Following the September 2024 FDA approval of osimertinib (Tagrisso) in non–small cell lung cancer (NSCLC), investigators have been pursuing the development of combination approaches using the addition of the third-generation EGFR TKI and other targeted therapeutics to safely enhance treatment regimens and improve outcomes for patients.1
“One of the research areas I’m most interested in is developing immune-based approaches for mutations that are traditionally viewed as more immune resistant, such as EGFR, ALK, and some KRAS subtypes,” Sandip P. Patel, MD,
a professor in the Department of Medicine at the University of California San Diego Health, said in an interview with OncologyLive. “Better understanding how we can harness [a patient’s] immune system to address their tumor type is something that we are a little further along in for smoking-related cancers, but there’s no reason never smoking-related tumors can’t be sensitive to different immune approaches as well. I’m very keen on developing novel immunotherapeutics to help this patient population.”
Osimertinib was examined as monotherapy following chemoradiation in adult patients with locally advanced, unresectable stage III NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations in the phase 3 LAURA trial (NCT03521154).2 During the 2025 European Lung Cancer Congress (ELCC), updated overall survival (OS) data from LAURA demonstrated that patients who received osimertinib (n = 143) experienced a median OS of 58.8 months (95% CI, 54.1-not calculable [NC]) compared with 54.0 months (95% CI, 42.1-NC) among patients who received placebo (n = 73; HR, 0.67; 95% CI, 0.40- 1.14; log-rank P = .140). The 48-month OS rates were 70% and 52%, respectively.
Prior data from LAURA supported the September 2024 FDA approval of osimertinib for the treatment of patients with locally advanced, unresectable NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy.1
EGFR-Targeted Combinations Display Efficacy in NSCLC
In the ongoing phase 2 ORCHARD study (NCT03944772), osimertinib is being evaluated in combination with multiple agents for the treatment of patients with EGFR-mutated NSCLC who experienced disease progression on frontline osimertinib.3 During ELCC, investigators presented updated findings from an arm of ORCHARD that is examining osimertinib in combination with datopotamab deruxtecan (Dato-DXd; Datroway). The primary end point of the trial is investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria; key secondary end points include progression-free survival (PFS), OS, duration of response, and safety.
“One area [where] we’ve made advances in NSCLC, particularly adenocarcinoma, has been around the use of precision oncology techniques in molecularly defined cohorts,” Patel noted. “One of the most common [alterations] is EGFR, for which we now have 3 reasonable frontline therapeutic options for patients. Unfortunately, patients can develop therapeutic resistance, so the idea of using similar precision approaches to address their targetable resistance has been an area of active interest. One study that has looked at this [approach] is ORCHARD.”
At a median follow-up of 13.4 months, patients who received osimertinib plus Dato-DXd at a dose of 4 mg/kg (n = 35) achieved a median PFS of 9.5 months (95% CI, 7.2-9.8) and those who received osimertinib with 6 mg/kg of Dato-DXd (n = 33) experienced a median PFS of 11.7 months (95% CI, 8.3-not calculable). The ORRs were 43% (80% CI, 31%-55%) and 36% (80% CI, 25%-49%), respectively, and the median times to onset of response were 2.7 months (range, 1.5-4.1) and 1.4 months (range, 1.2-2.1), respectively.
In terms of safety, patients who received 4 mg/kg or 6 mg/kg (n = 34) of Dato-DXd experienced treatment-related adverse effects (TRAEs) at a rate of 97%. Grade 3 or higher TRAEs (34% vs 56%, respectively), grade 3 or higher AEs (49% vs 74%), and serious AEs (31% vs 41%) were reported in both arms. One patient in the 4 mg/kg group experienced an AE leading to death.
The most common any-grade AEs in the 4-mg/kg group included nausea (57%), alopecia (51%), and stomatitis (51%). In the 6-mg/kg group, the most common any-grade AEs included nausea (74%), alopecia (68%), stomatitis (56%), cough (53%), and vomiting (50%).
Osimertinib is being further examined with and without Dato-DXd in the ongoing phase 3 TROPION-Lung14 (NCT06350097) and TROPION-Lung15 (NCT06417814) studies.4 TROPION-Lung14 is comparing osimertinib in combination with Dato-DXd with osimertinib monotherapy in patients with treatment-naive locally advanced or metastatic EGFR-mutated nonsquamous NSCLC. In TROPION-Lung15 Dato-DXd with or without osimertinib is being examined vs platinum-based doublet chemotherapy in patients with locally advanced or metastatic EGFR-mutated nonsquamous NSCLC who experienced disease progression on prior treatment with osimertinib.
“There are multiple other studies that are looking at [approaches to overcome frontline treatment] resistance,” Patel noted. “There are a variety of studies in progress, which will hopefully increase the number of therapeutic opportunities for our patients who have resistance to frontline EGFR-directed strategies in NSCLC.”
