Nivolumab Misses PFS Endpoint in Frontline Phase III NSCLC Study


Monotherapy with nivolumab failed to improve progression-free survival compared with physician's choice of combination chemotherapy for patients with PD-L1–positive non–small cell lung cancer.

Giovanni Caforio, MD

Monotherapy with nivolumab (Opdivo) failed to improve progression-free survival (PFS) compared with physician's choice of combination chemotherapy for patients with PD-L1—positive non–small cell lung cancer (NSCLC), according to topline findings from the phase III CheckMate-026 study that were released by the drug's developer, Bristol-Myers Squibb.

The CheckMate-026 study enrolled 541 patients with nonsquamous and squamous NSCLC to receive nivolumab at 3 mg/kg every 2 weeks or standard combination chemotherapy. All patients enrolled in the study had PD-L1 expression on ≥5% of tumor cells. Full results from the trial are being prepared for presentation at an upcoming medical meeting, according to the company.

In the CheckMate-026 study, those in the squamous population comparator arm received gemcitabine plus cisplatin or carboplatin. In the nonsquamous group, treatment consisted of pemetrexed with cisplatin or carboplatin. Patients remained on therapy until progression, toxicity, or the completion of 6 cycles. An independent radiology review committee reviewed results.

Topline findings from the study came as a surprise, since nivolumab's main competitor pembrolizumab (Keytruda) had demonstrated improvements in overall survival (OS) and PFS as a frontline monotherapy for patients with high PD-L1—expressing NSCLC, according to topline phase III findings reported in mid-June. This study, known as the KEYNOTE-024 trial, enrolled 305 patients with both squamous and nonsquamous NSCLC. The comparator arms included paclitaxel plus carboplatin, pemetrexed plus carboplatin or cisplatin, and gemcitabine plus carboplatin or cisplatin. Those with nonsquamous disease were offered pemetrexed maintenance therapy.

Patients in KEYNOYE-024 had tumors with ≥50% PD-L1 expression, representing a more selective group. Subsequent subgroup analyses of the CheckMate-026 study will continue to assess subpopulations, including PD-L1. Additionally, studies are looking at the addition of ipilimumab (Yervoy) to nivolumab in the frontline setting.

Early stage trials had shown promising results for nivolumab in the frontline setting for NSCLC. In the phase Ib CheckMate-012 study, upfront treatment with the combination of nivolumab and ipilimumab demonstrated an objective response rate (ORR) of 57% in patients with ≥1% PD-L1-expressing advanced NSCLC, according to pooled findings presented at the 2016 ASCO Annual Meeting.1

In the 3-arm study, patients received nivolumab alone or in combination with ipilimumab every 6 weeks (Q6W) or every 12 weeks (Q12W). Across the full population, which was not selected based on PD-L1 expression, single-agent nivolumab had an ORR of 23%. In the combination arms, the ORRs were 47% and 39%, in the Q12W and Q6W arms, respectively.

For the PD-L1 assessment, data were combined from the two combination arms. In those with ≥50% PD-L1 expression, the ORR was 92%. In patients who tested PD-L1-negative, the ORR with the combination regimen was 15%. In those with ≥1% PD-L1 expression, median PFS were 8.1 and 10.6 months, in the Q12W and Q6W arms, respectively. With single-agent nivolumab, median PFS was 3.5 months.

In addition to approvals in the second-line NSCLC setting, nivolumab has gained approvals for advanced melanoma, renal cell carcinoma (RCC), and Hodgkin's lymphoma. Additionally, an application is pending with the FDA for the treatment in patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN). “Opdivo has become a foundational treatment that is transforming cancer care across multiple tumor types," said Caforio.

Despite consistently demonstrating improvements in OS and ORR, nivolumab has frequently not improved PFS across phase III studies for approved and pending indications.

In the phase III CheckMate-141 study, the median PFS with nivolumab in SCCHN was 2.0 months compared with 2.3 months with investigator's choice of therapy (HR, 0.89; 95% CI, 0.70-1.10; P = .3236). Despite this lack of improvement, median OS was 7.5 months compared with 5.1 months with investigator's choice (HR, 0.70; 95% CI, 0.51-0.96; P = .0101) and the ORR was 13.3% with nivolumab and 5.8% for investigator's choice.2

Additionally, in the phase III CheckMate-025 study, median PFS was 4.6 months with nivolumab compared with 4.4 months with everolimus for patients with RCC (HR, 0.88; 95% CI, 0.75-1.03; P = .11). The ORR with nivolumab was 21.5% compared with 3.9% for those receiving everolimus. Median OS was 25.0 months with nivolumab versus 19.6 months with everolimus (HR, 0.73; 98.5% CI, 0.57-0.93; P = .002).3

A lack of PFS benefit was also demonstrated in some studies investigating nivolumab as a second-line therapy for NSCLC. In the phase III CheckMate-057 study, which enrolled patients with nonsquamous NSCLC, the median PFS was 2.3 months with nivolumab versus 4.3 months with docetaxel (HR, 0.89; 95% CI, 0.75-1.07). However, in the squamous population enrolled in the CheckMate-017 study, median PFS with nivolumab was 3.5 versus 2.8 months for docetaxel (HR, 0.63; 95% CI, 0.48-0.83).4

It is unclear when full findings from the CheckMate-026 study will be presented. The primary endpoint was PFS, with secondary outcome measures focused on ORR, OS, and PFS by tumor PD-L1 expression. Additionally, other trials continue to assess frontline treatment with the combination of nivolumab and ipilimumab.

In the 4-arm phase III CheckMate-227 trial, platinum-doublet chemotherapy is being compared with nivolumab alone or in combination with ipilimumab at 1 mg/kg Q6W or platinum-doublet chemotherapy. The primary endpoint is OS, and the study plans to enroll 1980 patients. The estimated primary completion date is January 2018 (NCT02477826).


  1. Hellmann MD, Gettinger SN, Goldman JW, et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol. 2016;34 (suppl; abstr 3001).
  2. Ferris RL, Blumenschein GR, Fayette J, et al. Further evaluations of nivolumab (nivo) versus investigator’s choice (IC) chemotherapy for recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CheckMate 141. J Clin Oncol. 2016;34 (suppl; abstr 6009).
  3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma [published online September 25, 2015]. N Engl J Med. 2015;373:1803-1813.
  4. Borghaei H, Brahmer JR, Horn L, et al. Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses. J Clin Oncol. 2016;34 (suppl; abstr 9025).

“While we are disappointed CheckMate-026 did not meet its primary endpoint in this broad patient population, we remain committed to improving patient outcomes through our comprehensive development program, including the ongoing phase III CheckMate-227 study exploring the potential of the combination of Opdivo plus Yervoy, for PD-L1—positive patients, and Opdivo plus Yervoy or Opdivo plus chemotherapy in PD-L1–negative patients," Giovanni Caforio, MD, chief executive officer, Bristol-Myers Squibb, said in a statement.

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