US FDA Approves Perioperative Treatment of Neoadjuvant Opdivo & Chemotherapy

US FDA approves perioperative treatment of neoadjuvant Opdivo & chemotherapy followed by surgery and adjuvant single-agent Opdivo for resectable NSCLC

Overview

Bristol Myers Squibb announced that the US Food and Drug Administration (FDA) approved Opdivo (nivolumab) for the treatment of adult patients with resectable (tumours =4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, for neoadjuvant treatment, in combination with platinum-doublet chemotherapy, followed by single-agent Opdivo as adjuvant treatment after surgery – otherwise referred to as perioperative therapy, which is used before and after surgery.  

Behind The Approval

• The approval is based on results from the CheckMate-77T trial, the company’s second positive phase 3 randomized trial with an immunotherapy-based combination for the treatment of resectable NSCLC.  
• Opdivo is now the only PD-1 inhibitor to demonstrate statistically significant and clinically meaningful benefits in this disease versus chemotherapy in both a neoadjuvant-only regimen and as part of a perioperative regimen.

Statement from an expert: The University of Texas

• Given the rates of disease recurrence in patients with resectable NSCLC, there is a clear need for options that can be administered before and after surgery that may target micrometastasis, help reduce the risk of cancer returning and improve the chance of successful surgical treatment,” said Tina Cascone, MD, PhD, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.  
• This approval is a step forward for patients with resectable disease, as the perioperative nivolumab plus neoadjuvant chemotherapy regimen can offer an improved event free survival (EFS) compared with neoadjuvant chemotherapy alone and has the potential for achieving a pathologic response (pCR) in one in four patients.

About CheckMate-77T Trial

• The CheckMate-77T trial evaluated the perioperative regimen of neoadjuvant Opdivo with platinum-doublet chemotherapy followed by surgery and adjuvant Opdivo monotherapy (n=229), compared to neoadjuvant platinum-doublet chemotherapy and placebo followed by surgery and adjuvant placebo (n=232) in adult patients with resectable NSCLC.  
• In the trial, the Opdivo arm improved EFS, a primary endpoint, compared to the chemotherapy and placebo treatment arm.  
• A high pCR rate was also observed as one of the pre-specified secondary endpoints.

The Outcomes

• The risk of disease recurrence, progression or death was reduced by 42% (EFS Hazard Ratio [HR] 0.58; 95% Confidence Interval [CI]: 0.43 to 0.78; P =0.00025) in patients treated in the Opdivo arm, compared to the chemotherapy and placebo arm, with a median follow-up of 25.4 months.  
• In addition, 18-month EFS was demonstrated in 70% of patients in the Opdivo arm, compared to 50% of patients in the chemotherapy and placebo arm. 
• Furthermore, 25% of patients in the Opdivo arm achieved pCR, while 4.7% of patients in the comparator arm achieved pCR in the intent-to-treat population (estimated treatment difference of 20.5%; 95% CI,14.3 to 26.6).

Warnings & Precautions: Opdivo

• Opdivo is associated with the following Warnings & Precautions: 

Severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity.  

• Treatment: Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue and dexamethasone is not recommended outside of controlled clinical trials.  

About Bristol Myers Squibb

• This milestone expands the role of Opdivo -based treatments and builds upon the foundation set by the FDA approval of neoadjuvant-only Opdivo plus chemotherapy in resectable NSCLC based on the CheckMate-816 trial,” said Wendy Short Bartie, senior vice president of US Oncology and Hematology at Bristol Myers Squibb. 
• With this new Opdivo -based regimen, we are reinforcing our commitment to helping improve patient outcomes and expanding our thoracic portfolio in early-stage disease.

Recommended Dose 

• The recommended dose for Opdivo in this indication is 360 mg with platinum-doublet chemotherapy on the same day every three weeks for up to four cycles or until disease progression or unacceptable toxicity, then continued as a single-agent Opdivo 480 mg every four weeks after surgery for up to 13 cycles (approximately one year) or until disease recurrence or unacceptable toxicity.  
• Opdivo approvals- The FDA previously approved Opdivo for adult patients with resectable (tumors =4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. Opdivo and Opdivo -based combinations have been approved by the FDA in the neoadjuvant, adjuvant or perioperative settings across four cancers to date, including lung cancer, melanoma, bladder cancer and esophageal/gastroesophageal junction cancer.

