Nivolumab/Ipilimumab Plus Chemo Improves OS in Frontline NSCLC

Fouad Namouni, MD, head, Oncology Development, Bristol-Myers Squibb

Fouad Namouni, MD

The first-line combination of nivolumab (Opdivo) plus low-dose ipilimumab (Yervoy) 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 for patients with advanced non—small cell lung cancer (NSCLC), meeting the primary endpoint of the phase III CheckMate-9LA trial (NCT03215706).¹

At the prespecified interim analysis, the safety profile of the immunotherapy/chemotherapy combination was also found to be consistent with prior results of each agent alone. Bristol-Myers Squibb (BMS), the developer of the PD-1 and CTLA-4 inhibitors, stated in a press release that it will complete a full evaluation of the phase III data. The findings will also be presented at an upcoming medical meeting and will be discussed with regulatory authorities.

“We are excited by the CheckMate-9LA results, which demonstrate the potential of Opdivo plus low-dose Yervoy to provide a survival benefit to patients with non—small cell lung cancer in the first-line setting when administered concomitantly with a limited course of chemotherapy,” Fouad Namouni, MD, head, Oncology Development, Bristol-Myers Squibb, stated in the press release. “These results build on the benefit the combination of Opdivo plus Yervoy has previously shown..and may provide a new therapeutic option for patients.”

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.

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.

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. CheckMate-9LA, a Phase 3 Trial Evaluating Opdivo (nivolumab) Plus Low-Dose Yervoy (ipilimumab) Combined with Chemotherapy, Meets Primary Endpoint Demonstrating Superior Overall Survival Compared to Chemotherapy Alone in First-Line Lung Cancer. Bristol-Myers Squibb. Published October 22, 2019. https://bit.ly/2MBIhyx. Accessed October 22, 2019.
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.