Chemotherapy and Osimertinib Combination Should Be the First-Line Treatment for All Advanced EGFR+ NSCLC

"Don't be afraid to give up the good to go for the great."John D. Rockefeller Time shapes nearly every aspect of the human experience, dictating how we navigate our daily lives and the legacies we leave behind. In oncology, patients and clinicians alike are driven by the pursuit of time. The FLAURA-2 trial achieved its primary end point of statistically improved median progression-free survival (mPFS) of osimertinib plus platinum-pemetrexed chemotherapy (osi-chemo) over osimertinib alone with a hazard ratio of 0.62 by investigator assessment. Blinded independent central review (BICR) assessment achieved the same hazard ratio (HR) of 0.62. Osi-chemo provided an absolute increase between 8.8 months (investigator-assessed) and 9.5 months (BICR-assessed) to reach a BICR-assessed mPFS of 29.5 months.1Blanchard D. Janne P. Cheng Y. et al.Osimertinib with or without chemotherapy in EGFR mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948Crossref PubMed Scopus (29) Google Scholar Importantly, the two critical prognostic factors (exon 19 deletion/L858R and brain metastasis [yes or no]) were balanced between the two study arms despite not being stratified for. The approximately 9 months mPFS improvement with osi-chemo ushered in the "third industrial revolution" in the first-line (1L) treatment of advanced EGFR+ NSCLC (mPFS of approximately 30 mo), preceded by the "first industrial revolution" where 1G EGFR tyrosine kinase inhibitors (TKIs) became standard of care (approximately 10 mo mPFS) and the "second industrial revolution" where 3G EGFR TKIs (approximately 20 mo mPFS) replaced 1L 1G EGFR TKI as standard of care. The current lack of overall survival (OS) benefit from FLAURA-2 should not dissuade clinicians from adopting osi-chemo as all six 1L 1G EGFR TKI versus chemotherapy phase 3 trials (WJTOG3405, NEJ002, EURTAC, OPTIMAL, ENSURE, CONVINCE) did not achieve OS benefit.2Greenhalgh J. Boland A. Bates V. et al.First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.Cochrane Database Syst Rev. 2021; 3: CD010383PubMed Google Scholar Similarly, the seminal AURA-3 trial did not achieve OS benefit.3Papadimitrakopoulou V.A. Mok T.S. Han J.Y. et al.Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.Ann Oncol. 2020; 31: 1536-1544Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar Nonetheless, the mPFS results of AURA-3 influenced health authorities in Asia to grant the first approval of four 3G EGFR TKIs (lazertinib, aumolertinib, furmonertinib, befotertinib) for EGFR T790M+ NSCLC based on the large phase 2 studies revealing similar ORR and duration of response as osimertinib in AURA-3 without requirement of similarly designed pivotal trials despite AURA-3's lack of OS benefit.4Lau S.C.M. Ou S.I. And still they come over troubled waters: can Asia's third-generation EGFR tyrosine kinase inhibitors (furmonertinib, aumolertinib, rezivertinib, limertinib, befotertinib, SH-1028, and lazertinib) affect global treatment of EGFR+ NSCLC.J Thorac Oncol. 2022; 17: 1144-1154Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Furthermore, a "FLAURA-2-like" designed trial of aumolertinib with or without chemotherapy as the 1L treatment of advanced EGFR+ NSCLC is being conducted in the People's Republic of China (NCT04923906), with BICR-assessed PFS as the primary end point. It will be important to follow whether the Chinese National Medical Products Administration will grant approval of aumolertinib plus chemotherapy on the basis of a highly likely mPFS benefit. Sequencing approach is an alternative to osi-chemo but needs to provide a mPFS of approximately 9 months. Todate the only published post-osi phase 3 trial is MARIPOSA-2.5Passaro A. Wang J. Wang Y. et al.Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.Ann Oncol. 