Frontline Immunotherapy Combo Setbacks Strike NSCLC

Sean Bohen, MD, PhD

Bristol-Myers Squibb (BMS) and AstraZeneca have each announced separate delays in the development of PD-1 and CTLA-4 inhibitor combinations as first-line therapies for patients with advanced or metastatic non—small cell lung cancer (NSCLC), according to statements from each of the companies.

In its statement, BMS noted that it would not be pursuing an accelerated approval for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as a frontline therapy for NSCLC. Instead, the company plans to delay the submission of data to the FDA until findings from a phase III study are available, most likely from the phase III CheckMate-227 trial.

Earlier this week, AstraZeneca also described modifications to its clinical development program for the combination of the PD-L1 inhibitor durvalumab with the CTLA-4 inhibitor tremelimumab. The primary endpoint of the phase III MYSTIC trial exploring the combination was adapted to include overall survival (OS) in addition to progression-free survival (PFS). With this change, the company now expects data for PFS in mid-2017 and findings for OS in 2018. At this time, the MYSTIC trial is no longer recruiting new participants (NCT02453282).

In addition to this change, AstraZeneca also expanded the phase III NEPTUNE trial , which is also exploring the combination of durvalumab and tremelimumab. Data for OS from this trial are anticipated in 2018. Additionally, a new phase III study, labeled PEARL, is being launched to further explore frontline durvalumab monotherapy for patents with PD-L1—positive NSCLC.

“The MYSTIC trial amendments, the NEPTUNE trial expansion, and initiation of the new PEARL trial are all designed to enhance our options in first-line NSCLC for immuno-oncology(IO)-IO combination as well as for IO monotherapy," Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement. "We continue to follow the science through both internal and external sources for the benefit of patients and look forward to sharing our first pivotal data in mid-2017.”

The combination of durvalumab and tremelimumab was explored in a phase Ib study for immunotherapy-naive patients with locally advanced or metastatic NSCLC. In this study, which was published in Lancet Oncology,¹ most patients had received at least 1 prior therapy. This study led to the establishment of a phase III dose of 20 mg/kg of durvalumab plus 1 mg/kg of tremelimumab every 4 weeks.

The objective response rate (ORR) was 23% in a cohort of 26 patients who received 10 to 20 mg/kg of durvalumab and 1 mg/kg of tremelimumab. The disease control rate was 35%. PD-L1 status did not appear to significantly impact results, with those testing positive on ≥25% of cells having an ORR of 22% and those testing negative (<25% of cells) experiencing an ORR of 29%.

A phase I study, CheckMate-012, also demonstrated promising findings for the combination of nivolumab and ipilimumab. In the study, nivolumab was administered at 3 mg/kg every 2 weeks with ipilimumab at 1 mg/kg every 6 weeks (n = 39) or every 12 weeks (n = 38). All patients in the trial were treated in the frontline metastatic setting.

In findings published in Lancet Oncology,² the ORRs with the combination were 47% and 38% in the ipilimumab every 12 weeks and every 6 week arms. The median PFS was 8.1 months when ipilimumab was given every 12 weeks versus 3.9 months in the every 6 week arm. The 1-year OS rate was not yet reached in the 12-week arm compared with a rate of 69% in the 6-week group.

The CheckMate-227 study continues to enroll participants, with a target enrollment goal of 2220 patients (NCT02477826). This trial is comparing platinum-based doublet chemotherapy with nivolumab monotherapy, the combination of nivolumab and ipilimumab, and the combination of nivolumab and platinum-based chemotherapy.

References:

1. Antonia S, Goldberg SB, Balmanoukian A, et al. Lancet Oncol. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicenter, phase 1b study [published online February 5, 2016]. Lancet Oncol. doi:10.1016/S1470-2045(15)00544-6.
2. Hellman MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol. 2017;18(1):31-41.