Myung-Ju Ahn, MD, PhD, Professor in the Department of Hematology and Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, South Korea, said the novel regimen of sintilimab, IBI305, and chemotherapy is a promising approach in EGFR-mutated nonsquamous non–small cell lung cancer (NSCLC).

“ORIENT-31 is the first large, randomized study demonstrating improvement in progression-free survival with chemotherapy plus an anti–PD-1 antibody and an antiangiogenic agent compared with pemetrexed/cisplatin (hazard ratio [HR] = 0.464; P < .0001). Based on this study, this regimen might be a reasonable option in patients with EGFR mutations who experience disease progression on tyrosine kinase inhibitors,” Dr. Ahn said.

The efficacy of a similar four-drug regimen was shown in IMpower150, where atezolizumab plus bevacizumab and carboplatin/paclitaxel significantly improved overall survival in patients with EGFR-sensitizing mutations (HR = 0.60). This was a very small subset, so a larger randomized study was needed to confirm these findings, she explained.

“To address this important issue, the ORIENT-31 trial was conducted and showed the four-drug regimen significantly improved progression-free survival…. So far, we have two studies to evaluate the role of antiangiogenic agents with checkpoint inhibitors in EGFR-mutated NSCLC,” Dr. Ahn noted.

Myung-Ju Ahn, MD, PhD

IMpower150 vs ORIENT-31

While acknowledging the limitations in making comparisons between studies, she pointed to some differences in outcomes and study characteristics:

• IMpower150 demonstrated a higher response rate (71% vs 44%) and duration of response (11.1 months vs 8.3 months) and longer progression-free survival (10.2 months vs 6.9 months).
• The studies had different chemotherapy backbones and checkpoint inhibitors.
• ORIENT-31 included younger patients, those with brain metastases, more never-smokers, patients with T790M mutations, and more patients with EGFR-sensitizing mutations; IMpower150 lacked some of this information.
• There were more grade ≥ 3 adverse events and treatment discontinuations in IMpower150.

Dr. Ahn further pointed out that ORIENT-31 may have been a more heavily pretreated and sicker population, since 35% had brain metastases and 30% had received treatment with first-, second-, and third-generation tyrosine kinase inhibitors. The somewhat worse outcomes might be attributed to this, she proposed.

“The progression-free survival benefit regardless of brain metastases is quite promising,” she added, though further evaluation of intracranial response and disease progression is needed.

Still to Come

Still to be determined are the overall survival benefit of the ­ORIENT-31 regimen, greater evidence of benefit in patients with T790M mutations previously treated with a third-generation agent, long-term duration of response (currently short for a four-drug regimen), efficacy of the four drugs vs sintilimab/chemotherapy, biomarkers of potential benefit, and long-term safety, considering maintenance is given for 20 months. “Finally,” she added, “cost is another issue to be discussed.”

The phase III ATLAS trial and the phase II GFPC 06-2018 trial are currently evaluating atezolizumab/bevacizumab plus chemotherapy (carboplatin/paclitaxel, pemetrexed/platinum, carboplatin/pemetrexed) in EGFR-mutated NSCLC after failure on tyrosine kinase inhibitors. 

DISCLOSURE: Dr. Ahn has served as an advisor or consultant to and received honoraria from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Merck, MSD, Ono, Roche, Takeda, and Alpha Pharmaceuticals.