FDA Grants Nivolumab/Ipilimumab Plus Chemo Priority Review in Frontline NSCLC

Sabine Maier, MD

The FDA has granted a priority review designation to nivolumab (Opdivo) plus ipilimumab (Yervoy) and chemotherapy for use as a frontline treatment for patients with metastatic or recurrent non—small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.¹

The FDA is scheduled to decide on the application by August 6, 2020. An application for the same indication has also been accepted by the European Medicines Agency, and approval for the regimen in this setting is also being sought in Japan.

“Despite treatment advances, there remains a serious unmet need for additional innovative treatment options for lung cancer patients globally,” Sabine Maier, MD, development lead, thoracic cancers, Bristol Myers Squibb (BMS), the developer of the PD-1 and CTLA-4 inhibitors, stated in a press release. “The FDA’s acceptance and EMA’s validation of our applications represent important milestones for patients with lung cancer, and we look forward to working with regulatory authorities to bring the first and only dual immunotherapy plus limited chemotherapy regimen to patients as soon as possible.”

The open-label, multicenter, randomized, phase III CheckMate-9LA trial evaluated nivolumab at 360 mg every 3 weeks plus ipilimumab at 1 mg/kg every 6 weeks plus 2 cycles of chemotherapy versus chemotherapy alone for up to 4 cycles followed by optional maintenance pemetrexed in the first-line setting for patients with advanced NSCLC, regardless of PD-L1 expression and histology.

Approximately 700 patients were enrolled in the study. Those who were enrolled on the experimental arm were treated for ≤2 years or until disease progression or unacceptable toxicity, while patients in the control arm were treated with ≤4 cycles of chemotherapy and optional pemetrexed maintenance, if eligible, until disease progression or toxicity.

To be eligible for enrollment, patients had to have histologically confirmed stage IV or recurrent NSCLC with squamous or nonsquamous histology, could not have received prior therapy, have an ECOG performance status of ≤1, measurable disease by RECIST v1.1 criteria, and be tested for PD-L1 expression via immunohistochemistry. Those with EGFR or ALK mutations that were sensitive to available targeted therapy or untreated central nervous system metastases were excluded from the trial.

The primary endpoint of the trial was OS in the intent-to-treat population; secondary endpoints included progression-free survival, overall response rate, and efficacy measures according to biomarkers. BMS reported the positive findings from the trial in October 2019; however, the actual data have not yet been made available.

Results of frontline nivolumab combined with ipilimumab in advanced NSCLC, regardless of PD-L1 expression status, were presented at the 2019 ESMO Congress. The final analysis was from part 1 of the phase III CheckMate-227 trial, demonstrating that PD-1 and CTLA-4 inhibition is effective in this patient population.^2,3

In a cohort of patients with PD-L1 expression ≥1%, the median OS with nivolumab and ipilimumab compared with chemotherapy was 17.1 months and 14.9 months, respectively (HR, 0.79; 97.72% CI, 0.65-0.96; P = .007). Moreover, the median OS was 17.1 months with the combination and 13.9 months with chemotherapy in patients regardless of PD-L1 expression status (HR, 0.73; 95% CI, 0.64-0.84).

Data also showed that, in the cohort of patients with PD-L1 ≥1% expression, the 1- and 2-year OS rates were 63% and 40% with nivolumab/ipilimumab and 56% and 33% with chemotherapy, respectively.

Moreover, an exploratory analysis of the nivolumab/ipilimumab combination, single-agent nivolumab, and chemotherapy-alone arms in patients whose tumors had PD-L1 expression ≥1% were also presented at the meeting. Here, the median OS was 17.1 months, 15.7 months, and 14.9 months, respectively (HR for nivolumab/ipilimumab vs chemo, 0.79; 97.72% CI, 0.65-0.96; HR for nivolumab vs chemotherapy, 0.88; 97.72% CI, 0.75-1.04). The 1-year OS rates for the combination, nivolumab, and chemotherapy were 63%, 57%, and 56%; the 2-year OS rates were 40%, 36%, and 33%, respectively.

By blinded independent central review, the median duration of response was 23.2 months, 15.5 months, and 6.2 months for nivolumab/ipilimumab, nivolumab, and chemotherapy, respectively. The rates of patients in response at 1 year were 64%, 63%, and 28%, respectively; the rates of those in response at 2 years were 49%, 40%, and 11%, respectively.

In part 1b of patients with PD-L1 expression <1%, the median OS was 17.2 months, 15.2 months, and 12.2 months with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy, respectively (HR for nivolumab/ipilimumab vs chemotherapy, 0.62; 95% CI, 0.48-0.78; HR for nivolumab/chemotherapy vs chemotherapy, 0.78; 95% CI, 0.60-1.02) The 1-year OS rates with nivolumab/ipilimumab, nivolumab/chemotherapy, and chemotherapy were 60%, 59%, and 51%, respectively; the 2-year OS rates were 40%, 35%, and 23%, respectively.

For all randomized patients, regardless of PD-L1 expression status, the 1-year OS rates with nivolumab/ipilimumab and chemotherapy were 62% and 54%, respectively; the 2-year OS rates were 40% and 30%, respectively.

No new safety findings of the combination were reported with longer follow-up. Grade 3/4 treatment-related adverse events were reported in 33%, 19%, and 36% of patients in the nivolumab/ipilimumab, single-agent nivolumab, and chemotherapy arms, respectively.

Based on these CheckMate-227 findings, the FDA granted a priority review designation to a supplemental biologics license application (sBLA) in January 2020 for the combination of nivolumab and ipilimumab for the first-line treatment of patients with metastatic or recurrent NSCLC that does not have EGFR or ALK genomic tumor aberrations. Under the Prescription Drug User Fee Act, the FDA will make a decision on the sBLA by May 15, 2020

Nivolumab is currently approved by the FDA for the treatment of patients with metastatic NSCLC with progression on or after platinum-based chemotherapy. Those with EGFR or ALK genomic tumor aberrations should have disease progression on an indicated therapy for these aberrations prior to receiving the PD-1 inhibitor.

References

1. Bristol Myers Squibb Announces Acceptance of U.S. and EU Regulatory Filings for Opdivo (nivolumab) Plus Yervoy (ipilimumab) Combined with Limited Chemotherapy in First-Line Lung Cancer. Published April 8, 2020. https://bit.ly/2wphHDx. Accessed April 8, 2020.
2. Peters S, Ramalingam SS, Paz-Ares L, et al. Nivolumab + low-dose ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non—small cell lung cancer: CheckMate-227 part 1 final analysis. Ann Oncol. 2019;30(5 suppl; abstr LBA4_PR). doi: 10.1093/annonc/mdz394.075
3. Hellmann MD, Paz-Ares L, Carbo RB, et al. Nivolumab plus ipilimumab in advanced non—small-cell lung cancer [published online September 28, 2019]. N Eng J Med. doi: 10.1056/NEJMoa1910231

The application for the regimen is based on findings from the phase III CheckMate-9LA trial, in which nivolumab plus low-dose ipilimumab given concomitantly with 2 cycles of chemotherapy showed superior overall survival (OS) compared with up to 4 cycles of chemotherapy alone followed by optional maintenance treatment in patients with advanced non—small cell lung cancer.