ASCO 2024 – Major Advances in the Treatment of Lung Cancer
Several clinical trials published at the American Society of Clinical Oncology (ASCO) annual meeting will impact the management of lung cancer. There were groundbreaking updates from long awaited clinical trials across stage, cancer histology type, and mutational status. The LAURA clinical firmly established that Osimertinib should become the new standard of care for patients with unresectable stage III EGFR-mutated NSCLC. Checkmate173 showed that Immuno-chemotherapy should remain the standard of care for stage IB-IIIA resectable NSCLC without known driver mutations. ADRIATIC showed the first major advance in systemic treatment for limited stage SCLC in decades with nearly a two-year overall survival advantage and demonstrated that durvalumab will become the new standard of care for patients with limited stage SCLC. Each of these studies are summarized in depth below.
Osimertinib – The New Standard of Care for Unresectable Stage III EGFR Mutated NSCLC
The ASCO Plenary session had strong thoracic oncology representation this year, starting with Dr. Ramalingam from Emory University who presented results from LAURA, a double-blind Phase III study of 216 patients who received Osimertinib vs placebo after chemoradiation for stage III unresectable EGFR-mutated NSCLC.1 The study showed remarkable increase in progression free survival (PFS) in patients receiving Osimertinib of 39.1 m vs 5.6m in the placebo group (HR 0.16). Additionally, patients receiving Osimertinib had much lower rates of local and distant progression (most notably brain metastases) with 22% in the Osimertinib group having new lesions compared to 68% in the placebo group. Interim overall survival (OS) data showed a positive trend in favor towards Osimertinib (although not statistically significant) despite 81% of patients crossing over to the Osimertinib arm during the study. Treatment with Osimertinib was generally well tolerated and toxicities were consistent with prior reports with no Grade 4/5 treatment related adverse events (TRAEs) observed. Results from this study suggest that Osimertinib should become the new standard of care for patients with unresectable stage III EGFR-mutated NSCLC who have not progressed after chemoradiotherapy. Data from this study is now available in the New England Journal of Medicine.
Durvlaumab The New Standard for Limited Stage SCLC
Next at the ASCO plenary was Dr. Spigel from Sarah Cannon Research Institute who presented the pivotal ADRIATIC phase III trial of 528 patients using adjuvant durvalumab with and without tremelimumab as consolidation treatment in patients with limited stage small-cell lung cancer (SCLC)) after chemoradiotherapy.2 The study found that patients receiving durvalumab had improved mOS of 55.9 months compared to 33.4 months (HR 0.73) in the placebo arm and improved mPFS of 16.6 months compared to 9.2 months (HR 0.76) in the placebo group. Treatment was well tolerated, and safety findings were consistent with known safety profile of durvalumab monotherapy in the post chemoradiotherapy setting. This study represents the first major advance in systemic treatment for limited stage SCLC in decades with nearly a two-year overall survival advantage and will become the new standard of care for patients with limited stage SCLC who have not progressed after chemoradiotherapy.
Lazertinib and Amivantamab Promising for Patients with Atypical EGFR Mutations
Dr. Byoung Cho of Yonsei Cancer Center provided an interesting update on Cohort C of the phase II single-arm study CHRYSALIS-2 concerning outcomes of 105 patients undergoing the combination of amivantamab plus Lazertinib in a heterogenous cohort of atypical EGFR-mutated NSCLC.4 In the first line setting, the objective response rate (ORR) was 57% with a clinical benefit rate of 84% and a mPFS of 19.5 months. Compared to real-world data using current standards of care, combination Lazertinib and amivantamab had a longer time to treatment discontinuation (14.0 vs 3.2 months) and 2-year overall survival (79% vs 44%). In conjunction with other ongoing clinical trials including MARIPOSA, PALOMA 2, and PALOMA 3, this adds to the increasing body of literature that amivantamab and lazertinib has efficacy across EGFR mutation types. This study also represents the largest prospective cohort for patients with atypical EGFR mutations and suggests that combination Lazertinib and amivantamab may represent an appealing treatment option for these patients compared to current standard of care.
Neoadjuvant Chemo-Immunotherapy The New Standard for Stage IB-IIIA NSCLC Without Known Driver Mutations.
A crucial update of the CheckMate 816 study was provided by Dr. Spicer of the McGill Thoracic Oncology Program. The phase III Checkmate 816 study established neoadjuvant nivolumab + chemotherapy as a standard of care for stage IB-IIIA resectable NSCLC without known driver mutations.6 At this 4-year update, nivolumab + chemo continued to improve event free survival (EFS) compared to chemotherapy alone (43.8 months vs 18.4 months, HR 0.66). Furthermore, nivolumab + chemotherapy continued to show OS improvement vs chemotherapy alone with a 13% survival advantage however median OS was not reached (HR 0.71). This update provides the first understanding of long-term benefits of neoadjuvant chemoimmunotherapy compared to chemotherapy alone and acts as a benchmark to assess the benefit of all further perioperative treatments for NSCLC.