2024; 35: 77-90https://doi.org/10.1016/j.annonc.2023.10.117Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar The EGFR TKI containing "quad" regimen (lazertinib + amivantamab + platinum doublet chemo [LACP]) in MARIPOSA-2 achieved statistically superior mPFS (8.3 mo) over chemotherapy (CP) (mPFS = 4.2 mo) alone (BICR-assessed HR = 0.44). Although an mPFS of 8.3 months is within the ballpark of 9 months, 92% of patients on LACP experienced grade 3 or greater toxicities and 77% patients had treatment interruption. Venous thromboembolic events occurred in 22% of patients on LACP compared with 5% in patients on CP leading to recommendation of prophylactic anticoagulation for the first 4 months of LACP.5Passaro A. Wang J. Wang Y. et al.Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.Ann Oncol. 2024; 35: 77-90https://doi.org/10.1016/j.annonc.2023.10.117Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar ACP (without lazertinib) also achieved improved mPFS (6.2 mo) over CP (HR = 0.48), but 6.2 months is short of the desired 9 months mPFS benefit osi-chemo provided. Non–EGFR TKI-containing "quad" regimens (chemotherapy + antiangiogenic agent + immune checkpoint inhibitor) was found to have superior mPFS over CP alone (4.2 mo) (ORIENT-31, mPFS of 7.2 mo, HR = 0.51).6Lu S. Wu L. Jian H. et al.Sintilimab plus chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer with disease progression after EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): second interim analysis from a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Respir Med. 2023; 11: 624-636Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Atezolizumab plus bevacizumab plus chemotherapy (ABCP) in IMpower151 (EGFR+ subgroup which constisuted about 52% of the enrolled patients) and ATTLAS both achieved mPFS of 8.5 months.7Zhou C. Dong X. Chen g et al.OA09.06. IMpower151: phase III study of atezolizumab + bevacizumab + chemotherapy in first-line metastatic nonsquamous NSCLC.J Thorac Oncol. 2023; 18: S64-S65Abstract Full Text Full Text PDF Google Scholar,8Park S, Kim TM, Han JY, et al. Phase III, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR or ALK mutated in non-small cell lung cancer (ATTLAS, KCSG-LU19-04) [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.23.01891. Accessed November 20, 2023.Google Scholar Nevertheless, only 11% (ORIENT-31), 18% (IMpower151),7Zhou C. Dong X. Chen g et al.OA09.06. IMpower151: phase III study of atezolizumab + bevacizumab + chemotherapy in first-line metastatic nonsquamous NSCLC.J Thorac Oncol. 2023; 18: S64-S65Abstract Full Text Full Text PDF Google Scholar and 9% (ATTLAS)8Park S, Kim TM, Han JY, et al. Phase III, randomized study of atezolizumab plus bevacizumab and chemotherapy in patients with EGFR or ALK mutated in non-small cell lung cancer (ATTLAS, KCSG-LU19-04) [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.23.01891. Accessed November 20, 2023.Google Scholar of patients with NSCLC were on post-3G EGFR TKI. In addition, IMpower151 ABCP did not result in statistical improvement (HR = 0.86) in mPFS over BCP (mPFS = 8.3 mo) in the EGFR/ALK subgroup.7Zhou C. Dong X. Chen g et al.OA09.06. IMpower151: phase III study of atezolizumab + bevacizumab + chemotherapy in first-line metastatic nonsquamous NSCLC.J Thorac Oncol. 2023; 18: S64-S65Abstract Full Text Full Text PDF Google Scholar As these non–EGFR TKI-containing regimens though tentalizingly promising were all single-country trials with very few patients who were purely post-3G EGFR TKI, it is premature to recommend ABCP (or similar combination) as post-osimertinib treatment (Fig. 1). Figure 1 reveals possible "best case scenario" outcomes of sequential therapy for us to argue even under optimal considtion, the mPFS2 did not reach our target goal of at least 9 months. Sequential use of regimens is limited by real-world situations of patients who inevitably drop out (such as those who have decline in PS). It is also true that some trials do not allow for a true crossover, leaving subsequent therapy up to the "standard of care" and depending on the authorization status of where the patients reside, they may or may not have access. Antibody-drug conjugates (ADCs) are also being developed in the post 3G EGFR TKI setting, but the currently reported efficacy is all at least in the third-line setting; post-osimertinib and post-chemotherapy with a mPFS of 5.5 (patritumab deruxtecan [HER3-DXd] from the HERTHENA-Lung-019Yu H.A. Goto Y. Hayashi H. et al.HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated non-small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy.J Clin Oncol. 