BioPharma, Pharma

AstraZeneca looks to salvage data from negative Imfinzi lung cancer study

The company pointed to better survival numbers in patients with high tumor mutational burden, in a presentation at the ESMO immuno-oncology congress in Geneva.

British drugmaker AstraZeneca is doing a deep dive into data from an immunotherapy study in lung cancer whose negative results were announced last month and said it has found a subset of patients who show improved survival.

The London-based company said Thursday that Imfinzi (durvalumab) demonstrated clinical activity in previously untreated metastatic non-small cell lung cancer. The analysis, from the Phase III MYSTIC study, was presented at the European Society for Medical Oncology’s Immuno-Oncology 2018 Congress in Geneva.

Imfinzi is a PD-L1 checkpoint inhibitor with accelerated Food and Drug Administration approval for urothelial carcinoma. The drug is being combined in several trials, including MYSTIC, with tremelimumab, a CTLA4 inhibitor.

The company said Nov. 16 that data from MYSTIC – which compared Imfinzi alone or combined with tremelimumab against standard-of-care platinum-based chemotherapy – failed to show improved overall survival for the monotherapy or the combination. However, while Imfinzi by itself did not improve survival, it showed a better hazard ratio of 0.76, compared with 0.85 for the combination. The Imfinzi monotherapy arm’s smaller hazard ratio means it showed a greater difference in survival versus the chemotherapy arm than the two-drug combination did.

The company said at the time that the favorable hazard ratio warranted further subgroup analysis.

The company said Thursday that Imfinzi monotherapy showed clinical activity, given the survival hazard ratio, in the primary analysis population of patients whose tumors express the PD-L1 protein on at least 25 percent of cancer cells, but the result was not statistically significant. Although the p value – a measure of statistical significance – was 0.036, below the 0.05 threshold normally used, MYSTIC’s design put the respective p-value thresholds for Imfinzi monotherapy and the two-drug combination at no greater than 0.0246 and no greater than 0.0123.

At the same time, after two years of follow-up, the percentage of patients still alive was 38.3 percent among those receiving Imfinzi monotherapy, versus 22.7 percent of those on chemotherapy. This was also the case among the 39.5 percent of chemotherapy patients who received subsequent immunotherapy treatment.

The latest data also included a prespecified exploratory analysis of what the company called a novel biomarker, blood tumor mutational burden, or bTMB. Patients who had high bTMB – meaning 16 mutations or more per megabase – showed better overall survival when treated with Imfinzi by itself and Imfinzi plus tremelimumab. Among those patients, there was a 38 percent reduction in risk of death compared with chemotherapy, while the monotherapy had an overall survival hazard ratio of 0.8 compared with chemotherapy.

“We are eager to continue following the science to fully understand the role of both PD-L1 and TMB as biomarkers to help select patients that may benefit from our immuno-oncology medicines, AstraZeneca head of immuno-oncology in global medicines development Hesham Abdullah said in a statement. “We are encouraged to see that Imfinzi monotherapy activity is consistent with the anti-PD-1 class in previously untreated patients with [metastatic NSCLC.”

Currently, the only checkpoint inhibitor approved for first-line NSCLC is Merck & Co.’s PD-1 inhibitor, Keytruda (pembrolizumab). Meanwhile, Bristol-Myers Squibb has an anti-CTLA4 drug on the market, Yervoy (ipilimumab), though it is not approved for NSCLC. First-line NSCLC represents a significant market, with lung cancers generally accounting for 14 percent of new cancers overall, and NSCLC constituting 80-85 percent of those. A positive result for MYSTIC, presuming it led to regulatory approval, would have made it a significant competitor against Keytruda in that space, particularly if it could be combined with tremelimumab.

AstraZeneca’s Imfinzi program suffered another setback last week when an analysis of the Phase III EAGLE study – comparing Imfinzi with or without tremelimumab against standard-of-care in head and neck cancer patients previously treated with platinum-based chemotherapy – also did not show an overall survival improvement. Those results leave Keytruda and Bristol-Myers Squibb’s PD-1 inhibitor, Opdivo (nivolumab), as the dominant players in that setting.

Photo: nopparit, Getty Images

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