Durvalumab Shows Overall Survival Benefit in Patients With Stage III NSCLC

Favorable initial progression-free survival (PFS) data on the drug durvalumab were validated in a phase 3 trial of the medication, and an added overall survival (OS) benefit was reported.

The outlook is good for AstraZeneca in the treatment of lung cancer, as study results unveiled by the company on September 25 showed that its checkpoint inhibitor durvalumab prolonged survival significantly compared with placebo in patients with stage III unresectable non-small cell cancer (stratified hazard ratio for death, 0.68; 99.73% CI, 0.47-0.997; P =.0025).¹

In addition to an overall survival (OS) benefit, data from the patient trial presented Tuesday at the IASLC’s 19th World Conference on Lung Cancer in Toronto, Canada, also showed that the progression-free survival (PFS) benefit — first announced in 2017 — had persisted in patients enrolled in the phase 3 trial. PFS was 17.2 months in the durvalumab group and 5.6 months in the placebo group. PFS was assessed on the basis of blinded independent central review.

In a 2:1 ratio, study investigators randomly assigned patients to receive durvalumab or placebo 10 mg/kg of body weight intravenously every 2 weeks for up to 12 months after concurrent chemoradiation. In total, 473 patients received durvalumab and 236 received placebo. Patients were required to finish their last dose of radiation therapy within 5 to 10 days prior to randomization.

At 24 months, the OS rate was 66.3% (vs 55.6% for placebo; 2-sided P =.005). The results of the study demonstrated that durvalumab can extend life. The median time to death or distant metastasis was 28.4 months with durvalumab compared with 16.2 months with placebo.

In addition, there were no new safety signals discovered as a result of treatment. More patients in the durvalumab group experienced grade 3 or grade 4 adverse events of any cause compared with the placebo group (30.5% compared with 26.1%, respectively).

Although the results of the trial are striking, when the PFS data were first released, investigators from the CHI Health St. Francis Cancer Treatment Center, Grand Island, Nebraska, questioned how patient staging was performed and whether patients were evaluated for “bronchoscopy or mediastinoscopy, positron-emission tomography-computed tomography, pathological evaluation of mediastinal lymph nodes, and magnetic resonance imaging of the brain” prior to being treated, as is suggested by national treatment guidelines.²

The investigators responded to the concern, saying at the time that their methods were robust enough that their calculated efficacy differences would likely remain valid even if they had included patients with occult stage IV disease in their analysis; however, they also acknowledged that definitions of staging can be tricky: “Global patterns do indeed vary regarding screening procedures to ascertain stage III disease,” the authors of the 2017 study wrote in a letter back to the concerned parties.³

In sum, the researchers concluded in The New England Journal of Medicine, “With the between-group difference in median progression-free survival remaining more than 11 months, the results of the analysis of overall survival indicate that the progression-free survival benefit has translated to a significant prolongation in overall survival.”¹

“The significant improvements in not only progression-free survival, but also overall survival, signal a true paradigm shift away from conventional chemotherapy and more towards the adoption of immunotherapy,” said Andrew Song, MD, resident physician in the department of radiation oncology at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. “Durvalumab was quickly adopted as a new standard of care for adjuvant therapy in stage III NSCLC per the updated NCCN guidelines of 2018, and now the updated analysis confirms the benefits for this line of management. One of the big questions that remains to be answered is how to harness the maximum benefits from immunotherapy, namely the timing of the administration of immunotherapy, especially in respect to radiation therapy, due to the known antitumor immunity that is induced by radiation. Further investigation for the possible roles of concurrent and/or neoadjuvant immunotherapy in the setting of unresectable stage III NSCLC is warranted.”

Read more of Cancer Therapy Advisor‘s coverage of the IASLC 2018 meeting by visiting the conference page.

Editor’s note: This article was updated to include a comment from Dr Song.

References

1. Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1809697.
2. Copur MS, Gauchan D, Ramaekers R. Durvalumab in stage III non-small-cell lung cancer [letter]. N Engl J Med. 2018;378(9):868-870.
3. Antonia SJ, Özgüroğlu M. Durvalumab in stage III non-small-cell lung cancer [letter]. N Engl J Med. 2018;378(9):868-870.