Durvalumab Shows Activity in Heavily Pretreated Patients With Non–Small Cell Lung Cancer


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The immune checkpoint inhibitor durvalumab (also known as MEDI4736) is active and achieves durable responses in patients with heavily pretreated advanced non–small cell lung cancer (NSCLC) that does not have any epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations, finds the phase II ATLANTIC trial.1

Trial results, reported for the first time in a plenary session and related press conference, showed that the overall response rate to single-agent durvalumab—an investigational antibody to the programmed cell death ligand 1 (PD-L1)—rose with the tumor’s level of positivity for that ligand, to nearly 31%. About half of patients with positive tumors were still alive at 1 year.

Data additionally showed that immune-mediated adverse events, predominantly hypothyroidism, occurred in up to one-fifth of patients but were readily manageable.


In this heavily pretreated population, durvalumab was active and showed long-lasting responses.
— Marina C. Garassino, MD

“In this heavily pretreated population, durvalumab was active and showed long-lasting responses,” summarized first author Marina C. Garassino, MD, Medical Director of the IRCCS Istituto Nazionale dei Tumori Foundation, in Milan, Italy. “Durvalumab was very well tolerated.”

The efficacy findings are especially noteworthy given that the patients were being treated in the third- or later-line setting, she maintained. “These kinds of patients in reality have a very poor prognosis. They are the typical patients for best supportive care, and they have a median survival time of 2 or 3 months.”

“Results are consistent with other anti–programmed cell death protein 1 (PD-1) and anti–PD-L1 compounds in metastatic NSCLC. We are awaiting the final results of several phase III trials … to clarify the role of durvalumab alone or in combination in NSCLC,” Dr. Garassino concluded. These studies include the MYSTIC and NEPTUNE trials (first-line durvalumab plus the immune checkpoint inhibitor tremelimumab [also known as CP-675,206] vs standard of care in metastatic NSCLC), the ARCTIC trial (third-line durvalumab plus tremelimumab vs standard of care in metastatic NSCLC), and the PACIFIC trial (durvalumab monotherapy after chemoradiation therapy in stage III NSCLC).

Study Details

Patients enrolled in the ATLANTIC trial had locally advanced or metastatic NSCLC and had received at least two prior lines of therapy. They were treated with intravenous durvalumab on an open-label basis every 2 weeks for up to a year.

Initially, patients were eligible for the trial regardless of level of PD-L1 tumor positivity by immunohistochemistry, but the protocol was amended partway through, so only those with high levels were eligible.

Results by Trial Cohorts

Dr. Garassino reported results for the two trial cohorts having EGFR and ALK wild-type tumors, which are known to have a better response to immune checkpoint inhibitors. Cohort 2 had 265 patients with a varied PD-L1 status; high expression in this cohort was defined using a cutoff of ≥ 25% of tumor cells positive. Cohort 3 had 68 patients, all of whom had high PD-L1 expression, in this case defined using a cutoff of ≥ 90% of tumor cells positive.

Results showed that in cohort 2, the overall response rate (the trial’s primary endpoint) was 7.5% among patients whose tumors had low or negative PD-L1 expression and 16.4% among patients whose tumors had high expression, Dr. Garassino reported. The median duration of response was not reached and 12.3 months, respectively.

The median duration of progression-free survival was 1.9 in patients whose tumors had low or negative PD-L1 expression and 3.3 months in patients whose tumors had high expression. The corresponding median duration of overall survival was 9.3 and 10.9 months, with 1-year overall survival rates of 34.5% and 47.7%.

Durvalumab as Third- or Later-Line Therapy for NSCLC

  • A phase II, single-arm trial among 333 patients with EGFR/ALK wild-type NSCLC in the third or later line of therapy found that the overall response rate was 16.4% and 30.9% in patients with ≥ 25% and ≥ 90% of tumor cells positive for PD-L1, respectively.
  • Corresponding rates of 1-year overall survival were 47.7% and 50.8%.
  • Immune-mediated adverse events, predominantly hypothyroidism, occurred in 10.2% and 20.6% of patients.

The response rate was consistent across patients stratified by various characteristics. “The benefit goes across all the subgroups. It is independent of the line of treatment, and of note, it is present also for patients with central nervous system metastases,” Dr. Garassino noted.

The rate of treatment-related adverse events in cohort 2 overall was 59.2%, and the rate of grade 3 or worse treatment-related adverse events was 8.3%. Immune-mediated adverse events were seen in 10.2% of patients; hypothyroidism accounted for the largest share of cases, and pneumonitis was rare.

Cohort 3 had an overall response rate of 30.9%, and the median duration of response was not reached. The median duration of progression-free survival was 2.4 months, and the median duration of overall survival was not reached. The 1-year rate of overall survival was 50.8%.

In this cohort, the rate of treatment-related adverse events was 67.6%, and the rate of grade 3 or worse treatment-related adverse events was 17.6%. Immune-mediated adverse events were seen in 20.6% of patients; again, hypothyroidism predominated.

It is unclear exactly why the rate of immune-mediated adverse events was twice as high in cohort 3, according to Dr. Garassino. “One idea can be that these patients have not yet reached the median overall survival, and they have been on treatment for a long time,” she proposed.

“These results are not controlled, and there is obviously the bias of selection in this kind of population,” she acknowledged, discussing the trial’s limitations. ■

Disclosure: Marina C. Garassino, MD, has received research support from Pfizer and is a consultant for AstraZeneca, Bristol-Myers Squibb, Celgene, Roche, Merck Sharp & Dohme, and Eli Lilly.

Reference

1. Garassino MC, Vansteenkiste JF, Kim J, et al: Durvalumab in ≥ 3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: Results from the phase 2 ATLANTIC study. 2016 World Conference on Lung Cancer. Abstract PL04a.03. Presented December 7, 2016.


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“Taken together, ATLANTIC’s findings show that “durvalumab is active in heavily pretreated patients, and its degree of activity is related to programmed cell...


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