2023; 41: 5363-5375Crossref PubMed Scopus (13) Google Scholar) to 5.8 months (datopotamab deruxtecan [Dato-DXd] from the TROPION-Lung-05).10Paz-Ares L. Ahn M.J. Lisberg A.E. et al.1314MO TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs).Ann Oncol. 2023; 34: S755-S756Abstract Full Text Full Text PDF Google Scholar Intriguingly, Dato-DXd achieved a HR of 0.38 among a small subgroup of patients with actionable genomic alterations in TROPION-Lung01.11Ahn M.J. Lisberg A. Paz-Ares L. et al.LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01.Ann Oncol. 2023; 34: S1254-S1335Google Scholar In the same setting of post-EGFR TKI and post-chemotherapy, Bl-B01D1 (a bispecific EGFR/HER3 ADC just licensed to BMS outside greater China) has achieved a mPFS of 5.6 months.12Zhang L. Ma Y. Zhao Y. et al.1316MO BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with non-small lung cancer: updated results from first-in-human phase 1 study.Ann Oncol. 2023; 34: S758Abstract Full Text Full Text PDF Google Scholar The trial comparing HER3-DXd versus platinum-based chemotherapy immediately post-3G EGFR TKI (HERTHENA-Lung02, NCT05338970) is ongoing and results are eagerly anticipated. Almost all major subgroups of patients with EGFR+ NSCLC benefited from FLAURA-2 (exon 19 deletion, L858R, baseline brain metastasis present). Although there was an absolute 6.6 months of increase in mPFS among patients without baseline brain metastasis with osi-chemo, the HR was 0.75 (95% confidence interval [CI]: 0.55–1.03).1Blanchard D. Janne P. Cheng Y. et al.Osimertinib with or without chemotherapy in EGFR mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948Crossref PubMed Scopus (29) Google Scholar,13Jänne PA, Planchard D, Kobayashi K, et al. CNS efficacy of osimertinib with or without chemotherapy in EGFR-mutated advanced non–small-cell lung cancer [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.23.02219. Accessed December 15, 2023.Google Scholar The addition of chemotherapy to osimertinib increased intracranial response from 71% to 78%, with reduction in cumulative central nervous system progression from 23% to 9% was found, likely from elimination of persistent cells and maximum cytoreduction.1Blanchard D. Janne P. Cheng Y. et al.Osimertinib with or without chemotherapy in EGFR mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948Crossref PubMed Scopus (29) Google Scholar,13Jänne PA, Planchard D, Kobayashi K, et al. CNS efficacy of osimertinib with or without chemotherapy in EGFR-mutated advanced non–small-cell lung cancer [e-pub ahead of print]. J Clin Oncol. https://doi.org/10.1200/JCO.23.02219. Accessed December 15, 2023.Google Scholar Per protocol design, in FLAURA-2, patients without baseline brain metastasis did not receive regularly scheduled brain imaging. Therefore, one cannot rule out had brain images been regularly scheduled, statistically significant HR benefit might have been achieved in patients without baseline brain metastasis (as asymptomaic brain metastasis would likely been detected at an earlier inerval) given the additional efficacy of intracranial and extracranial effect of chemotherapy. In comparison, the MARIPOSA trial (where regularly scheduled brain imaging were performed on all patients) the HR was for patients with or without brain metastasis was the same at 0.69 with MARIPOSA patients with baseline brain metastasis mPFS improvement from 13.0 to 18.3 months versus from 13.8 to 24.9 months (HR = 0.47) in osi-chemo patients with baseline brain metastasis.14Cho B.C. Felip E. Spira A.I. et al.LBA14 amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial.Ann Oncol. 