By Dr. Kanak Parmar
Perioperative systemic therapy for resectable non-small cell lung cancer
Surgical resection followed by adjuvant chemotherapy has been the standard of care for the last few decades (2). While cisplatin-based platinum-doublet adjuvant chemotherapy remained the standard of care for nearly two decades, given the modest survival benefit and a larger rate of systemic recurrence, there has always been a need for more effective systemic therapy in the perioperative setting to improve survival. The more recent inclusion of targeted therapy and immunotherapy in the neoadjuvant and adjuvant regimens has demonstrated improvement in event-free survival (EFS) and disease-free survival (DFS). Osimertinib was approved in December 2020 as adjuvant therapy for early-stage resectable non-small cell lung cancer with sensitizing EGFR mutation following surgery and chemotherapy and atezolizumab was FDA-approved in this setting in October 2021. ADAURA was a phase III trial that assessed the role of adjuvant osimertinib therapy vs. placebo for up to 3 years in resectable NSLC with EGFR driver mutations following surgical resection and adjuvant chemotherapy
KEYNOTE-091, also known as PEARLS, is a triple-blind, randomized, phase III study that evaluated the efficacy of pembrolizumab versus placebo after complete resection in treating stage IB to IIIA NSCLC in an adjuvant setting (5). The study demonstrated significant improvement in DFS in the pembrolizumab arm, in the overall population, with a median DFS of 53.6 months in the pembrolizumab arm compared to the median DFS of 42.0 months in the placebo arm (HR 0.76; P=0.0014)(5). Pembrolizumab is now FDA-approved as adjuvant treatment following surgical resection and adjuvant chemotherapy for patients with stage IB (≥4 cm) – IIIA NSCLC, irrespectively of PD-L1 expression. Interestingly, on subgroup analysis, the study did not demonstrate DFS benefit with pembrolizumab for those with PD-L1≥50%.
While pembrolizumab and atezolizumab are approved in the adjuvant setting, chemotherapy plus nivolumab is now approved in the neoadjuvant setting. This is based on the results of the CheckMate-816 study, which is an open-label, randomized, phase III study that randomized patients to either receive nivolumab plus platinum-doublet chemotherapy or platinum-doublet chemotherapy in the neoadjuvant settings with resectable, stage IB-IIIA NSCLC without EGFR and ALK alterations(6). The study demonstrated significant improvement in complete pathological response and event-free survival in the nivolumab plus chemotherapy arm.
Several ongoing phase III studies are evaluating perioperative immunotherapy (neoadjuvant + adjuvant immunotherapy), including KEYNOTE-671 (NCT03425643), IMPOWER-030 (NCT03456063), AEGEAN (NCT03800134), and CheckMate-77T (NCT04025879). Additionally, BR.31 (NCT02273375), MERMAID-1 (NCT04385368), MERMAID-2 (NCT04642469), and ANVIL (NCT02594944) are phase III studies which are utilizing immunotherapy in the adjuvant settings.
Systemic therapy for stage IV NSCLC without driver mutation
POSEIDON is an open-label, phase III study with a three-arm design, which evaluated the efficacy of tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in the first-line mNSCLC with advanced EGFR/ALK-negative NSCLC(7). The study demonstrated significant improvement in PFS (6.2 vs. 4.8 months, HR 0.72, P .0003) and OS (14.0 vs. 11.7 months, HR 0.77, P = .0030) in the T+D+CT arm and PFS 5.5 vs. 4.8 months (HR 0.74, P .0009) in the D+CT arm when compared with CT. Based on the results of this trial, tremelimumab in combination with durvalumab plus platinum-based chemotherapy is now approved for stage IV NSCLC without the sensitizing EGFR/ ALK alteration (7).
Systemic therapy for stage IV NSCLC with a driver mutation
The KRAS p.G12C mutation occurs in approximately 13% of non–small-cell lung cancers (NSCLCs). It encodes a GTPase superfamily protein that mediates the intracellular signaling of activated tyrosine kinase receptors by switching between inactive GDP-bound and active GTP-bound states. Historically, the KRAS pathway has been considered undruggable because of the lack of allosteric regulatory sites needed for drug binding. This has been modified KRAS G12C mutant protein that resides beneath de switch II region, adjacent to the mutant cysteine that allows the binding of small inhibitory molecules and, favors the affinity of KRAS for GDP in its inactive state (8). Earlier, sotorasib, an irreversible G12C inhibitor, was approved on May 28, 2021, for stage IV NSCLC based on the results of the Codebreak-100 study (9). Additionally, on December 12, 2022, the FDA granted accelerated approval to adagrasib for locally advanced or metastatic KRAS G12C mutant NSCLC in the second-line setting (10). This approval was based on the KRYSTAL-1 study results. KRYSTAL-1 (NCT03785249) is a multicohort Phase 1/2 study evaluating adagrasib as monotherapy in patients with NSCLC previously treated with platinum-based chemotherapy and anti-PD-1/L1 therapy (11). The study demonstrated an ORR of 42.9%, median DOR of 8.5 months, median PFS of 6.5 months (95% CI 4.7–8.4), and median OS of 12.6 months. A phase III clinical trial, KRYSTAL-12, is currently ongoing to compare adagrasib with docetaxel in previously treated patients with KRAS G12C-mutated NSCLC (NCT04685135) (6). Another phase 2/3 trial, KRYSTAL-7, is currently underway to evaluate the combination of adagrasib with pembrolizumab versus adagrasib monotherapy in first-line treatment in patients with advanced KRAS G12C-mutated NSCLC (NCT04613596).
DESTINY-Lung01 is an open-label phase II study that evaluated the safety and efficacy of trastuzumab deruxtecan (T-DXd) at a dose of 6.4mg/kg in patients previously treated, HER2-overexpressing or HER2-mutant NSCLC(12). 91 patients with NSCLC with activating HER2 mutations were treated with trastuzumab deruxtecan. The study demonstrated an objective response rate of 55%, a median duration of response of 9.3 months, a median PFS of 8.2 months, and a median overall survival of 17.8 months. Additionally, DESTINY-Lung02 evaluated the benefit-risk profile of trastuzumab deruxtecan at 5.4 mg/kg and 6.4 mg/kg in pts with previously treated HER2 mutant NSCLC in the prespecified cohort (NCT04644237). The study demonstrated similar efficacy results but a more favorable safety profile at a 5.4 mg/kg dosing regimen. Based on the results of the DESTINY-Lung02 study, the FDA granted accelerated approval to T-DXd on August 11, 2022.
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