Merck KGaA's Pfizer Inc.-partnered Bavencio (avelumab), already approved to treat some cancers, failed to outperform docetaxel in treating patients with difficult-to-treat non-small-cell lung cancers (NSCLC), the companies said. Results of the phase III Javelin Lung 200 study showed it missing the prespecified endpoint of improving overall survival (OS) in NSCLC patients with unresectable, recurrent or metastatic PD-L1-positive tumors that progressed after treatment with a platinum-containing doublet therapy.

The companies suggested that, with 26.4 percent of patients in the chemotherapy arm crossing over to immune checkpoint inhibitors outside the study and 5.7 percent of those in the avelumab arm doing the same, the outcome may have been confounded. "With immune checkpoint inhibitors approved for patients with previously treated, advanced non-small-cell lung cancer, higher percentages of immunotherapy-naive patients are receiving subsequent checkpoint inhibitors in their progressive treatments," primary investigator Fabrice Barlesi said in a statement accompanying the news.

"Detailed analyses of the results of the trial will inform Merck's broader clinical development program, including the ongoing lung trials," EMD Serono representative Melissa Lauer told BioWorld. Those results will be submitted for presentation at an upcoming medical congress, and the companies aim to share the data with regulatory agencies, they said.

During 2017, the FDA approved Bavencio in March for Merkel cell carcinoma and in May for advanced bladder cancer. But adding NSCLC could vastly expand its potential customer base in the U.S., where the drug is marketed by Darmstadt, Germany-based Merck KGaA's U.S. arm, EMD Serono Inc. (See BioWorld Today, Sept. 5, 2014, and March 24, 2017.)

Bavencio is a human antibody specific for PD-L1, or programmed death ligand-1. As an immunotherapy, it's designed to act by binding to PD-L1, preventing tumor cells from using it for protection against white blood cells, such as T cells, exposing them to anti-tumor responses.

While advanced NSCLC was previously treated primarily with chemotherapy, in recent years, tyrosine kinase inhibitors and immunotherapies, such as Opdivo (nivolumab, Bristol-Myers Squibb Co.), Keytruda (pembrolizumab, Merck & Co. Inc.), and Tecentriq (atezolizumab, Genentech Inc.) have come to dominate therapy.

No fewer than 115 candidates targeting metastatic NSCLC

Highlighting how fierce the race to capture market share in the field remains, no fewer than 115 experimental therapies are currently in phase I, II or III development to treat metastatic NSCLC, according to Cortellis Clinical Trials Intelligence. And, as Merck and Pfizer's story clearly illustrates, the number of avenues companies are exploring can be numerous.

EMD Serono supplied BioWorld with a list of no fewer than five studies of avelumab underway in NSCLC. The Javelin Lung 100 study is a phase III randomized open-label, multicenter trial to assess the safety and efficacy of avelumab, compared with platinum-based doublet chemotherapy, in patients with metastatic NSCLC who have not previously received any systemic treatment for their NSCLC. The trial is ongoing with estimated completion dates in mid-2019 and mid-2024, respectively.

The ongoing Javelin Lung 101 phase Ib/II dose-finding trial is evaluating the safety and efficacy of avelumab in combination with either Pfizer's crizotinib or lorlatinib in patients with advanced or metastatic NSCLC. Estimated completion dates are February 2019 and August 2020, respectively.

Javelin Medley, another study underway, is a phase Ib/II randomized open-label, multicenter dose-finding trial of avelumab in combination with other immune modulators in patients with selected locally advanced or metastatic solid tumors, including NSCLC. Its primary completion and estimated trial completion dates are December 2019 and February 2020, respectively.

Another ongoing combinatorial twist is Javelin PARP Medley, a phase Ib/II trial investigating the combination of avelumab and Pfizer's PARP inhibitor talazoparib in patients with locally advanced or metastatic solid tumors, including NSCLC. It's expected to wrap up in March 2020.

In addition, the NSCLC cohorts from the phase I Javelin Solid Tumor and Solid Tumor Japan studies are ongoing.

Avelumab is also part of at least two other NSCLC studies, including a phase Ib dose-finding study combining it with Debiopharm International SA's Debio-1143, an oral, small-molecule inhibitor of apoptosis proteins, and planned tests with Array Biopharma Inc.'s binimetinib.

In January, Forty Seven Inc., of Menlo Park, Calif., inked a deal with Merck to conduct a phase Ib trial combining CD47-targeting candidate Hu5F9-G4 with Bavencio in patients with ovarian cancer. Forty Seven said it would also work with Genentech Inc., a unit of Basel, Switzerland-based Roche Holding AG, which will sponsor two clinical trials combing Hu5F9-G4 with PD-L1 antibody Tecentriq (atezolizumab) in patients with acute myeloid leukemia and urothelial cancer.

Though the Javelin Lung 200 study is Bavencio's first recorded miss in NSCLC, it's not the drug's first trial failure. In November 2017, Merck reported that Bavencio failed to show superior OS over physician's choice chemotherapy for patients with unresectable, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma during the Javelin Gastric 300 trial.

In December 2017, the FDA granted Bavencio breakthrough status in combination with kinase inhibitor Inlyta (axitinib) for treatment-naïve patients with advanced renal cell carcinoma.