Opdivo Misses Endpoint in Phase 3 Lung Cancer Study

When compared with physician’s choice of combination chemotherapy, Opdivo (nivolumab) failed to improve progression-free survival (PFS) for patients with PD-L1—positive non–small cell lung cancer (NSCLC), according to topline findings from the phase 3 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 Opdivo at 3 mg/kg every two weeks or standard combination chemotherapy. All patients enrolled in the study had PD-L1 expression on 5 percent or more 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 six cycles. An independent radiology review committee reviewed results.

Topline findings from the study came as a surprise, since Opdivo's main competitor Keytruda (pembrolizumab) 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 3 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 percent or more 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 Yervoy (ipilimumab) to Opdivo in the frontline setting.

“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 3 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, chief executive officer, Bristol-Myers Squibb, said in a statement.

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

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

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

In addition to approvals in the second-line NSCLC setting, Opdivo 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, Opdivo has frequently not improved PFS across phase 3 studies for approved and pending indications.

In the phase 3 CheckMate-141 study, the median PFS with Opdivo in SCCHN was 2.0 months compared with 2.3 months with investigator's choice of therapy. Despite this lack of improvement, median OS was 7.5 months compared with 5.1 months with investigator's choice and the ORR was 13.3 percent with Opdivo and 5.8 percent for investigator's choice.

Additionally, in the phase 3 CheckMate-025 study, median PFS was 4.6 months with Opdivo compared with 4.4 months with Afinitor (everolimus) for patients with RCC. The ORR with Opdivo was 21.5 percent compared with 3.9 percent for those receiving Afinitor. Median OS was 25.0 months with Opdivo versus 19.6 months with Afinitor.

A lack of PFS benefit was also demonstrated in some studies investigating Opdivo as a second-line therapy for NSCLC. In the phase 3 CheckMate-057 study, which enrolled patients with nonsquamous NSCLC, the median PFS was 2.3 months with Opdivo versus 4.3 months with docetaxel. However, in the squamous population enrolled in the CheckMate-017 study, median PFS with Opdivo was 3.5 versus 2.8 months for docetaxel.

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 Opdivo and Yervoy.

In the four-arm phase 3 CheckMate-227 trial, platinum-doublet chemotherapy is being compared with Opdivo alone or in combination with Yervoy at 1 mg/kg Q6W or platinum-doublet chemotherapy. The primary endpoint is OS, and the study plans to enroll 1,980 patients. The estimated primary completion date is January 2018 (NCT02477826).