Presentation by Dr Millie Das, MD, Stanford University
At the Total Health 2023 ASCO Review held in Napa Valley, California, Dr Millie Das, MD, from Stanford University presented lung cancer updates from the 2023 American Society for Clinical Oncology (ASCO) Annual Meeting, with a focus on results from four key clinical trials.
In early-stage non-small cell lung cancer (NSCLC), Dr Das highlighted results from the ADAURA trial of a targeted therapy, Osimertinib, as an adjuvant (post-surgery) treatment in stage IB – IIIA NSCLC patients whose tumors have an epidermal growth factor receptor mutation (EGFRm). This Phase III study included patients with non-squamous type NSCLC with EGFR Ex19del or L858R type mutations whose disease had been completely surgically resected with negative surgical margins. Patients in the trial received adjuvant treatment with either Osimertinib or placebo for up to 3 years, or until disease progression, with the primary endpoint of disease-free survival (DFS), and a key secondary endpoint of overall survival (OS). Previously reported findings from the trial had already shown a significant improvement in DFS for patients receiving Osimertinib versus placebo, and results reported at this year’s ASCO showed significant improvement in OS as well, for patients with stage II – IIIA disease (5-year OS, 85% vs. 73%; hazard ratio [HR]=0.49; P=0.0004), as well as for patients with stage IB/II/IIIA disease (88% vs. 78%; HR=0.49; P<0.0001). The benefit of Osimertinib was observed across all subgroups of patients, regardless of race, stage, or type of EGFRm. Summarizing, Dr Das noted ADAURA is the first Phase III study to demonstrate a survival benefit using a targeted treatment for patients with EGFRm stage NSCLC, and these results establish Osimertinib as a standard of care for patients with resected stage IB – IIIA EGFR-positive NSCLC. She noted a remaining question from the trial of what drives the survival benefit with this agent – whether it is patient cure or just delayed recurrence – if the latter, she noted, a longer or perhaps indefinite adjuvant treatment with Osimertinib may be beneficial.
A second trial which Dr Das highlighted for patients with early-stage NSCLC was KEYNOTE-671. This trial examined the use of an immunotherapy, pembrolizumab (or placebo), in combination with a platinum-type chemotherapy as neoadjuvant (pre-surgery) treatment, followed by surgery and adjuvant pembrolizumab (or placebo) treatment. Patients in this trial had resectable stage II, IIIA, or IIIB NSCLC and no prior treatment, and the primary endpoints were event-free survival (EFS) as well as OS. The results of the trial showed an EFS benefit for patients in the pembrolizumab arm as compared to the placebo arm (24-month EFS 62.4% vs. 40.6%) with the benefit being statistically significant (HR=0.58; P<0.00001), and generally observed across all of the patient subgroups examined. Results for OS also appeared to favor pembrolizumab, although the significance boundary for OS was not met, and Dr Das noted that longer follow up will be needed. Response rates also significantly favored pembrolizumab with major pathologic responses (mPR) seen in 30.2% and 11.0% of patients (P<0.00001), and complete pathologic responses (pCR) seen in 18.1% and 4.0% of patients (P<0.00001). With regard to safety of the regimen, Dr Das noted there were no new safety signals associated with the regimen overall, and the percentage of grade 3/4 adverse events (AEs) was low. Lingering questions from this trial, Dr Das noted, include which patients actually require additional adjuvant immunotherapy; in this regard, she suggested that patients who achieve a pCR likely do not need further adjuvant therapy with pembrolizumab, and that adjuvant treatment might be most beneficial for those who do not achieve pCR. She also noted that while the data are promising from the trial, the regimen is not yet FDA-approved.
For advanced NSCLC, Dr Das highlighted first pivotal study results with a new oral targeted therapy, sunvozertinib, for patients whose tumors have EGFR Exon 20 insertion-type (ins) mutations. Patients in the trial had locally advanced or metastatic NSCLC with confirmed EGFR exon20ins, they could have received between 1 and 3 prior lines of treatment, and all had to have progressed after prior platinum-based chemotherapy. Dr Das noted the demographic characteristics of the EGFR exon20ins patient population in the trial, which included younger age (median 58 years), female predominance (59.8%), a majority of never-smokers (67%) and approximately one-third had brain metastases at baseline. The objective response rate (ORR) was 60.8%, with a disease control rate of 87.6%. Most patients had measurable shrinkage of their tumors and the median duration on treatment was 7 months, with the longest being 19.2 months. In terms of the toxicity profile of sunvozertinib, Dr Das noted that, similar to other EGFR-targeting therapies, diarrhea and rash were commonly seen, and other events more specific to the drug included blood creatine phosphokinase (CPK) and creatinine increases. Summarizing the results, Dr Das noted the encouraging efficacy and safety of sunvozertinib seen in the trial, and that the observed ORR compares favorably with other FDA- approved drugs for this NSCLC population with EGFR exon20ins. She further noted the efficacy seen in patients with baseline brain metastases. A Phase III trial comparing sunvozertinib with platinum-based chemotherapy in the first line setting for EGFR exon20ins NSCLC is currently underway.
Small Cell Lung Cancer (SCLC)
For patients with small cell type lung cancer (SCLC) whose disease has relapsed, Dr Das highlighted “first in-Human dose escalation” results for a novel treatment called an IgG-like T-cell engager. The agent (BI 764532) recognizes certain SCLC tumors that express a molecule called delta-like ligand 3 (DLL3+) and targets them for destruction by T-cells of the immune system. The trial evaluated the use of increasing doses of BI 764532 in patients with SCLC or neuroendocrine carcinoma (NEC) with the objective of determining the maximum tolerated dose (MTD) and any dose-limiting toxicities (DLTs); patients were treated for a maximum of 36 months or until their disease progressed. Cytokine release syndrome (CRS) is an immune reaction that is most commonly associated with this type of T-cell engager therapy, and was seen in about 59% of the patients in the study; the CRS events, however, were predominantly of grade 1 or 2 and were manageable with supportive care measures. The percentage of patients with treatment related AEs leading to discontinuation of the drug was low (4%). All of the DLTs that were observed were reversible, and the MTD has not been reached. With regard to efficacy, tumor shrinkage was seen across a range of doses for BI 764532, and the response rate was 26% in the SCLC patients, with a disease control rate of 51%. At the time of data cutoff for the trial, responses were still ongoing in 14 of 18 responding patients. Summarizing, Dr Das noted the encouraging efficacy observed in the study and the acceptable and manageable toxicity of BI 764532, with a low rate of discontinuation due to treatment-related AEs. She added that these results compare favorably with other DLL3-targeting agents, including tarlatamab, another T-cell engager type agent that has shown promise in this setting.
Quick Summary: ASCO 2023 Lung Cancer Updates
Small Cell Lung Cancer
Speaker’s Disclosure Information: Dr Das reported the following relationships and commercial interests for this presentation: Consulting: Genentech (uncompensated), Eurofins; Advisory Board: Astra Zeneca, Beigene, Sanofi/Genzyme, Janssen, Regeneron; Research: Merck, Genentech, CellSight, Novartis, Abbvie, United Therapeutics, Verily, Varian, Celgene