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Durvalumab alone, with tremelimumab does not improve lung cancer survival

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Naiyer Rizvi

Durvalumab alone and combined with tremelimumab failed to improve OS as first-line immunotherapy in unselected patients with metastatic non-small cell lung cancer, according to late-breaking results from the MYSTIC trial presented at ESMO Immuno-Oncology Congress.

“Immunotherapy has rapidly become a first-line treatment option in NSCLC, as shown in the 2018 ESMO Clinical Practice Guidelines for metastatic disease,” Pilar Garrido, MD, head of the thoracic tumor section in the medical oncology department at Ramón y Cajal University Hospital in Madrid, said in a press release. “The ESMO Immuno-Oncology Congress showcases cutting-edge developments in this fast-moving field, such as the highly anticipated MYSTIC trial.”

Although the use of immune checkpoint inhibitors combined with chemotherapy has been successfully evaluated in various trials as a first-line treatment for metastatic NSCLC, data are lacking on the use of two immune checkpoint inhibitors without chemotherapy.

“Some patients are worried about the side effects of chemotherapy and prefer to delay it,” Garrido, who was not involved in the study, said. “Avoiding the use of chemotherapy in the first-line setting also leaves an effective rescue option when immunotherapy fails.”

In the MYSTIC trial, Naiyer Rizvi, MD, director of thoracic oncology and immunotherapeutics at Columbia University Medical Center, and colleagues evaluated 1,118 patients with metastatic NSCLC randomly assigned 1:1:1 to receive 20 mg/kg IV durvalumab (Imfinzi, AstraZeneca) alone every 4 weeks, 20 mg/kg durvalumab combined with up to four doses of 1 mg/kg IV tremelimumab (CP-675,206, AstraZeneca) every 4 weeks, or six cycles of chemotherapy.

OS for durvalumab alone vs. chemotherapy, and OS and PFS for durvalumab-tremelimumab vs. chemotherapy among patients whose tumor cells demonstrated 25% or greater PD-L1 expression — based on the Ventana PD-L1 (SP142) assay (Roche) — served as the study’s primary endpoints.

Overall, 488 patients (44%) had PD-L1 expression of 25% or greater.

Median OS did not improve among patients who received durvalumab alone (16.3 months vs. 12.9 months; HR = 0.76; 97.54% CI, 0.56, 1.01) or with tremelimumab (11.9 months vs. 12.9 months; HR = 0.85; 98.77% CI, 0.61-1.17) compared with patients who received chemotherapy.

“While not reaching statistical significance, durvalumab monotherapy gave a clinically meaningful median OS improvement of 16.3 months compared to 12.9 months in patients with 25% or greater PD-L1 expression,” Rizvi said in the press release.

Patients assigned durvalumab-tremelimumab had median PFS of 3.9 months, compared with 5.4 months among those assigned chemotherapy (HR = 1.05; 99.5% CI. 0.72-1.53).

A total of 39.5% of patients in the chemotherapy group received immunotherapy after cessation, vs. 6.1% of patients in the durvalumab monotherapy group and 3.1% of patients in the durvalumab-tremelimumab group.

Researchers observed grade 3 to grade 4 treatment-associated adverse events among 14.6% of patients in the durvalumab monotherapy group, 22.1% in the durvalumab-tremelimumab group, and 33.8% in the chemotherapy group.

In an exploratory analysis, researchers evaluated survival in relation to high or low tumor mutational burden (TMB) in the blood, for which they defined high TMB as 16 or more mutations per megabase, and low TMB as fewer than 16 mutations per megabase.

Of the more than 70% of patients with TMB data, 40% had high TMB.
-TMB patients, those assigned durvalumab plus tremelimumab show a median OS of 16.5 months, whereas those assigned chemotherapy showed a median OS of 10.5 months (HR = 0.64), and those assigned durvalumab monotherapy had a median OS of 11 months.

At 2 years, 39% of the high-TMB patients on durvalumab-tremelimumab were still alive, compared with 30% of those in the durvalumab group and 18% of those in the chemotherapy group.
Conversely, among the low-TMB patients, researchers observed a median OS of 8.5 months among patients in the durvalumab-tremelimumab group, compared with 12.2 months in the durvalumab monotherapy group and 11. 6 months in the chemotherapy group.

“This analysis shows that appropriate biomarkers are needed to select the patients most likely to benefit from combination therapy in first line,” Garrido said. “The challenge now is to prospectively validate them prior to implementation in clinical practice.” – by Jennifer Byrne

Reference:

Rizvi N, et al. Abstract LBA6. Presented at: ESMO Immuno-Oncology Congress; Dec. 13-16, 2018; Geneva, Switzerland.

Disclosures : Rizvi reports advisory board roles with AbbVie, AstraZeneca, Bellicum Pharmaceuticals, Bristol-Myers Squibb, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Gritstone, Janssen, Merck, NeoGenomics Laboratories, Novartis, OncoMed Pharmaceuticals, Pfizer and Regeneron; equity in ARMO, Bellicum Pharmaceuticals, Gritstone and OncoMed Pharmaceuticals; and royalties from PGDX. Please see the abstract for all other authors’ relevant financial disclosures. HemOnc Today could not confirm Garrido’s disclosures at the time of reporting.