Another combination approach in EGFR-mutated NSCLC was evaluated in the phase 3 MARIPOSA trial (NCT04487080).5 MARIPOSA compared the EGFR/MET bispecific antibody amivantamab-vmjw (Rybrevant) plus the EGFR TKI lazertinib (Lazcluze) with lazertinib or osimertinib monotherapy in patients with treatment-naive EGFR-mutated advanced NSCLC.
At a median follow-up of 37.8 months, data from the final OS analysis of MARIPOSA presented during ELCC demonstrated that patients who received amivantamab plus lazertinib (n = 429) achieved a median OS that was not reached (NR; 95% CI, 42.9-NR) compared with 36.7 months (95% CI, 33.4-41.0) among patients who received osimertinib (n = 429; HR, 0.75; 95% CI, 0.61-0.92; P < .005). The 42-month OS rates were 56% and 44%, respectively. Additionally, the median intracranial PFS was 25.4 months (95% CI, 20.1-29.5) vs 22.2 months (95% CI, 18.4-26.9), respectively (HR, 0.79; 95% CI, 0.61-1.02; P = .07).
Prior findings from MARIPOSA supported the August 2024 FDA approval of lazertinib plus amivantamab for the frontline treatment of patients with locally advanced or metastatic NSCLC harboring EGFR exon 19 deletions or exon 21 L858R substitution mutations.6
“The [MARIPOSA] regimen makes sense for patients who want to maximize their antitumor benefit [and who] understand the toxicities, particularly gastrointestinal and skin toxicities, that could develop with the use of this therapeutic combination, as well as the amount of time that coming into the infusion center takes vs taking a pill,” Patel said. “It’s an important discussion to have with our patients around what I consider the 3 frontline regimens, which are the standards of care [SOC]: amivantamab plus lazertinib; chemotherapy plus osimertinib; or osimertinib alone. [Osimertinib monotherapy] is for patients who want to maximize quality of life with an oral-only regimen. These 3 [options] represent the SOC, with amivantamab plus lazertinib having an OS benefit at the cost of [increased] toxicity.”
Investigators Gather at ILCC to Further Discuss Combination Approaches and More
Patel cochaired the 26th Annual International Lung Cancer Congress® (ILCC) hosted by Physicians’ Education Resource®, LLC, with Roy S. Herbst, MD, PhD, and Heather A. Wakelee, MD, FASCO, at the end of July. Investigators from across the field of lung cancer convened to further discuss the development of combination approaches in the space.7
In advance of the event, Patel said he expected to see “a continued emphasis on the appropriate use of precision therapeutics in the correct setting, meaning those patients with EGFR mutations get EGFR-directed therapy and those patients with KRAS mutations will often get immunotherapy up front. [We are] thinking about how we can best use immunologic approaches in the curative-intent setting and increasing the number of patients with the opportunity to receive neoadjuvant or perioperative chemoimmunotherapy to maximize our cure rates for these patients, which fundamentally requires us to improve our low-dose CT screening rates for former smokers or those who’ve recently quit.”
References
- FDA approves osimertinib for locally advanced, unresectable (stage III) non-small cell lung cancer following chemoradiation therapy. FDA. September 25, 2024. Accessed April 17, 2025. bit.ly/3RTKZQF
- Ramalingam SS, Ozguroglu M, Ahn MJ, et al. Osimertinib (osi) after definitive chemoradiotherapy (CRT) in patients (pts) with unresectable (UR) stage III EGFR-mutated (EGFRm) non-
small cell lung cancer (NSCLC): updated overall survival (OS) analysis from the LAURA study. J Thorac Oncol. 2025;20(suppl 1):S123-S124. doi:10.1016/S1556-0864(25)00379-X - Le X, Hendriks L, Morabito A, et al. Osimertinib (osi)+ datopotamab deruxtecan (Dato-DXd) in patients (pts) with EGFR- mutated (EGFRm) advanced NSCLC (aNSCLC) whose disease progressed on first-line (1L) osi: ORCHARD. J Thorac Oncol. 2025;20(suppl 1):S2-S4. doi:10.1016/S1556-0864(25)00196-0
- Three phase 3 trials of datopotamab deruxtecan-based combinations initiated in patients with advanced nonsquamous non-small cell lung cancer. News release. Daiichi-Sankyo. October 30, 2024. Accessed April 21, 2025. bit.ly/3GkKzQX
- Yang JCH, Kim YJ, Lee SH, et al. Amivantamab plus lazertinib vs osimertinib in first-line (1L) EGFR-mutant (EGFRm) advanced NSCLC: final overall survival (OS) from the phase III MARIPOSA study. J Thorac Oncol. 2025;20(suppl 1):S6-S8. doi:10.1016/ S1556-0864(25)00199-6
- FDA approves lazertinib with amivantamab-vmjw for non-small lung cancer. FDA. Updated August 20, 2024. Accessed April 21, 2025. bit.ly/3Y5PP0P
- 26th Annual International Lung Cancer Congress. Physicians’ Education Resource LLC. Accessed April 17, 2025. bit.ly/4lC4H14