The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC)
Editorial Commentary

The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC)

Yuji Uehara1,2,3 ORCID logo, Aaron C. Tan4,5 ORCID logo

1Department of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan; 2Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan; 3Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 4Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; 5Duke-NUS Medical School, National University of Singapore, Singapore, Singapore

Correspondence to: Aaron C. Tan, MD, PhD. Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore, Singapore. Email: aaron.tan@singhealth.com.sg.

Comment on: Passaro 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;35:77-90.

Keywords: Osimertinib; lazertinib; amivantamab; tyrosine kinase inhibitor; bispecific antibody

Received: 24 January 2024; Accepted: 26 March 2024; Published online: 06 June 2024.

doi: 10.21037/actr-24-7

Introduction

The current standard of care (SOC) in first-line (1L) treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) is the 3rd-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib, which has shown improved progression-free survival (PFS) and overall survival (OS) compared to 1st-generation TKIs, although this may change with the recent positive PFS results from the FLAURA2 and MARIPOSA studies (1,2). For second-line (2L) treatment, the SOC is platinum-based chemotherapy, which historically yields a median PFS of 4.4–5.5 months in patients progressing on 1L osimertinib (3,4). Amivantamab, an EGFR-mesenchymal-epithelial transition (MET) bispecific antibody with preclinical evidence showing it directs immune cell activity through ligand blocking, receptor degradation, and engagement of effector cells, is approved for the treatment of patients with EGFR exon 20 insertion mutations whose disease has progressed following platinum-based chemotherapy (5-7). In patients progressing on osimertinib, the phase I CHRYSALIS study demonstrated an overall response rate (ORR) of 36% [95% confidence interval (CI): 22–51%] and a median PFS of 4.9 months (95% CI: 3.7–9.5 months) (8).

This commentary will focus on the results of the global, randomized, phase III MARIPOSA-2 study, which evaluated amivantamab and chemotherapy with and without lazertinib in patients with advanced NSCLC harboring EGFR mutations (exon 19 deletions or L858R), following disease progression on osimertinib (9). Enrolling 657 patients, the MARIPOSA-2 study demonstrated a statistically significant improvement in the primary endpoint of PFS by blinded independent central review. This improvement was observed for both the combination of amivantamab, lazertinib, and chemotherapy (quad) and for amivantamab plus chemotherapy (triplet) compared to chemotherapy alone [median PFS: 8.3 months (quad) vs. 6.3 months (triplet) vs. 4.2 months (chemotherapy); hazard ratio 0.44 (quad) and 0.48 (triplet); P<0.001 for both]. These results represent clinically meaningful improvements in PFS over the current SOC, platinum-based chemotherapy, suggesting that these regimens could become a new SOC option.

How does MARIPOSA-2 fit into clinical practice?

While both the quad and triplet regimens exhibited statistically significant improvements in PFS, the toxicity of both arms is substantial. This raises the question of whether a PFS gain of 2–4 months is worth the associated toxicity. Dose interruptions, reductions, and discontinuations were observed in 77%, 65%, and 34% of patients in the quad regimen, and 65%, 41%, and 18% in the triplet regimen, respectively. Notably, the adverse events in the quad regimen required a protocol amendment to delay the start of lazertinib until after carboplatin was complete, addressing unacceptable hematologic and gastrointestinal adverse events. Due to short follow-up after the regimen modification, and to investigate the safety and efficacy of the modified regimen, a separate open-label, randomized extension cohort is ongoing, comparing the modified regimen of amivantamab, lazertinib, and chemotherapy versus amivantamab and chemotherapy. The modified regimen limits the treatment duration of lazertinib, which might not only reduce the toxicity but also the efficacy of treatment. Furthermore, dose reduction of these regimens at initiation may be an alternative strategy to address these toxicities. Moreover, venous thromboembolism (VTE) occurred in 22%, 10%, and 5% of patients in the quad regimen, triplet regimen, and chemotherapy arms, respectively.