2023; 34: S1306Abstract Full Text Full Text PDF Google Scholar The chemotherapy including maintenance pemetrexed in the FLAURA-2 protocol is given concurrently with osimertinib until progression and cumulative toxicities is a valid concern for both patients and clinicians. The median cycles of chemotherapy in FLAURA-2 were 16 (4 + 12 maintenance cycles), which is consistent with two other phase 3 trials of chemotherapy and 1G EGFR TKI: Tata Memorial Centre trial with 15 cycles (4 + 11)15Noronha V. Patil V.M. Joshi A. et al.Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.J Clin Oncol. 2020; 38: 124-136Crossref PubMed Scopus (286) Google Scholar and NEJ009 with 20 cycles (4 + 16).16Miyauchi E. Morita S. Nakamura A. et al.Updated analysis of NEJ009: gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR.J Clin Oncol. 2022; 40: 3587-3592Crossref PubMed Scopus (25) Google Scholar Existing data thus suggest that 12 months of chemotherapy may be sufficient to achieve the reported mPFS benefit in FLAURA-2. Importantly, the mean relative dose intensity of osimertinib was 95% in the combination arm and 98% in the osimertinib arm indicating that concurrent chemotherapy administration did not affect the cumulative dosing of osimertinib. In addition, the difference in median total and actual osimertinib exposure time was 1.3 months in the combination arm (0.3 mo in the osimertinib arm), again indicating aggregate osimertinib interruption time during chemotherapy was short. Whether the mPFS was positively correlated to the length of chemotherapy is an important question to be addressed from the FLAURA-2 database. A "no chemotherapy" regimen is an aspirational goal for medical oncologists and patients alike. MARIPOSA revealed statistically superior improvement in mPFS of lazertinib plus amivantamab (LA) over osimertinib with a HR of 0.70, an absolute increase of 7.1 months in mPFS to a total mPFS of 23.7 months by BICR assessment.14Cho B.C. Felip E. Spira A.I. et al.LBA14 amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial.Ann Oncol. 2023; 34: S1306Abstract Full Text Full Text PDF Google Scholar Simple crosstrial comparison revealed all three values of LA (HR, absolute increase in mPFS, total mPFS) were all numerically inferior to osi-chemo. In addition, the LA regimen resulted in grade greater than or equal to 3 toxicities in 75% of the patients, dose reduction in 83% of the patients, and venous thromboembolic event in 37% of the patients. It will be important to report the mean and median relative dose intensity of lazertinib and amivantamab to provide further granularity on the tolerability of LA. Although amivantamab is not "chemo," in MARIPOSA, it was given intravenously weekly for the first five weeks and then every 2 weeks, a schedule that requires more than 50% more time demand than osi-chemo on patients and caregivers plus additional resouces to manage the dermatologic toxicities.17Belzer A. Nguyen M.O. Talsania A. Haldas J. Smith J. Leventhal J.S. Spectrum of dermatologic adverse events associated with amivantamab use.JAMA Dermatol. 2023; 159: 109-111Crossref PubMed Scopus (4) Google Scholar Both FLAURA-2 and MARIPOSA reported preliminary PFS2 benefit with osi-chemo (HR = 0.7; 95% CI: 0.52–0.93) and LA (HR = 0.75; 95% CI: 0.58–0.98) regimens, respectively,1Blanchard D. Janne P. Cheng Y. et al.Osimertinib with or without chemotherapy in EGFR mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948Crossref PubMed Scopus (29) Google Scholar,14Cho B.C. Felip E. Spira A.I. et al.LBA14 amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): primary results from MARIPOSA, a phase III, global, randomized, controlled trial.Ann Oncol. 