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Anti-PD 1 Drug Extends PFS in Stage III NSCLC

— Progression-free survival three times longer with durvalumab after chemoradiation

Ƶ MedicalToday

MADRID -- Patients with inoperable, locally advanced non-small cell lung cancer (NSCLC) had a threefold improvement in median progression-free survival (PFS) when they received the PD-1 inhibitor durvalumab after chemoradiation, a placebo-controlled clinical trial showed.

Median PFS increased from 5.6 months with placebo to 16.8 months with durvalumab. Analyses of response rate, time to death or distant metastasis, and PFS at 12 and 18 months all demonstrated significant advantages in favor of durvalumab.

Action Points

  • The PD-1 inhibitor durvalumab provided significant increase in progression-free survival in patients with stage III, unresectable non-small cell lung cancer (NSCLC) who had received chemoradiotherapy.
  • Note that the results of this planned interim analysis of a placebo-controlled trial represent the first major therapeutic advance in years for patients with locally advanced NSCLC.

The results represent the first major therapeutic advance in years for patients with locally advanced NSCLC, Luis Paz-Ares, MD, said here at the meeting.

"This is a very robust and clinically significant improvement for patients," said Paz-Ares, of University Hospital Doce de Octubre in Madrid. "The improvement in progression-free survival with durvalumab was observed across all prespecified subgroups. Patients receiving durvalumab had a lower incidence of new lesions, including new brain metastases, compared with patients receiving placebo. The safety profile was consistent with that of other immunotherapies."

"All in all, I think durvalumab is a promising new option for patients with stage III, locally advanced non-small cell lung cancer."

Although data remain immature for analysis of overall survival, "the magnitude of progression-free survival benefit supports this combination [chemoradiation plus durvalumab] as a new standard of care for unresectable stage III non-small cell lung cancer," said Pilar Garrido, MD, of Ramon y Cajal University Hospital in Madrid. "Further research is needed regarding the duration and timing of immunotherapy, the best regimen of chemoradiation to combine with it, and the selection of patients most likely to benefit based on predictive markers."

Results of the trial, , were published simultaneously online by the .

About a third of patients with NSCLC have stage III, locally advanced disease at diagnosis. With few exceptions, these patients have unresectable disease, said Paz-Ares. Standard of care consists of concurrent chemoradiation therapy using platinum-based combination chemotherapy. Patients with stage III NSCLC have a median PFS of 8 to 10 months, and about 15% remain alive at 5 years.

To test whether durvalumab could improve this outlook, investigators enrolled 713 patients with unresectable disease that had not progressed after standard platinum-based chemoradiation and randomized them 2:1 to the drug or placebo. Treatment continued until disease progression, death, or development of unacceptable toxicity. The trial had co-primary endpoints: PFS by blinded independent committee review and overall survival.

Following chemoradiation with durvalumab in the trial reduced the hazard for progression or death by by nearly half compared with placebo (HR 0.52, 95% CI 0.42-0.65, P<0.0001). The durvalumab group had a 12-month PFS of 55.9% versus 35.3% for the placebo group and 18-month PFS of 44.2% versus 27.0%. Durvalumab significantly prolonged the median time to death or distant metastasis (23.2 versus 14.6 months, P<0.0001).

The objective response rate was 28.4% versus 16.0% with placebo (P<0.001). Among responding patients, the median duration of response was more prolonged with durvalumab, as 72.8% of responses to durvalumab were ongoing at 18 months as compared with 46.8% of responses in the placebo group.

Patients in the placebo group had more than a 50% higher incidence of new lesions that developed during treatment (32.1% versus 20.4% of patients in the durvalumab arm). New lesions in the brain (11.0% versus 5.5%), lung (17.3% versus 11.8%), and lymph nodes (11.4% versus 5.7%) accounted for most of the difference between treatment groups.

Overall, the adverse event rates were similar between treatment groups. Grade 3/4 adverse events occurred in 29.9% of patients in the durvalumab group versus 26.1% in the placebo group. Grade 5 (fatal) events occurred in 4.4% and 5.6% of the durvalumab and placebo arms. Rates of discontinuation because of adverse events were 15.4% with durvalumab and 9.8% with placebo.

Immune-mediated adverse events occurred substantially more often in the durvalumab arm (24.2% versus 8.1%), but rates of grade 3/4 immune-mediated adverse events were similar between the treatment groups (3.4% and 2.6% with durvalumab and placebo, respectively).

"These positive findings in an unselected patient population, irrespective of baseline expression of PD-L1 on tumor cells, suggest that durvalumab may be an effective adjuvant therapy in patients with stage III disease after standard treatment," Paz-Ares and co-authors concluded in the journal article. "Uncertainty about the potential mechanisms driving the interaction between immunotherapy and chemoradiotherapy warrants further investigation."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined Ƶ in 2007.

Disclosures

The study was supported by AstraZeneca.

Paz-Ares disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Roche, Lilly, Boehringer Ingelheim, Novartis, and Ariad.

Primary Source

European Society for Medical Oncology

Paz-Ares L, et al "PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy in patients with stage III, locally advanced, unresectable NSCLC" ESMO 2017; Abstract LBA1.