When considering both the benefits and toxicity, the use of the MARIPOSA-2 regimens is questionable for universal application, although some patient subgroups may benefit from these regimens (Figure 1). Firstly, since serious adverse events are expected to increase in real-world practice and anticoagulation is recommended for the VTE prophylaxis, these regimens could be appropriate for patients with good performance status and younger patients. In other cases, it is essential to identify biomarkers that can predict which patients might benefit more from a triplet regimen as opposed to a quad regimen, or who might be better suited for a dose reduction strategy. Secondly, given that response rates were significantly higher in the triplet and quad groups versus chemotherapy alone [64% (triplet), 63% (quad), and 36% (chemo)], patients with a high tumor burden and symptoms requiring an immediate response may benefit from the triplet or quad regimens. Additionally, the intracranial PFS benefit of the triplet or quad regimens versus chemotherapy [12.5 months (triplet), 12.8 months (quad), and 8.3 months (chemo)] suggests that patients might benefit from these regimens regardless of the presence of brain metastases, even though the exact mechanism of this benefit is not fully understood. Although antibodies such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) do not cross the blood-brain barrier (10), they have shown some efficacy, possibly through the activation of the systemic immune system, suggesting that amivantamab might have an anti-central nervous system (CNS) effect due to its immune cell activity (11,12). Moreover, while biomarker analysis from the MARIPOSA-2 study is yet to be reported, the phase I CHRYSALIS study suggested that MET immunohistochemistry expression could predict response to the amivantamab and lazertinib regimen (8). Thus, patients with high MET expression could benefit from these regimens. Finally, the initial treatment chosen will affect subsequent treatment options. If amivantamab and lazertinib (MARIPOSA-1 study), or osimertinib and chemotherapy (FLAURA2 study), are used in the 1L treatment, the MARIPOSA-2 regimens may not be appropriate as 2L treatments (1,2).

Figure 1 Personalized management of patients following progression on 3rd generation EGFR-TKIs. mPFS, median progression-free survival; MET, mesenchymal-epithelial transition; TKI, tyrosine kinase inhibitor; AMP, amplification; EGFR, epidermal growth factor receptor; ADC, antibody-drug conjugate; PS, performance status; VEGF, vascular endothelial growth factor; ICIs, immune checkpoint inhibitors; SCLC, small cell lung cancer; TME, tumor microenvironment; TMB, tumor mutational burden; PD-L1, programmed death ligand 1; TIL, tumour-infiltrating lymphocytes.

In the MARIPOSA-2 trial, these quad and triplet regimens improved clinical outcomes without the need for biomarker selection. Indeed, in the phase I CHRYSALIS study, among the 16 responders in the osimertinib-relapsed cohort, eight patients had EGFR-related and/or MET-related resistance mechanisms; however, eight did not have resistance mechanisms identified by next-generation sequencing (NGS) (8). This suggests that some patients in unselected population may still be sensitive to EGFR and MET-based inhibition, possibly due to targeting the MET pathway or the immune-based anti-tumor response of amivantamab.

Personalized treatment strategy in the post 3rd-generation EGFR-TKI

At present, there are no targeted therapies approved for use in the post-osimertinib setting. Other than platinum-based chemotherapy, there are four types of potential strategies following progression on 3rd-generation EGFR-TKIs (Figure 1 and Table 1): EGFR-MET bispecific antibody (amivantamab-based therapy, AZD9592) (26), targeted therapies either alone or in combination, antibody-drug conjugates (ADCs), and chemoimmunotherapy plus vascular endothelial growth factor (VEGF) inhibitors. The EGFR C797S mutation and MET amplification represent common targetable resistance mechanisms (27). Fourth-generation EGFR-TKIs have been developed to target EGFR C797S, and combining osimertinib with c-Met inhibitors, such as tepotinib, capmatinib, and savolitinib, has shown clinical benefit (13-15). These strategies are appealing not only for their efficacy but also for the advantages they offer, including the use of oral agents that eliminate the need for intravenous infusions and avoid toxic chemotherapy, ultimately helping to maintain quality of life. Regarding ADCs, in the phase II HERTHENA-Lung01 trial, HER3-DXd demonstrated clinically meaningful efficacy with a manageable safety profile following progression on 3rd-generation EGFR-TKIs (17). The phase III HERTHENA-Lung02 trial, comparing it with platinum-based chemotherapy, is ongoing in the same clinical setting (17). In terms of immunotherapy, although the pivotal phase III KEYNOTE-789 and CheckMate722 studies recently failed to show a benefit of immunotherapy plus chemotherapy regimens over chemotherapy alone (21,22), the phase III IMpower 150, ATTLAS, and ORIENT-31 studies suggest that adding VEGF inhibitors to immunotherapy could overcome the immunosuppressive tumor microenvironment inherent to EGFR-mutant NSCLC (23-25,28). While these phase III studies were conducted without biomarker selection and were compared to platinum-based chemotherapy, the efficacious drugs targeting EGFR C797S, MET amplification, and small-cell lung cancer transformation require molecular or histologic tests to identify the resistance mechanism before starting 2L treatment. In the future, we ideally will identify the best treatment for each patient, also incorporating patient (age, performance status, and comorbidities) and tumor characteristics (brain metastasis, tumor burden, resistant mechanism, tumor microenvironment) (Figure 1). Moreover, we could consider how to sequence these treatments to extend OS, using pretreatment genetic alterations. For example, pretreatment characteristics such as EGFR exon 19 deletion, absence of whole genome duplication, and TP53 alterations might predict the likelihood of developing the T790M mutation before the onset of 1st/2nd-generation EGFR-TKIs (29), which could suggest the potential benefit of the sequential use of 1st/2nd-generation EGFR-TKIs followed by 3rd-generation EGFR-TKIs in some populations. Although the use of 1st/2nd-generation EGFR-TKIs is not the SOC for 1L treatment in current practice, predicting a tumor’s evolutionary trajectory through permanent genetic alterations (such as types of driver mutations and concomitant genetic alterations) could lead to the optimal sequencing of therapies for patient with EGFR-mutant NSCLC.

