Dual disappointments from the challenging field of advanced lung cancer announced Friday highlighted continuing challenges in addressing the disease, still the leading cause of cancer death in the U.S. despite substantial progress. Astrazeneca plc and its biologics arm Medimmune reported that, for people with metastatic non-small-cell lung cancer (NSCLC), neither the anti-PD-L1 antibody Imfinzi (durvalumab) nor a combination of that drug with the anti-CTLA-4 candidate tremelimumab improved overall survival vs. standard-of-care chemotherapy for previously-untreated patients in the phase III Mystic trial. Astrazeneca's partner Hutchison China Meditech Ltd. (Chi-Med) also reported phase III results showing that, despite improving progression-free survival, its small-molecule inhibitor of VEGF receptors, fruquintinib, failed to improve OS for advanced NSCLC patients who had failed two lines of systemic chemotherapy.

Chi-Med investors carried the brunt of the bad news, with company shares (NASDAQ:HCM) falling $6.44, or 17.6 percent in trading that reached more than seven times its normal volume. Shares closed at $30.16 on Friday.

The Chinese market launch for fruquintinib's approved indication, advanced colorectal cancer, under the brand name Elunate is "imminent," the company said. Chi-Med's partner in commercialization, Eli Lilly and Co., is leading the push. But third-line NSCLC had been a highly anticipated area of expansion for Chi-Med, especially considering the need for lung-cancer therapies in China, where rates of the disease are high. (See BioWorld, Sept. 12, 2018.)

To build its case, the company's phase III Faluca trial randomized 527 patients with advanced non-squamous NSCLC who had failed two lines of systemic chemotherapy at a 2:1 ratio to receive either 5 mg of fruquintinib orally once per day, on a three-weeks-on/one-week-off cycle, plus best supportive care (BSC) or placebo plus BSC. But instead of supporting the expansion, Chi-Med said the trial fell short on OS.

"While the study demonstrates a significant reduction in disease progression in this challenging lung cancer patient population, we are disappointed that this benefit did not translate into an increase in overall survival," said Simon To, Chi-Med's chairman.

Despite the bad news, neither fruquintinib's nor Chi-Med's story in lung cancer is over. For starters, fruquintinib did appear safe in the study, even showing statistically significant improvements in all secondary endpoints of the trial, which included PFS, objective response rate, disease control rate and duration of response.

More importantly though, the drug is still being studied in a phase II trial in combination with Astrazeneca's Iressa (gefitinib) in patients with untreated advanced or metastatic NSCLC. Chi-Med is also moving toward anticipated readouts from combination trials of savolitinib, a mesenchymal epithelial transition factor receptor tyrosine kinase inhibitor, and Astrazeneca's Tagrisso (osimertinib) in other NSCLC settings.

Still a 'cornerstone'

Astrazeneca also faced bad news Friday, stemming from its phase III Mystic trial, a randomized, open-label study that tested Imfinzi monotherapy vs. Imfinzi plus tremelimumab in previously-untreated patients with stage IV NSCLC. Imfinzi is already approved for unresectable, stage III NSCLC in more than 40 countries and Mystic had already surfaced bad news in the metastatic setting last summer, when Astrazeneca reported PFS data from the trial. But at the time, the company had downplayed expectations the PFS data might foreshadow a missed OS endpoint. Friday's update put to bed any doubt that the measure would contrast in a surprising and positive way. (See BioWorld, July 31, 2017.)

In the primary analysis of patients whose tumors expressed PD-L1 on 25 percent or more of their cancer cells, neither the monotherapy nor the combination beat platinum-based chemotherapy on OS. But while the OS result did not meet statistical significance, a hazard ratio (HR) of 0.76 (97.54 percent CI 0.564-1.019; nominal p=0.036) was observed with Imfinzi monotherapy, the company reported. The combination therapy had an HR of 0.85 (98.77 percent CI 0.611-1.173; nominal p=0.202). The data support further analysis in exploratory subgroups, Astrazeneca said.

Sean Bohen, Astrazeneca's executive vice president of Global Medicines Development and chief medical officer, said his team was "encouraged to see that Imfinzi monotherapy activity is in line with that of the anti-PD-1 class" in the patients tested, but disappointed that the results missed statistical significance. "We remain confident in Imfinzi as the cornerstone of our I-O program," he added, noting other ongoing tests of the drug.

In metastatic lung cancer, those tests include Pearl, which is evaluating Imfinzi monotherapy vs. chemotherapy; Neptune, a study of Imfinzi plus tremelimumab vs. chemotherapy; and Poseidon, an evaluation of Imfinzi plus chemotherapy vs. Imfinzi plus tremelimumab and chemotherapy vs. chemotherapy. None of the trials are impacted by the new Mystic OS data, Astrazeneca told BioWorld.

"We continue to evaluate the efficacy of this IO-IO combination across our phase III program in a variety of tumor types and stages of disease to optimize clinical benefit," said Astrazeneca spokeswoman Mel Solomon. "We believe that a combination strategy – whether IO-IO, IO-chemotherapy, or IO-small molecule – is crucial to the future success of immuno-oncology treatment in multiple tumor types."

Astrazeneca shares (NYSE:AZN) fell 73 cents on Friday to close at $40.67.

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