CheckMate-77T Trial

• CheckMate-77T is a phase 3 randomized, double-blind, multi-center trial evaluating neoadjuvant Opdivo in combination with platinum-doublet chemotherapy followed by surgery and single-agent adjuvant Opdivo, compared to neoadjuvant platinum-doublet chemotherapy and placebo followed by surgery and adjuvant placebo in patients with resectable NSCLC.
• In the CheckMate-77T study, a total of 461 patients were randomized to receive either neoadjuvant Opdivo 360 mg with platinum-doublet chemotherapy every three weeks, or placebo and platinum-doublet chemotherapy every three weeks, until disease progression or unacceptable toxicity, for up to four cycles, followed by single-agent Opdivo 480 mg after surgery every four weeks or placebo every four weeks, until disease progression or unacceptable toxicity, for up to thirteen cycles (approximately one year).  
• The primary endpoint of the trial is event-free survival determined by Blinded Independent Central Review (BICR). 
• Secondary endpoints of the trial include pathologic complete response and major pathologic response, both determined by Blinded Independent Pathological Review (BIPR), as well as overall survival and safety.

Common Adverse Reactions

The most common adverse reactions (reported in =20%) in patients receiving Opdivo in combination with chemotherapy (n= 228) were anaemia (39.5%), constipation (32.0%), nausea (28.9%), fatigue (28.1%), alopecia (25.9%), and cough (21.9%).

Serious adverse Reactions

• Serious adverse reactions occurred in 21% of patients who received Opdivo in combination with platinum-doublet chemotherapy as neoadjuvant treatment (n=228).  
• The most frequent (=2%) serious adverse reaction was pneumonia.  
• Fatal adverse reactions occurred in 2.2% of patients, due to cerebrovascular accident, Covid-19 infection, haemoptysis, pneumonia, and pneumonitis (0.4% each).

In Checkmate 77T, 5.3% (n=12) of the Opdivo-treated patients who received neoadjuvant treatment, did not receive surgery due to adverse reactions. The adverse reactions that led to cancellation of surgery in Opdivo-treated patients were cerebrovascular accident, pneumonia, and colitis/diarrhoea (2 patients each) and acute coronary syndrome, myocarditis, haemoptysis, pneumonitis, Covid-19, and myositis (1 patient each).

Serious adverse reactions occurred in 22% of the patients who received single-agent Opdivo as adjuvant treatment (n=142).  The most frequent serious adverse reaction was pneumonitis/ILD (2.8%).  One fatal adverse event due to Covid-19 occurred.  The perioperative regimen had a safety profile consistent with previously reported Opdivo studies in NSCLC and no new safety signals were identified.

About Lung Cancer

• Lung cancer is the leading cause of cancer deaths in the United States.  
• The two main types of lung cancer are non-small cell and small cell.  Non-small cell lung cancer (NSCLC) represents up to 85% of diagnoses.  
• For some non-metastatic early-stage NSCLC patients, surgery may be able to be used as a singular option for treatment.  
• However, 30% to 55% of patients can develop recurrence, contributing to a need for treatment options administered before surgery (neoadjuvant) and after surgery (adjuvant) to improve long-term outcomes.  
• Survival rates vary depending on the stage and type of the cancer when diagnosed.

Opdivo: Indication

Opdivo  (nivolumab) 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+ platinum-doublet chemotherapyOpdivo (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+ platinum-doublet chemotherapy

Opdivo (nivolumab) in combination with platinum-doublet chemotherapy, is indicated for neoadjuvant treatment of adult patients with resectable (tumors =4 cm or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements, followed by single-agent Opdivo as adjuvant treatment after surgery.

• Opdivo indication in UC

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 for resected esophageal or gastroesophageal junction cancer

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).
Checkmate adjuvant treatment

• 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 816–neoadjuvant non-small cell lung cancer, in combination with platinum-doublet chemotherapy; 
• Checkmate 77T–neoadjuvant treatment with platinum-doublet chemotherapy for non-small cell lung cancer followed by single-agent Opdivo as adjuvant treatment after surgery.