Table 1

Major trials for EGFR-mutated NSCLC patients following progression on 3rd generation EGFR-TKIs

Study name Phase Intervention arm Comparator arm Biomarker selection ORR, % Median PFS, months PFS, HR (95% CI) OS, HR (95% CI) Grade 3 or higher AEs, % Reference
Bispecific antibody (EGFR-MET bispecific antibody)
   NCT04988295 (MARIPOSA-2) 3 Amivantamab + chemotherapy Carboplatin + pemetrexed None 64 (n=263) vs. 36 (n=131) 6.2 vs. 4.2 0.48 (0.36–0.64) 0.77 (0.49–1.21) 72 vs. 48 (9)
3 Amivantamab + lazertinib + chemotherapy Carboplatin + pemetrexed None 63 (n=263) vs. 36 (n=131) 8.3 vs. 4.2 0.44 (0.35–0.56) 0.96 (0.67–1.35) 92 vs. 48 (9)
   NCT02609776 (CHRYSALIS) 1 Amivantamab + lazertinib None 36 (n=45) 4.9 (8)
   NCT05647122 1 AZD9592 None
Targeted therapy
   NCT04862780 (SYMPHONY) 1/2 BLU-945 (EGFR + T790M/C797S inhibitor), BLU-945 + osimertinib None
   NCT04820023 1/2 BBT-176 (EGFR + T790M/C797S inhibitor) None
   NCT03940703 (INSIGHT 2) 2 Tepotinib (MET inhibitor) + osimertinib MET amplification 44 (n=98)a, 52 (n=31)b 5.4a, 4,6b 28 (13)
   NCT04816214 3 Capmatinib (MET inhibitor) + osimertinib Platinum + pemetrexed MET amplification
   NCT03778229 (SAVANNAH) 2 Savolitinib (MET inhibitor) + osimertinib MET overexpression and/or amplification 32 (n=193), 49 (n=108)c 5.3 (14)
   NCT02143466 (TATTON) 1 Savolitinib (MET inhibitor) + osimertinib MET amplification 33 (n=69) 5.5 57 (15)
   NCT05261399 (SAFFRON) 3 Savolitinib (MET inhibitor) + osimertinib Platinum + pemetrexed MET overexpression and/or amplification
   NCT05015608 (SACHI) 3 Savolitinib (MET inhibitor) + osimertinib Platinum + pemetrexed None
   NCT03944772 (ORCHARD) 2 Gefitinib + osimertinib C797S mutation
Necitumumab (anti-EGFR mAb) + osimertinib EGFR alterations
Alectinib (ALK inhibitor) + osimertinib ALK rearrangement
Selpercatinib (RET inhibitor), osimertinib RET rearrangement
Savolitinib (MET inhibitor) + osimertinib MET alterations
Chemotherapy
   NCT04765059 (COMPEL) 3 Osimertinib + platinum + pemetrexed Platinum + pemetrexed None
   TORG1938 (EPONA Study) 2 Osimertinib + platinum + pemetrexed Platinum + pemetrexed CNS progression on osimertinib
ADCs
   NCT03784599 (TRAEMOS) 2 Trastuzumab emtansine (HER2 ADC) + osimertinib HER2 overexpression 4 (n=27) 2.8 41 (16)
   NCT04619004 (HERTHENA-Lung01) 2 Patritumab deruxtecan (HER3 ADC) None 30 (n=225) 5.5 65 (17)
   NCT05338970 (HERTHENA-Lung02) 3 Patritumab deruxtecan (HER3 ADC) Osimertinib None
   NCT04676477 1 Patritumab deruxtecan (HER3 ADC) + osimertinib None (18)
   NCT03539536 2 Telisotuzumab vedotin (MET ADC) MET overexpression 12 (n=43) (18)
   NCT02099058 1 Telisotuzumab vedotin (MET ADC) + erlotinib or osimertinib MET overexpression 27 (n=15)d 64 (19)
   NCT04484142 (TROPION-Lung05) 2 Datopotamab deruxtecan (TROP2 ADC) None 44 (n=78) 48 (20)
Chemoimmunotherapy
   NCT03515837 (KEYNOTE789) 3 Pembrolizumab + platinum + pemetrexed Platinum + pemetrexed None 29 (n=245) vs. 27 (n=247) 5.6 vs. 5.5 0.80 (0.65–0.97) 0.84 (0.69–1.02) 44 vs. 39 (21)
   NCT02864251 (CheckMate722) 3 Nivolumab + platinum + pemetrexed Platinum + pemetrexed None 31 (n=144) vs. 27 (n=150) 5.6 vs. 5,4 0.75 (0.56–1.00) 0.82 (0.61–1.10) 45 vs. 29 (22)
   NCT03991403 (ATTLAS)e 3 Atezolizumab + bevacizumab + platinum + pemetrexed Platinum + pemetrexed None 70 (n=151) vs. 42 (n=74) 8.5 vs. 5.6 0.62 (0.45–0.86) 1.01 (0.69–1.46) 35 vs. 15 (23)
   NCT03802240 (ORIENT-31) 3 Sintilimab + platinum + pemetrexed Chemotherapy None 55 (n=158) vs. 47(n=160) 5.5 vs. 4.3 0.72 (0.55–0.94) 0.98 (0.72–1.34) 56 vs. 49 (24,25)
Sintilimab + IBI305 (bevacizumab biosimilar) + platinum + pemetrexed Chemotherapy None 65 (n=148) vs. 47 (n=160) 7.2 vs. 4.3 0.51 (0.39–0.67) 0.97 (0.71–1.32) 41 vs. 49 (24,25)

