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Adding Chemo to AstraZeneca's Tagrisso Delayed Progression but Worsened Toxicities, Study Finds

Lung Cancer

NEW YORK – For patients with EGFR-mutant advanced non-small cell lung cancer, adding chemotherapy to AstraZeneca's EGFR inhibitor Tagrisso (osimertinib) improved progression-free survival more than Tagrisso alone, researchers reported Monday at the International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC).

While Tagrisso is already approved in the US as first-line treatment for advanced, EGFR-mutated NSCLC patients, most patients do experience disease recurrence, begging the question as to whether treatment combinations — including with established chemotherapy agents — might prolong benefit.

Pasi Janne, the director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, presented results from the Phase III FLAURA2 trial, in which 551 patients with stage IIIB to IV, EGFR-mutated NSCLC randomly received either Tagrisso or Tagrisso with pemetrexed and platinum-based chemotherapy followed by maintenance treatment with Tagrisso and pemetrexed.

In both arms, around 40 percent of patients had central nervous system metastases. In terms of biomarker status, 61 percent of those in the combination treatment arm and 60 percent of patients on just Tagrisso had EGFR exon 19 deletions, and 38 percent of patients in both arms had EGFR L858R mutations.

The median progression-free survival for patients in the combination arm was 25.5 months versus 16.7 months in the Tagrisso monotherapy arm. This benefit translated to a 38 percent reduction in the risk of disease progression or death with the addition of chemo.

"Based on these findings, we would conclude that osimertinib plus platinum-pemetrexed offers a new first-line treatment option for patients with advanced, EGFR-mutant non-small cell lung cancer," Janne said.

The progression-free survival benefit with the addition of chemo was consistently observed across all patient subgroups, including sex, race, EGFR mutation type and testing method, age, smoking history, and central nervous system metastasis status.

When researchers focused just on the patients who had central nervous system metastases, the median progression-free survival was 24.9 months with Tagrisso-chemo versus 13.8 months with Tagrisso. Among patients without central nervous system metastases, the median progression-free survival was 27.6 months on the combo versus 21 months on the monotherapy.

Broken down by EGFR mutation type, Janne shared that patients on the combination who had exon 19 deletions lived for a median of 27.9 months without their cancers recurring versus 19.4 months on the monotherapy. Patients with EGFR L858R mutations lived for a median of 24.7 months and 13.9 months without cancer progression on Tagrisso-chemo and Tagrisso, respectively.

Although overall survival data were not mature when Janne presented the FLAURA2 results, he noted that there is a trend suggesting that overall survival may not be significantly different between the two arms. He added, however, that the majority of patients who progressed on the Tagrisso monotherapy arm went on to receive chemotherapy afterward, so a crossover effect could be at play.

The objective response rate was 83 percent among patients who received Tagrisso-chemo and 76 percent for those on the monotherapy. 

Although pairing Tagrisso with chemo improved progression-free survival, it also added toxicities. Patients who received the combination regimen experienced more frequent and severe side effects, including neutropenia, thrombocytopenia, and anemia.

"Most of the common adverse events that were found in the combination were related to chemotherapy toxicities," Janne noted, pointing out that there were no grade 4 adverse events in the Tagrisso monotherapy arm. Moreover, since patients experienced toxicities that oncologists often encounter in patients receiving these chemo agents, Janne said investigators were able to manage these adverse events as they do in standard medical practice.

In a discussion of the FLAURA2 data following Janne's presentation, Yi-Long Wu, a professor of oncology at the Guangdong Provincial People's Hospital in China, called the results "very exciting," particularly the greater degree of progression-free survival benefit seen among patients with central nervous system metastases. Still, Wu questioned whether the benefit is enough to outweigh the added risks.

The incidence of any adverse event of grade 3 or higher increased from 11 percent in the monotherapy arm to 54 percent in the combination arm, he pointed out. The incidence of any serious adverse event increased from 5 percent to 19 percent, respectively.

"The data show that longer progression-free survival benefit comes at a cost of higher toxicity," Wu said.

Wu shared that when the Chinese Thoracic Oncology Group (CTONG) surveyed 71 physicians about which treatment they'd choose in light of data showing a 10-month progression-free survival benefit with Tagrisso-chemo versus Tagrisso monotherapy, 84.5 percent still chose monotherapy versus the combination. Most indicated they would want to see a longer benefit on the combination treatment — 18 months or more — before they'd favor it.

When CTONG surveyed patients and their families, most said they'd also choose the single agent versus the combination regimen despite a 10-month progression-free survival benefit. Fifty-seven percent of patients and their families said they would want to see a progression-free survival improvement longer than 24 months before choosing the combination.

"This is a signal that physicians say the chemo is tolerable, but most patients do not tolerate chemotherapy psychologically," Wu said.

Ultimately, Wu underscored that the clinical use of Tagrisso-chemo in this first-line treatment setting will need to be supported not only by clinical data but also by patients. "Should FLAURA2 [make Tagrisso-chemo] standard-of-care for EGFR-mutant advanced non-small cell lung cancer in the first-line setting? I would say not yet," Wu said, with the caveat that the combination should at least be an option, particularly for patients with central nervous system metastases.

He added that the field needs to continue to explore Tagrisso combinations with more efficacy and convenience and less toxicity. Wu mentioned several clinical trials evaluating Tagrisso with agents like Genentech's anti-angiogenic drug Avastin (bevacizumab) and AstraZeneca's MET inhibitor savolitinib. There's also a question as to whether Tagrisso might be combined with an antibody-drug conjugate.

Beyond the progression-free survival results presented Monday, Janne said his team is now evaluating patient-reported outcomes and assessing resistance mechanisms via circulating tumor DNA analysis within FLAURA2.

AstraZeneca, meanwhile, referred to the FLAURA2 results as compelling evidence of a "new benchmark for progression-free survival" in this treatment setting. "We look forward to bringing this potential treatment regimen to patients with advanced lung cancer to further delay disease progression, especially for patients with the greatest unmet need including those with central nervous system metastasis at diagnosis," Susan Galbraith, AstraZeneca's executive VP of oncology R&D, said in a statement on Monday.