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Immunotherapy Combo Flops in Metastatic NSCLC

<ѻý class="mpt-content-deck">— Durvalumab plus tremelimumab failed to improve survival versus chemotherapy
MedpageToday

An immunotherapy combination failed to improve survival versus chemotherapy as initial treatment for patients with metastatic non-small cell lung cancer (NSCLC), results of a randomized trial showed.

Patients had a median overall survival of 11.9 months with the PD-1 inhibitor durvalumab (Imfinzi) plus the CTLA-4 inhibitor tremelimumab versus 12.9 months for chemotherapy-treated patients with PD-L1 positive tumors. Single-agent durvalumab led to a median overall survival of 16.3 months. Although "clinically meaningful," the difference in favor of durvalumab monotherapy did not achieve statistical significance, Naiyer Rizvi, MD, of Columbia University Medical Center in New York, reported at the Congress in Geneva, Switzerland.

An exploratory analysis of patients whose tumors had a high tumor mutational burden (TMB), a potential marker of susceptibility to immunotherapy, showed a 6-month improvement in survival with durvalumab versus chemotherapy.

"The results of the exploratory analysis need to be validated in a future trial," Rizvi said in a statement. "TMB is measured with a simple blood test and might be an easy way to select patients for this treatment."

The results are disappointing, as lung cancer specialists have pinned a lot of hopes on immunotherapy as a better-tolerated and more effective alternative to chemotherapy for patients with metastatic disease, said Hossein Borghaei, DO, of Fox Chase Cancer Center in Philadelphia. The results in the subset of patients with high TMB cannot be accepted as valid until they have been corroborated in a separate clinical trial evaluating that specific patient population.

"This is more frustrating than anything else, because I thought we could have come up with chemotherapy-sparing drugs that can be at least as effective -- and I was hoping more effective -- than standard chemotherapy," Borghaei told ѻý. "This trial doesn't support that kind of approach, at least in an unselected patient population."

Even in the patients selected by PD-L1 expression, durvalumab alone or combined with tremelimumab didn't meet criteria for statistical significance, he acknowledged.

With regard to the TMB analysis, Borghaei said cancer specialists are "starting to pay more attention to this" with respect to the use of immunotherapy, but TMB has yet to reach standard-of-care status.

Earlier this year the FDA approved durvalumab as initial therapy for unresectable stage III NSCLC, following results from the PACIFIC trial showing improved progression-free survival (PFS) versus chemotherapy. An updated analysis showed the PD-1 inhibitor also improved overall survival.

Rizvi reported findings from the randomized, phase III MYSTIC trial, which evaluated durvalumab alone or in combination with tremelimumab versus platinum-based chemotherapy as initial treatment for metastatic (stage IV) NSCLC.

MYSTIC included 1,118 patients, who were randomized to three treatment groups: durvalumab alone, durvalumab plus tremelimumab, or platinum-based chemotherapy. The trial had a primary endpoint of overall survival versus chemotherapy in patients with tumors exhibiting ≥25% PD-L1 expression (N=488).

The primary analysis showed that the immunotherapy combination did not improve survival as compared with chemotherapy (HR 0.85, 98.77% CI 0.611-1.73, P=0.202). The 3.4-month difference in survival observed with single-agent durvalumab did not meet prespecified criteria for statistical significance (HR 0.76, 97.54% CI 0.54-1.019, P=0.036). Median progression-free survival with the combination was also no better than the PFS of patients in the chemotherapy arm (3.9 vs 5.4 months, HR 1.05, 99.5% CI 0.722-1.534, P=o.705).

The exploratory analysis of survival by TMB used a mutation count of ≥16 to define high TMB. The analysis showed that patients with high TMB had a median overall survival of 16.5 months with the immunotherapy combination versus 10.5 months with chemotherapy and 11.0 months with durvalumab alone. Additionally, 39% of the combination arm and 30% of patients treated with single-agent durvalumab remained alive at 2 years, as compared with 18% of the TMB subgroup treated with chemotherapy. Patients with low TMB had a median overall survival of 8.5 months with the combination, 12.2 months with durvalumab monotherapy, and 11.6 months with chemotherapy.

Though exploratory in nature, data from the TMB analysis supported findings from CheckMate 227 trial of nivolumab (Opdivo) and ipilimumab (Yervoy), which showed better PFS with an immunotherapy combination in patients whose tumors had high TMB, Rizvi noted.

  • author['full_name']

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

Disclosures

The study was supported by AstraZeneca.

Rizvi disclosed relationships with AbbVie, AstraZeneca, Bristol-Myers Squibb, Merck Serono, Genentech, GlaxoSmithKline, Janssen, Lilly, Merck, Novartis, Pfizer, Regeneron, Neogenomics, Oncomed, Gritstone, Bellicum, ARMO, and PGDX.

Primary Source

ESMO Immuno-Oncology Congress

Rizvi NA, et al "Durvalumab with or withing tremelimumab vs platinum-based chemotherapy as first-line treatment for metastatic non-small cell lung cancer: MYSTIC" ESMO Immuno-Oncology 2018; Abstract LBA6.