a, directed by FISH (MET GCN ≥5 and/or MET/CEP7 ≥2). b, directed by liquid biopsy by NGS (MET plasma GCN ≥2.3; Archer). c, ORR in patients with IHC 3+ staining ≥90% tumor cells and MET copy number ≥10. d, reported in the cohort of telisotuzumab vedotin (MET ADC) + erlotinib. e, included EGFR or ALK mutated NSCLC. EGFR, epidermal growth factor receptor; mAb, monoclonal antibody; NSCLC, non-small cell lung cancer; TKIs, tyrosine kinase inhibitors; ORR, overall response rate; PFS, progression-free survival; HR, hazard ratio; CI, confidence interval; OS, overall survival; AE, adverse events; ADC, antibody-drug conjugate; ALK, anaplastic lymphoma kinase; RET, rearranged during transfection; MET, mesenchymal-epithelial transition; CNS, central nervous system; HER2, human epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization; NGS, next-generation sequencing; GCN, gene copy number.

Conclusions

Amivantamab combined with chemotherapy, both with and without lazertinib, are the first treatments to demonstrate clinical benefit over chemotherapy alone in post-osimertinib settings within a randomized controlled trial, potentially representing a new SOC option. However, considering the substantial toxicity associated with these regimens, alongside the emergence of alternative strategies—such as targeted therapies for on-target resistance mechanisms, combined targeted therapies (3rd-generation EGFR-TKIs and therapies targeting off-target resistance mechanisms), ADCs, and chemoimmunotherapy in conjunction with VEGF inhibitors—a personalized 2L strategy becomes crucial to select the best treatment for each individual patient with EGFR-mutant NSCLC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-7/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-7/coif). A.C.T. has received consulting fees from Amgen, Bayer and Pfizer, and honoraria from Amgen, Bayer, Pfizer, AstraZeneca, Guardant Health, Merck and Roche. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

