The sustained overall survival benefit with durvalumab and significant disease-free survival benefit benefit with osimertinib in the adjuvant setting represent major advances in the field of non–small cell lung cancer, fueling research with each modality in localized settings.
The sustained overall survival benefit with durvalumab (Imfinzi) and significant disease-free survival benefit (DFS) benefit with osimertinib (Tagrisso) in the adjuvant setting represent major advances in the field of non–small cell lung cancer (NSCLC), fueling research with each modality in localized settings.
In unresectable stage III disease, a dearth of progress had been made prior to the read out of the phase 3 PACIFIC trial, said Zosia Piotrowska, MD, MHS. In the study, patients who had not progressed on definitive platinum-based chemoradiation were randomized 2:1 to 10 mg/kg of durvalumab every 2 weeks for up to 1 year (n = 476) or placebo (n = 237).
Four-year follow-up data from the study presented at the 2020 ESMO Congress confirmed the OS and progression-free survival (PFS) advantage durvalumab had displayed in the primary and 3-year analyses. Specifically, the median OS was 47.5 months (95% CI, 38.4-52.6) with durvalumab versus 29.1 months with placebo (95% CI, 22.1-35.1), translating to a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.57-0.88).1 The 4-year OS rates were 49.6% and 36.3%, respectively.
“The take-home is that we saw continued, maintained marked OS benefit when patients received adjuvant durvalumab following the completion of concurrent chemotherapy and radiation,” Piotrowska, a medical oncologist at Massachusetts General Hospital and an assistant professor at Harvard Medical School, said in a presentation during a 2020 Institutional Perspectives in Cancer webinar on lung cancer.
Moreover, the median PFS was 17.2 months (95% CI, 12.3-23.8) with durvalumab versus 5.6 months with placebo (95% CI, 4.6-7.7), translating to a 45% reduction in the risk of progression or death (HR, 0.55; 95% CI, 0.44-0.67). The 4-year PFS rates were 35.3% and 19.5%, respectively.
According to a prespecified analysis, patients with PD-L1 expression of 25% or greater as well as less than 25% derived benefit from durvalumab, suggesting that PD-L1 should not be used as a biomarker of response. However, in a post-hoc analysis, patients with less than 1% PD-L1 expression fared better with placebo.
“The overall population did benefit from durvalumab, and it’s hard to draw conclusions from this post-hoc analysis particularly given the small number of patients that fell into the less than 1% subgroup,” said Piotrowska.
With that said, adjuvant durvalumab should be considered for all patients with stage III NSCLC who complete chemoradiation with the exception of patients with oncogenic drivers, such as EGFR, underlying autoimmune conditions, and immunosuppression.
In the resectable setting, the ADAURA trial was the focus of attention at the 2020 ASCO Annual Meeting. The phase 3 study randomized patients with completely resected stage IB to IIIA EGFR-mutant NSCLC with or without prior chemotherapy to 80 mg of osimertinib once daily or placebo for up to 3 years.
Following a recommendation from the International Data Monitoring Committee, the study was unblinded early due to efficacy. The results of the unplanned interim analysis demonstrated a significant improvement in DFS with osimertinib. Specifically, the EGFR TKI led to a median DFS that was not reached (95% CI, 38.8-not calculable) versus 19.4 months with placebo (95% CI, 16.6-24.5), reflecting an 83% reduction in the risk of disease progression or death (HR, 0.17; 95% CI, 0.12-0.23; P < .0001).2 The 3-year DFS rates were 80% and 28%, respectively.
“This benefit in DFS was maintained across stages, and it was even higher in the stage III patients with a hazard ratio of 0.12. We’re very curious whether we’ll see an OS benefit with adjuvant osimertinib,” said Piotrowska.
The drug was also well tolerated despite the occurrence of skin and gastrointestinal toxicities, which were generally low grade, said Piotrowska.
In December 2020, the FDA approved osimertinib as an adjuvant therapy for patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test, following tumor resection.
During the live program and following the presentation of the data, Piotrowska asked the viewers whether they would prescribe adjuvant osimertinib, to which more than half (52%) said they would.
“At our institution, all of us are enthusiastic about these data. Of course, we would like to see more data, but we do think it’s compelling and it looks like many in the audience agree,” said Piotrowska.
Shifting to the role of adjuvant immunotherapy, the modality is far from affecting practice patterns, explained Piotrowska. However, a number of studies, such as ANVIL (NCT02595944), IMpower010 (NCT02486718), BR31 (NCT02273375), and KEYNOTE-019 (NCT02504372) are ongoing and eagerly anticipated.
Similarly, neoadjuvant therapy is under study in the Lung Cancer Research Foundation LEADER trial (LCMC4) in which 1000 patients with early-stage disease will be tested for 10 targetable alterations, and those with an appropriate target will receive a neoadjuvant TKI.
“The role of adjuvant immunotherapy remains unknown, but we’re looking forward to those studies as well as studies looking at neoadjuvant immunotherapy and TKIs and other translational studies to help improve our adjuvant and neoadjuvant treatment strategies,” concluded Piotrowska.
1. Faivre-Finn C, Vicente D, Kurata T, et al. Durvalumab after chemoradiotherapy in stage III NSCLC: 4-year survival update from the phase III PACIFIC trial. Ann Oncol. 2020;31(4):S1178-S1179. doi:10.1016/j.annoncc.2020.08.2281
2. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients with stage IB-IIIA EGFR mutation-positive NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
Will you offer adjuvant osimertinib for patients with EGFR+ NSCLC based on ADAURA?