About the company: Bristol Myers Squibb

• 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.

Statement from an expert: The University of Texas

• Given the rates of disease recurrence in patients with resectable NSCLC, there is a clear need for options that can be administered before and after surgery that may target micrometastasis, help reduce the risk of cancer returning and improve the chance of successful surgical treatment,” said Tina Cascone, MD, PhD, associate professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.  
• This approval is a step forward for patients with resectable disease, as the perioperative nivolumab plus neoadjuvant chemotherapy regimen can offer an improved event free survival (EFS) compared with neoadjuvant chemotherapy alone and has the potential for achieving a pathologic response (pCR) in one in four patients.

About CheckMate-77T trial

• The CheckMate-77T trial evaluated the perioperative regimen of neoadjuvant Opdivo with platinum-doublet chemotherapy followed by surgery and adjuvant Opdivo monotherapy (n=229), compared to neoadjuvant platinum-doublet chemotherapy and placebo followed by surgery and adjuvant placebo (n=232) in adult patients with resectable NSCLC.  
• In the trial, the Opdivo arm improved EFS, a primary endpoint, compared to the chemotherapy and placebo treatment arm.  
• A high pCR rate was also observed as one of the pre-specified secondary endpoints.

The Outcomes

• The risk of disease recurrence, progression or death was reduced by 42% (EFS Hazard Ratio [HR] 0.58; 95% Confidence Interval [CI]: 0.43 to 0.78; P =0.00025) in patients treated in the Opdivo arm, compared to the chemotherapy and placebo arm, with a median follow-up of 25.4 months.  
• In addition, 18-month EFS was demonstrated in 70% of patients in the Opdivo arm, compared to 50% of patients in the chemotherapy and placebo arm. 
• Furthermore, 25% of patients in the Opdivo arm achieved pCR, while 4.7% of patients in the comparator arm achieved pCR in the intent-to-treat population (estimated treatment difference of 20.5%; 95% CI,14.3 to 26.6).

Warnings & Precautions: Opdivo

• Opdivo is associated with the following Warnings & Precautions: 

Severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, dermatologic adverse reactions, nephritis and renal dysfunction; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); embryo-fetal toxicity.  

• Treatment: Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue and dexamethasone is not recommended outside of controlled clinical trials.  

About Bristol Myers Squibb

• This milestone expands the role of Opdivo -based treatments and builds upon the foundation set by the FDA approval of neoadjuvant-only Opdivo plus chemotherapy in resectable NSCLC based on the CheckMate-816 trial,” said Wendy Short Bartie, senior vice president of US Oncology and Hematology at Bristol Myers Squibb. 
• With this new Opdivo -based regimen, we are reinforcing our commitment to helping improve patient outcomes and expanding our thoracic portfolio in early-stage disease.

Recommended Dose 

• The recommended dose for Opdivo in this indication is 360 mg with platinum-doublet chemotherapy on the same day every three weeks for up to four cycles or until disease progression or unacceptable toxicity, then continued as a single-agent Opdivo 480 mg every four weeks after surgery for up to 13 cycles (approximately one year) or until disease recurrence or unacceptable toxicity.  
• Opdivo approvals- The FDA previously approved Opdivo for adult patients with resectable (tumors =4 cm or node positive) NSCLC in the neoadjuvant setting, in combination with platinum-doublet chemotherapy. Opdivo and Opdivo -based combinations have been approved by the FDA in the neoadjuvant, adjuvant or perioperative settings across four cancers to date, including lung cancer, melanoma, bladder cancer and esophageal/gastroesophageal junction cancer.

CheckMate-77T Trial

CheckMate-77T is a phase 3 randomized, double-blind, multi-center trial evaluating neoadjuvant Opdivo in combination with platinum-doublet chemotherapy followed by surgery and single-agent adjuvant Opdivo, compared to neoadjuvant platinum-doublet chemotherapy and placebo followed by surgery and adjuvant placebo in patients with resectable NSCLC.