Update on Frontline Nivolumab/Ipilimumab Combo Demonstrates Positive OS Results in PD-L1+ NSCLC

Martin Reck, MD, PhD

Martin Reck, MD, PhD

Nivolumab (Opdivo) in combination with a low dose of ipilimumab (Yervoy) demonstrated an improvement in overall survival (OS) compared with chemotherapy in patients with newly diagnosed non—small cell lung cancer (NSCLC) whose tumors have PD-L1 expression ≥1%.¹

Bristol-Myers Squibb (BMS), the company developing the immunotherapy agents, announced results from part 1a of the phase III CheckMate 227 trial in a press release. The company plans for complete findings from part 1 of the trial to be presented at an upcoming medical meeting.

“The nivolumab plus ipilimumab results from Part 1a of CheckMate-227 offers the potential for a chemo-sparing regimen that demonstrates an OS benefit to first-line [treatment of patients with] lung cancer,” said Martin Reck, MD, PhD, of Lung Clinic Grosshansdorf in Hamburg, Germany, and the lead CheckMate 227 study investigator, in a press release.

An exploratory analysis of patients in part 1b of the trial who were negative for PD-L1 expression also showed that a survival benefit was seen with the nivolumab and low-dose ipilimumab combination. “I am also encouraged to see activity in PD-L1 expressors and non-expressors, and look forward to seeing the full data presented in the future,” Reck added.

The open-label, randomized phase III trial consists of multiple parts all evaluating nivolumab-based regimens in comparison with platinum-doublet chemotherapy in the frontline setting in patients with advanced NSCLC regardless of histology (NCT02477826).

Part 1a is focused on nivolumab and low-dose ipilimumab or single-agent nivolumab compared with chemotherapy in patients with PD-L1 expression, and part 1b includes patients whose tumors do not express PD-L1. Part 2 is assessing nivolumab plus chemotherapy versus chemotherapy alone for all patients regardless of their PD-L1 expression levels.

Patients were required to have PD-L1 testing via immunohistochemistry and an ECOG performance status of 0 or 1. Those with untreated central nervous system metastases, an active or suspected autoimmune disease, and hepatitis or HIV were excluded from entering the trial.

The primary endpoints of part 1 are OS in patients with positive PD-L1 expression and progression-free survival (PFS) in patients with tumor mutational burden (TMB) ≥10 mutations/megabase regardless of PD-L1 expression. Secondary endpoints include objective response rate and disease-related symptom improvements. The company noted that both co-primary endpoints have been met in part 1. 

“CheckMate 227 is the first phase III trial to demonstrate that patients with lung cancer can achieve superior overall survival with a dual immunotherapy combination versus chemotherapy,” Fouad Namouni, MD, the head of oncology development at BMS, said in a press release. “Lung cancer is the third tumor type where the Opdivo plus Yervoy regimen has shown a significant overall survival benefit in a randomized phase III3 trial, reinforcing the importance of Yervoy in the treatment of cancer. We thank the patients and investigators who participated in this trial.”

Initial results from part 2 of the CheckMate 227 trial revealed that the primary endpoint of OS was not met in patients with newly diagnosed nonsquamous NSCLC regardless of their PD-L1 expression levels, failing to show a statistically significant improvement with nivolumab plus chemotherapy over chemotherapy alone.²The median OS was 18.83 months with the combination versus 15.57 months for chemotherapy alone (HR, 0.86; 95% CI, 0.69-1.08). At 1 year, the OS rate was 67.3% with chemoimmunotherapy versus 59.2% with chemotherapy alone.

However, there was a more significant difference in OS observed in an exploratory analysis of patients with previously untreated squamous NSCLC. The median OS was 18.27 months with nivolumab and chemotherapy versus 11.96 months with chemotherapy (HR, 0.69; 95% CI, 0.50-0.97).

“While this is not the outcome we had hoped for, the Opdivo plus chemotherapy one-year landmark overall survival in the non-squamous population was consistent with the experimental arms in previously-reported trials of immunotherapy/chemotherapy combination regimens,” Namouni added in a press release.

Updated data from part 1 and 2 of the CheckMate 227 trial both suggest that no new safety signals were observed with the nivolumab-based regimens from previous experience with each agent.^1,2

The company had submitted a supplemental biologics license application (sBLA) to the FDA for the nivolumab/ipilimumab combination for the treatment of patients with previously untreated advanced NSCLC and TMB ≥10 mutations/megabase (high TMB), which was accepted for review in June 2018. In January 2019, however, the company decided to withdraw the sBLA after discussions with the FDA.³

Earlier results from the CheckMate 227 trial, which supported the sBLA, showed that at 1 year, the PFS rate with the combination was 43% in patients with high TMB compared with 13% in patients who received platinum-doublet chemotherapy.⁴

A further exploratory analysis of patients with stage IV or recurrent NSCLC and TMB <10 mutations/megabase that was submitted to the FDA also did not show a significant difference in survival outcomes between the immunotherapy combination and chemotherapy in patients with high and low TMB.⁵

In this analysis, the median OS for the combination in patients with TMB &ge;10 mutations/megabase was 23.03 versus 16.72 months for the chemotherapy arm (HR, 0.77; 95% CI, 0.56-1.06). Among patients with TMB <10 mutations/megabase, the median OS was 16.20 versus 12.42 months, respectively (HR, 0.78; 95% CI, 0.61-1.00).

References:

1. Bristol-Myers Squibb Announces CheckMate -227 Part 1a Meets Co-Primary Endpoint of Overall Survival [press release]. Princeton, NJ: Bristol-Myers Squibb Company; July 24, 2019. https://bit.ly/2M5VxeW. Accessed July 25, 2019.&nbsp;
2. Bristol-Myers Squibb Provides Update on Part 2 of CheckMate -227 [press release]. Princeton, NJ: Bristol-Myers Squibb Company; July 24, 2019. https://bit.ly/32PyxXu. Accessed July 25, 2019.&nbsp;
3. Bristol-Myers Squibb Reports Fourth Quarter and Full Year Financial Results. Bristol-Myers Squibb. Published January 24, 2019. https://bit.ly/2FMWGpr. Accessed July 25, 2019.
4. Hellman MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden.N Engl J Med.2018;378(22):2093-2104. doi: 10.1056/NEJMoa1801946.
5. Bristol-Myers Squibb Provides Update on the Ongoing Regulatory Review of Opdivo Plus Low-Dose Yervoy in First-Line Lung Cancer Patients with Tumor Mutational Burden &ge;10 mut/Mb [press release]. Princeton, NJ: Bristol-Myers Squibb Company; October 19, 2018. https://bit.ly/2ySdgOC. Accessed July 25, 2019.&nbsp;