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Combination Immunotherapy, Third-Generation TKI Improve Survival in Advanced Lung Cancer

BARCELONA – Researchers at the annual meeting of the European Society for Medical Oncology in Barcelona on Saturday presented new results from two trials that indicated advanced non-small cell lung cancer (NSCLC) patients would benefit from treatment with a combination of nivolumab and ipilimumab (Bristol-Myers Squibb's Opdivo and Yervoy), or the third-generation EGFR-tyrosine kinase inhibitor osimertinib (AstraZeneca's Tagrisso).

Solange Peters, from the Centre Hospitalier Universitaire Vaudois in Switzerland, presented the final results of part one of the CheckMate-227 study, a phase III study looking at the efficacy of nivolumab and ipilimumab in advanced NSCLC patients. The study analyzed progression-free survival (PFS) in patients with a tumor mutational burden (TMB) of 10 or more mutations per megabase as its primary endpoint — in 2018, the company shared data from CheckMate-227 demonstrating that the drug combination resulted in significantly better progression-free survival for patients with a high TMB.

This year, the researchers presented data on the trial's secondary endpoint, overall survival (OS) in patients with tumor PD-L1 expression of 1 percent or more.

The 1,189 patients in the trial with PD-L1 of 1 percent or more were chemo-naive, with stage IV or recurrent NSCLC without EGFR or known ALK alterations. They were randomized to receive either nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The 550 patients in the trial with PD-L1 of less than 1 percent were randomized to receive either nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

They found that for patients with PD-L1 of 1 percent or more, OS was significantly longer with nivolumab plus ipilimumab compared to chemotherapy. PFS, objective response rates, and duration of response also favored the drug combination, Peters reported. Improved OS was also observed in patients with PD-L1 of less than 1 percent and in all randomized patients.

In the patients with PD-L1 expression of 1 percent or more, median OS in the combination group was 17.1 months compared to 15.7 months for nivolumab alone and 14.9 month with chemotherapy. This was statistically and clinically significant, Peters noted, adding that almost half the patients in the chemotherapy arm eventually crossed over to the combination regimen. Median PFS was 5.1 months, 4.2 months, and 5.6 months, respectively. And the median duration of response was 142 months, 109 months, and 119 months, respectively.

In the patients with PD-L1 expression of less than 1 percent, median OS in the combination group was 17.2 months compared to 15.2 months for nivolumab plus chemotherapy, and 12.2 months for chemotherapy alone. And in the randomized patient group, median OS was 17.1 months for the combination therapy and 13.9 months for chemotherapy.

Peters noted that these results prove the utility of adding an anti-CTLA4 treatment to an anti-PD-L1 therapy in NSCLC, and that the combination regimen presents a new front-line option for these patients, including those who are unselected by any biomarkers.

In discussing the paper, the National Cancer Institute of Milan's Marina Garassino pointed to the speed at which new treatment regimens are becoming available for NSCLC patients. Three years ago at ESMO, the discussion was centered around how to select patients for treatment, she said. Last year, researchers were talking about adding immunotherapy to chemotherapy. Now, the discussion is about combining multiple immunotherapies. The promise of CheckMate-227 is to provide patients with a chemotherapy-sparing regimen that creates long-lasting response.

However, she also noted that the key in treating advanced NSCLC patients effectively is in understanding which patients to treat with which regimen. Researchers will need some time "to understand the right treatment algorithms," Garassino said.

Suresh Ramalingam of the Winship Cancer Institute of Emory University then presented final OS results from the phase III FLAURA trial, a study of osimertinib in EGFR-mutated advanced NSCLC compared to first-generation EGFR-TKIs gefitinib (AstraZeneca's Iressa) and erlotinib (Roche's Tarceva).

The researchers assigned 279 patients to osimertinib and 277 patients to the comparator EGFR-TKIs. About 25 percent of the patients in the comparator arms eventually crossed over to the osimertinib arm, Ramalingam said. The study showed that osimertinib provided a statistically significant and clinically meaningful improvement in OS compared to the first-generation TKIs in patients with EGFR-mutated advanced NSCLC.

Median OS was 38.6 months for the osimertinib group compared to 31.8 months for the other EGFR-TKIs. The 12-month survival rate was 89 percent compared to 83 percent, respectively, while the 24-month survival rates were 74 percent and 59 percent. The 36-month survival rates were 54 percent and 44 percent, respectively.

Importantly, Ramalingam noted, osimertinib has better penetration to the brain, and has the ability to produce a response in 70 percent to 90 percent of brain metastases. Further, the drug blocks the T790m pathway, which is the most common resistance pathway. Osimertinib is also the first TKI to show improvement in OS over other TKIs, he added.

Ramalingam emphasized that these results reinforce the use of osimertinib as a first-line treatment in EGFR-mutated NSCLC. "You can either give the best treatment first or roll the dice," he said, adding that two out of three advanced NSCLC patients don't live long enough to try a second-line treatment.

Pilar Garrido, an associate professor of medical oncology at Universidad de Alcalá in Madrid, noted that EGFR mutation rates vary in different populations, so the relevance of the FLAURA results could vary depending on the patient population being treated.

However, she added, the OS results from the study were statistically significant and clinically relevant, and clinicians need to make sure that all NSCLC patients are tested for EGFR and offer TKIs to patients as the best first-line treatment.