Frontline Durvalumab Plus Tremelimumab Falls Short in Phase III NSCLC Trial

Sean Bohen, MD, PhD

Frontline durvalumab (Imfinzi), either in combination with tremelimumab or as a single agent, did not improve progression-free survival (PFS) in patients with stage IV metastatic non—small cell lung cancer (NSCLC) compared with standard platinum-based chemotherapy.

AstraZeneca, the manufacturer of durvalumab and tremelimumab, reported in a press release that the anti—PD-L1/CTLA-4 combination failed to meet the primary endpoint of improving PFS compared with standard of care in patients whose tumors express PD-L1 on at least 25% of their cancer cells.

The company noted that the randomized, open-label, phase III trial will continue to assess 2 additional primary endpoints of overall survival (OS) for durvalumab monotherapy and the durvalumab/tremelimumab combination. Those results are anticipated early next year.

“While the results from the MYSTIC trial for progression-free survival in first-line stage IV non-small cell lung cancer compared with standard of care are disappointing, the trial was designed to assess overall survival and we look forward to evaluating the remaining primary endpoints of overall survival for both mono- and combination therapy,” AstraZeneca chief medical officer Sean Bohen, MD, PhD, said in the press release.

The MYSTIC trial is evaluating durvalumab alone or combined with tremelimumab versus standard platinum-based chemotherapy for the treatment of patients with EGFR and ALK wild-type locally-advanced or metastatic NSCLC. The dual blockade approach focuses on 2 locations in the immune system: durvalumab targets the tumor microenvironment and tremelimumab zeroes in on priming lymph nodes.

MYSTIC was initiated in 2015 and investigators planned to enroll 675 patients at 167 medical centers across 17 countries, including the United States, Canada, Japan, Korea, Thailand, Russia, and Australia.

Durvalumab had demonstrated promising single-agent activity in NSCLC, and positive results were published in The Lancet Oncology in 2016 for a phase Ib study examining the durvalumab/tremelimumab combination in 102 patients with locally advanced or metastatic NSCLC. Patients enrolled in the study could have received any number of prior systemic treatments, but had to be immunotherapy-naïve.

Among 63 patients who were evaluable for tumor response, there were 11 (17%) objective responses and 18 patients (29%) achieved disease control by 24 weeks. Response was ongoing in 9 of 11 patients at the time of data cutoff, and 2 additional patients with ongoing response were awaiting a confirmatory scan.

Among 58 patients in the EGFR/ALK wild-type population, 11 (19%; 95% CI, 10-31) achieved an objective response.

Overall, grade 3/4 toxicity occurred in 43 of 102 evaluable patients, most often colitis, diarrhea, elevated lipase, and elevated liver function tests. However, in the dose combination selected for phase III evaluation (durvalumab at 20 mg/kg every 4 weeks plus tremelimumab at 1 mg/kg), grade 3/4 events occurred in 4 of 22 patients.

In results from the phase III PACIFIC trial announced in May, durvalumab was associated with significantly improved PFS when used as a sequential treatment in patients with locally-advanced, unresectable stage III NSCLC who had not progressed following standard care with platinum-based chemotherapy and radiotherapy. AstraZeneca intends to present these initial findings from the PACIFIC trial at an upcoming medical meeting.

Prior to that study, results from the phase II ATLANTIC trial presented in 2016 at the 17th World Lung Cancer Conference showed that durvalumab demonstrated a clinical benefit in the second-line setting and beyond in heavily pretreated patients with locally advanced or metastatic stage IIIb/IV NSCLC.

In the study, the level of response increased with higher levels of PD-L1 expression. The highest overall response rate (ORR) of 30.9% (95% CI, 20.2-43.3) occurred in patients with PD-L1 expression on ≥90% of tumor cells. ORR was 16.4% (95% CI, 10.8-23.5) in patients with PD-L1 expression ≥25%, and 7.5% (95% CI, 3.1-14.5) in patients with PD-L1 expression levels <25%.

Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol. 2016 Mar;17(3):299-308.