Durvalumab Combo Misses OS Endpoint in Frontline Metastatic NSCLC

Sean Bohen, MD, PhD

The frontline combination of durvalumab (Imfinzi) and tremelimumab did not induce a statistically significant improvement in overall survival (OS) compared to standard chemotherapy in patients with metastatic (stage IV) non—small cell lung cancer (NSCLC).

AstraZeneca (MedImmune) reported in a press release that final OS data from the phase III MYSTIC trial showed a hazard ratio (HR) of 0.85 (98.77% CI, 0.611-1.173; P =.202) in patients with PD-L1 expression ≥25% who received durvalumab/tremelimumab versus standard platinum-based chemotherapy. The HR for OS was improved with durvalumab monotherapy versus standard chemotherapy; however, the benefit was still not statistically significant (HR, 0.76; 97.54% CI, 0.564-1.019; P = .036).

There were no new safety signals with the combination or single-agent durvalumab. AstraZeneca is continuing to examine the study data in exploratory subgroups.

“We are encouraged to see that Imfinzi monotherapy activity is in-line with that of the anti—PD-1 class in previously-untreated patients with stage IV non–small cell lung cancer; however, we are disappointed that these results missed statistical significance,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development and chief medical officer at AstraZeneca, said in a statement.

“We remain confident in Imfinzi as the cornerstone of our IO program and continue to evaluate its potential in ongoing non-small cell lung cancer trials, including Imfinzi and Imfinzi plus tremelimumab in combination with chemotherapy,” added Bohen.

The open-label phase III MYSTIC trial accrued patients with EGFR/ALK wild-type locally advanced or metastatic NSCLC at 167 centers in 17 countries. Patients were randomized to durvalumab monotherapy, durvalumab/tremelimumab, or standard chemotherapy. The primary endpoints were OS for the durvalumab arms in patients with PD-L1 expression on ≥25% of their tumor cells as measured by the VENTANA PD-L1 (SP263) Assay.

In February 2018, the FDA approved durvalumab for the treatment of patients with locally advanced, unresectable stage III NSCLC who have not progressed following chemoradiotherapy.

The approval was based on the phase III PACIFIC trial, in which the PD-L1 inhibitor durvalumab improved median progression-free survival (PFS) by 11.2 months compared with placebo (16.8 vs 5.6 months; HR, 0.52; 95% CI, 0.42-0.65; P <.0001).¹ The 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%, again favoring the durvalumab arm.

At the time of the submission OS data were not yet mature. However, subsequent findings showed that patients treated with durvalumab after chemoradiotherapy demonstrated a 24-month OS rate of 66.3% (95% CI, 61.7%-70.4%) compared with 55.6% (95% CI, 48.9-61.8) in patients who received placebo (two-sided P = .005).^2,3 Durvalumab significantly prolonged OS compared with placebo (HR, 0.68; 99.73% CI, 0.469-0.997; P = .00251). Median OS was not reached in the durvalumab group and was 28.7 months in the placebo arm.

The randomized, double-blind, placebo-controlled, multicenter phase III PACIFIC trial included 713 patients with stage III NSCLC who did not have disease progression after 2 or more cycles of platinum-based chemoradiotherapy. Investigators randomly assigned patients 2:1 to receive either 10 mg/kg of durvalumab intravenously (n = 476) or placebo (n = 237) every 2 weeks for up to 12 months after chemoradiotherapy.

Ongoing phase III trials of frontline durvalumab in stage IV NSCLC include PEARL (single-agent durvalumab vs standard chemotherapy), NEPTUNE (durvalumab/tremelimumab vs standard chemotherapy), and POSEIDON (durvalumab/chemotherapy or durvalumab/tremelimumab/chemotherapy versus standard chemotherapy).

References

1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non—small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929 doi: 10.1056/NEJMoa1709937.
2. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab versus placebo after chemoradiotherapy in stage III NSCLC: updated results from PACIFIC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract PL02.01.
3. Antonia S, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online ahead of print September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809697.