CROWN Study - Lorlatinib Demonstrated the Longest PFS ever Reported in Advanced NSCLC
An update of the randomized phase III CROWN study regarding lorlatinib vs crizotinib in treatment naïve patients with ALK-mutated advanced NSCLC was provided Dr. Solomon of Peter MacCallum Cancer Centre. In this 5-year analysis median PFS of lorlatinib had still not been reached compared to mPFS of crizotinub of 9.1 months (HR 0.19).5 This PFS benefit was present irrespective of the presence or absence of brain metastases and in patients with brain metastases the time to intracranial progression was far superior in lorlatinib (HR 0.03). At the time of analysis, the required number of OS events has not yet been reached. The major adverse events observed were consistent with prior analyses and included hypertriglyceridemia, weight increase, hypercholesterolemia, and hypertension. These side effects lead to a dose reduction in 23% of patients and discontinuation in 11% of patients. Efficacy was seen in all subgroups including those with poor prognostic markers including TP53 and EML4:ALK fusions. This PFS of lorlatinib corresponds to the longest PFS reported in advanced NSCLC and an unprecedented improvement in outcomes for patients with ALK-mutated NSCLC.
Of the several mesothelioma sessions, Dr. Popat of Royal Marsden Hospital stood out for his presentation of ETOP 13-18 BEAT-meso, a phase III international open-label study of 400 patients investigating bevacizumab and chemotherapy with or without atezolizumab in first-line unresectable pleural mesothelioma.3 While differences in overall survival were not uniformly statistically significant across the two subgroups, patients with non-epithelioid mesothelioma, PD-L1 TPS >1%, and poor prognosis via EORTC score had improved overall survival with atezolizumab compared to without. Progression free survival was uniformly significantly improved in patients receiving atezolizumab compared to without (9.2 months vs 7.6 months HR 0.72). Similarly, patients with non-epithelioid mesothelioma, PD-L1 TPS >1%, and poor prognosis via EORTC had improved PFS when receiving atezolizumab. Patients receiving atezolizumab experienced more thrombocytopenia, elevated creatinine and dermatologic TRAEs than patients receiving VEGF inhibitors and chemotherapy alone, but quality of life assessments were not different between the two arms. Overall atezolizumab may be a reasonable addition to bevacizumab and chemotherapy especially in the treatment of non-epithelioid mesothelioma.
Zenocutuzumab - the first approved systemic therapy for patients with NRG1 fusion–positive NSCLC or pancreatic adenocarcinoma.
Zenocutuzumab targeted therapy approved for treatment of pancreatic ductal adenocarcinoma and non-small cell lung cancer with NRG1 fusions.
Immunotherapy After Chemoradiotherapy Promising in Limited-Stage Small Cell Lung Cancer
Adjuvant therapy with Imfinzi (durvalumab) significantly improved survival outcomes for patients with limited-stage SCLC
Breakthrough in Understanding Tamoxifen's Effectiveness in Breast Cancer: Gut Bacteria Play a Crucial Role
Since tamoxifen is taken orally and travels through the digestive system, variations in patient responses may be connected to the gut microbiome—the trillions of bacteria in our intestines that differ significantly from one person to another.
References
1. Ramalingam SS, Kato T, Dong X, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable stage (stg) III epidermal growth factor receptor-mutated (EGFRm) NSCLC: Primary results of the phase 3 LAURA study. JCO. 2024;42(17_suppl):LBA4-LBA4. doi:10.1200/JCO.2024.42.17_suppl.LBA4
2. Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). JCO. 2024;42(17_suppl):LBA5-LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5
3. Popat S, Felip E, Dafni U, et al. BEAT-meso: A randomized phase III study of bevacizumab (B) and standard chemotherapy (C) with or without atezolizumab (A), as first-line treatment (TX) for advanced pleural mesothelioma (PM)—Results from the ETOP 13-18 trial. JCO. 2024;42(17_suppl):LBA8002-LBA8002. doi:10.1200/JCO.2024.42.17_suppl.LBA8002
4. Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK + non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. JCO. 2024;42(17_suppl):LBA8503-LBA8503. doi:10.1200/JCO.2024.42.17_suppl.LBA8503
5. Byoung C, Wang Y, Felip E, et al. Amivantamab plus lazertinib in atypical EGFR-mutated advanced non-small cell lung cancer (NSCLC): Results from CHRYSALIS-2. JCO. 2024;42(16_suppl 16):doi:10.1200/JCO.2024.42.16_suppl.8516
6. Spicer J, Girard N, Provencio M, et al. Neoadjuvant nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with resectable NSCLC: 4-year update from CheckMate 816. JCO. 2024;42(17_suppl):LBA8010-LBA8010. doi:10.1200/JCO.2024.42.17_suppl.LBA8010