2023; 34: S1306Abstract Full Text Full Text PDF Google Scholar indicating post-progression treatment is effective even if standard chemotherapy was used in the 1L setting in osi-chemo. Although patient preference is crucial in treatment decision-making, in those fit to receive osi-chemo, it is imperative that accurate data be provided so the "right" decision can be made. The taboo of combining chemotherapy with EGFR TKI originated from early lack of OS improvement in large-scale trials in unselected NSCLC (INTACT 1, INTACT 2, TRIBUTE, TALENT)18Dandara D.R. Gumberlock P.H. Epidermal growth factor receptor tyrosine kinase inhibitors plus chemotherapy: case closed or is the jury still out?.J Clin Oncol. 2005; 23: 5856-5858Crossref PubMed Scopus (74) Google Scholar and re-enforced from the detriment in OS with the combination approach in EGFR T790M+ NSCLC in IMPRESS19Mok T.S.K. Kim S.W. Wu Y.L. et al.Gefitinib plus chemotherapy versus chemotherapy in epidermal growth factor receptor mutation-positive non-small-cell lung cancer resistant to first-line gefitinib (IMPRESS): overall survival and biomarker analyses.J Clin Oncol. 2017; 35: 4027-4034Crossref PubMed Scopus (133) Google Scholar during a time when our knowledge of EGFR mutations was rudimentary and next-generation EGFR TKIs were unavailable. This perception began to change with the positive OS data from combination chemotherapy and gefitinib15Noronha V. Patil V.M. Joshi A. et al.Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer.J Clin Oncol. 2020; 38: 124-136Crossref PubMed Scopus (286) Google Scholar,16Miyauchi E. Morita S. Nakamura A. et al.Updated analysis of NEJ009: gefitinib-alone versus gefitinib plus chemotherapy for non-small-cell lung cancer with mutated EGFR.J Clin Oncol. 2022; 40: 3587-3592Crossref PubMed Scopus (25) Google Scholar,20Rotow J.K. Janne P.A. What's old is new again: revisiting up-front chemotherapy in EGFR-mutated non-small-cell lung cancer.J Clin Oncol. 2020; 38: 107-110Crossref PubMed Scopus (3) Google Scholar and now shattered by FLAURA-2. The FLAURA-2 investigators, although correctly stating that the exact mechanisms of the benefit found in osi-chemo are unknown, suggested that chemotherapy complements the targeted effects of osimertinib by having a nonselective antitumor effect and overcomes the intratumor heterogeneity.1Blanchard D. Janne P. Cheng Y. et al.Osimertinib with or without chemotherapy in EGFR mutated advanced NSCLC.N Engl J Med. 2023; 389: 1935-1948Crossref PubMed Scopus (29) Google Scholar Furthermore, although future studies on predictive biomarkers may further refine the patient population most likely to benefit from osi-chemo, there are currently no sequential therapies that can reliably make up the 9 months advantage with osi-chemo. Our ultimate goal is the pursuit of time for our patients, and osi-chemo provides this next-level opportunity. Lanyi Nora Chen: Conceptualization, Data curation, Writing—original draft, Writing—review and editing. Alexandria T. M. Lee: Conceptualization, Data curation, Writing—original draft, Writing—review and editing. Misako Nagasaka: Conceptualization, Data curation, Validation, Writing—original draft, Writing—review and editing. Sai-Hong Ignatius Ou: Conceptualization, Data curation, Validation, Writing—original draft, Writing—review and editing, Visualization, Supervision. Dr. Nagasaka has received consulting fees from Caris Life Sciences; has received honoraria from AstraZeneca, Daiichi Sankyo, Novartis, Eli Lilly, Pfizer, EMD Serono, and Genentech; is a speaker for Mirati, Takeda, Janssen, and Blueprint Medicine; and has received travel support from AnHeart Therapeutics. Dr. Ou has received honorarium from AnHeart Therapeutics, BMS, Claris Life Science, Pfizer, JNJ/Janssen, Daiichi Sankyo, Eli Lilly, OncLive, and DAVA Oncology LLP; has received research funding to his institution from BluePrint Medicines, Daiichi Sankyo, ERASCA Theperatucis, Janssen/JNJ, Merus, Mirati Thepereutics, Merck, Nuvalent, Pfizer, Roche, Revolution Medicine, Sanofi, and Takeda; is a scientific advisory board member of Elevation Oncology and AnHeart Therapeutics; and has stock ownership in Turning Point Therapeutics, Elevation Oncology, MBrace Therapeutics, BlossomHill Therapeutics, Lilly, Nuvalent, and Theseus Pharmaceuticals. Drs. Chen and Lee declare no conflict of interest.