FDA Grants Durvalumab Breakthrough Designation for NSCLC

Sean Bohen, MD, Phd

The FDA has granted durvalumab (Imfinzi) a breakthrough therapy designation to treat patients with locally-advanced, unresectable non-small cell lung cancer (NSCLC) whose disease has not progressed following platinum-based chemoradiation.

AstraZeneca and its global biologics research and development arm MedImmune, announced the FDA action in a press release. The designation, which will expedite the development and review of durvalumab in this setting, is based on interim results from the phase III PACIFIC trial, in which the PD-L1 inhibitor significantly improved progression-free survival (PFS) compared with placebo. AstraZeneca has not released any details from PACIFIC, but said data have been submitted for presentation at an upcoming medical meeting.

“For patients who have not progressed following chemoradiation therapy, the only current option is active monitoring,” Sean Bohen, MD, Phd, executive vice president, Global Medicines Development and Chief Medical Officer at AstraZeneca, said in a statement. “Unfortunately, for the majority of patients, their cancer will progress to metastatic disease, typically within 12 months. Imfinzi is the first immuno-oncology medicine to show a clinically-significant benefit in this earlier, nonmetastatic setting, so we hope to bring it to patients as soon as possible.”

The double-blind PACIFIC trial was conducted at 235 centers in 26 countries and included an “all-comer” patient population who had locally-advanced, unresectable (stage III) NSCLC with no disease progression after concurrent therapy with platinum-based chemotherapy and radiation. Patients were randomized in a 2:1 ratio to durvalumab or placebo. PFS was the primary endpoint, along with overall survival (OS).

Results from the phase II ATLANTIC trial presented late last year 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 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 of <25%.

The 1-year OS rates were 48% and 51% in patients with PD-L1 levels of ≥25% and ≥90%, respectively. The median OS was 9.3 months, 20.9 months, and not yet reached in the <25%, ≥25%, and ≥90% PD-L1 expression groups, respectively. In the 3 cohorts, the median PFS was 1.9, 3.3, and 2.4 months, respectively.

Most adverse events (AEs) were low grade and resolved with treatment delay and/or immunosuppressive interventions. Treatment-related AEs leading to discontinuation occurred in 2.7% of patients.

Earlier this month, AstraZeneca announced that frontline durvalumab (Imfinzi), either in combination with tremelimumab or as a single agent, did not improve PFS in patients with stage IV metastatic NSCLC compared with standard platinum-based chemotherapy.

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. According to AstraZeneca, the randomized, open-label, phase III trial will continue to assess 2 additional primary endpoints of OS for durvalumab monotherapy and the durvalumab/tremelimumab combination. Those results are anticipated early next year.

Durvalumab is also being tested in the adjuvant NSCLC setting in the phase III ADJUVANT trial. Investigators are also assessing durvalumab as monotherapy and in combination with tremelimumab in first-line for patients with stage 4 NSCLC in the phase III NEPTUNE, and PEARL trials. The POSEIDON trial is evaluating durvalumab with and without tremelimumab in combination with chemotherapy.