  1. Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. N Engl J Med 2023;389:1935-48. [Crossref] [PubMed]
  2. Cho BC, Felip E, Spira AI, 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:S1306. [Crossref]
  3. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015;16:990-8. [Crossref] [PubMed]
  4. Mok TS, Wu YL, Ahn MJ, et al. Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer. N Engl J Med 2017;376:629-40. [Crossref] [PubMed]
  5. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study. J Clin Oncol 2021;39:3391-402. [Crossref] [PubMed]
  6. Vijayaraghavan S, Lipfert L, Chevalier K, et al. Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther 2020;19:2044-56. [Crossref] [PubMed]
  7. Moores SL, Chiu ML, Bushey BS, et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res 2016;76:3942-53. [Crossref] [PubMed]
  8. Cho BC, Kim DW, Spira AI, et al. Amivantamab plus lazertinib in osimertinib-relapsed EGFR-mutant advanced non-small cell lung cancer: a phase 1 trial. Nat Med 2023;29:2577-85. [Crossref] [PubMed]
  9. Passaro 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;35:77-90. [Crossref] [PubMed]
  10. Pardridge WM. Drug transport across the blood-brain barrier. J Cereb Blood Flow Metab 2012;32:1959-72. [Crossref] [PubMed]
  11. Reck M, Ciuleanu TE, Lee JS, et al. Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1. J Thorac Oncol 2023;18:1055-69. [Crossref] [PubMed]
  12. Galstyan A, Markman JL, Shatalova ES, et al. Blood-brain barrier permeable nano immunoconjugates induce local immune responses for glioma therapy. Nat Commun 2019;10:3850. [Crossref] [PubMed]
  13. Tan DSW, Kim TM, Guarneri V, et al. Tepotinib + osimertinib for EGFR mutant (EGFRm) NSCLC with MET amplification (METamp) after first-line (1L) osimertinib. J Clin Oncol 2023;41:9021. [Crossref]
  14. Ahn MJ, Marinis FD, Bonanno L, et al. EP08.02-140 MET Biomarker-based Preliminary Efficacy Analysis in SAVANNAH: savolitinib+osimertinib in EGFRm NSCLC Post-Osimertinib. J Thorac Oncol 2022;17:S469-70. [Crossref]
  15. Hartmaier RJ, Markovets AA, Ahn MJ, et al. Osimertinib + Savolitinib to Overcome Acquired MET-Mediated Resistance in Epidermal Growth Factor Receptor–Mutated, MET-Amplified Non–Small Cell Lung Cancer: TATTON. Cancer Discov 2023;13:98-113. [Crossref] [PubMed]
  16. Jebbink M, de Langen AJ, Monkhorst K, et al. Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR Mutation-Positive NSCLC. JTO Clin Res Rep 2023;4:100481. [Crossref] [PubMed]
  17. Yu HA, 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;41:5363-75. [Crossref] [PubMed]
  18. Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin (Teliso-V) monotherapy in patients (pts) with previously treated c-Met–overexpressing (OE) advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2022;40:9016. [Crossref]
  19. Camidge DR, Barlesi F, Goldman JW, et al. Phase Ib Study of Telisotuzumab Vedotin in Combination With Erlotinib in Patients With c-Met Protein–Expressing Non–Small-Cell Lung Cancer. J Clin Oncol 2023;41:1105-15. [Crossref] [PubMed]
  20. Paz-Ares L, Ahn MJ, Lisberg AE, 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:S755-6. [Crossref]
  21. Yang JCH, Lee DH, Lee JS, Fan Y, de Marinis F, Okamoto I, et al. Pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor (TKI)-resistant, EGFR-mutant, metastatic nonsquamous NSCLC: Phase 3 KEYNOTE-789 study. J Clin Oncol 2023;41:LBA9000. [Crossref]
  22. Mok TSK, Nakagawa K, Park K, et al. LBA8 Nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) with disease progression after EGFR tyrosine kinase inhibitors (TKIs) in CheckMate 722. Ann Oncol 2022;33:S1561-2. [Crossref]
  23. Park S, Kim TM, Han JY, et al. Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non-Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04). J Clin Oncol 2024;42:1241-51. [Crossref] [PubMed]
  24. Lu 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;11:624-36. [Crossref] [PubMed]
  25. Lu S, Wu L, Jian H, et al. Sintilimab plus bevacizumab biosimilar IBI305 and chemotherapy for patients with EGFR-mutated non-squamous non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor therapy (ORIENT-31): first interim results from a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 2022;23:1167-79. [Crossref] [PubMed]
  26. Comer F, Mazor Y, Hurt E, et al. Abstract 5736: AZD9592: An EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting key oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond. Cancer Res 2023;83:5736. [Crossref]
  27. Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br J Cancer 2019;121:725-37. [Crossref] [PubMed]
  28. Reck M, Mok TSK, Nishio M, et al. Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial. Lancet Respir Med 2019;7:387-401. [Crossref] [PubMed]
  29. Chua KP, Teng YHF, Tan AC, et al. Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic Opportunities. Clin Cancer Res 2021;27:5939-50. [Crossref] [PubMed]
doi: 10.21037/actr-24-7
Cite this article as: Uehara Y, Tan AC. The Butterfly effect—will the MARIPOSA-2 study alter the trajectory of EGFR mutated non-small cell lung cancer (NSCLC). AME Clin Trials Rev 2024;2:33.

Article Options

Download Citation

Share