in public equity ("PIPE") financing that is expected to result in gross proceeds of approximately $230 million to the Company, before deducting placement agent fees and offering expenses (Press release, Magenta Therapeutics, JAN 22, 2024, View Source [SID1234639408]). The PIPE financing included participation from both new and existing investors, including Bain Capital Life Sciences, RA Capital Management, Avidity Partners, Fairmount, Venrock Healthcare Capital Partners, RTW Investments, Great Point Partners LLC, Octagon Capital, Janus Henderson Investors, Vestal Point Capital, Logos Capital, Catalio Capital Management, Woodline Partners LP, Ally Bridge Group, Tellus BioVentures, StemPoint Capital LP and a large investment management firm.

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Pursuant to the terms of the securities purchase agreement, Dianthus is selling an aggregate of 14,500,500 shares of its common stock at a price of $12.00 per share and, in lieu of common stock to certain investors, pre-funded warrants to purchase up to 4,666,332 shares of common stock at a purchase price of $11.999 per pre-funded warrant, which represents the per share purchase price for the common stock less the $0.001 per share exercise price for each pre-funded warrant. The PIPE financing is expected to close on or about January 24, 2024, subject to satisfaction of customary closing conditions.

The Company intends to use the net proceeds from the PIPE financing, together with the Company’s existing cash, cash equivalents, and marketable securities, for research and development expenditures focused on product development and for general corporate purposes, including capital expenditures, working capital and potential business development activities.

Jefferies, Evercore ISI, Stifel, Guggenheim Securities, and Raymond James are acting as placement agents for the PIPE financing.

The offer and sale of the foregoing securities are being made in a transaction not involving a public offering and the securities have not been registered under the Securities Act of 1933, as amended, and may not be reoffered or resold in the United States except pursuant to an effective registration statement or an applicable exemption from the registration requirements. Concurrently with the execution of the securities purchase agreement, Dianthus and the investors entered into a registration rights agreement pursuant to which the Company has agreed to file a registration statement with the Securities and Exchange Commission (the "SEC") registering the resale of the shares of common stock sold in the PIPE financing, as well as the shares of common stock underlying the pre-funded warrants sold in the PIPE financing.