Schneider Urges Closer Review of Mechanisms of Resistance in Relapsed NSCLC

Targeted Therapies in OncologyMarch II, 2024
Volume 13
Issue 4
Pages: 57

Though osimertinib is the preferred frontline approach to treatment for those with non-small cell lung cancer with classic EGFR mutations, acquired resistance mechanisms invariably develop.

Jamie L. Schneider, MD, PhD

Jamie L. Schneider, MD, PhD

Assistant in Medicine

Massachusetts General Hospital

Instructor in Medicine

Harvard Medical School

Boston, MA

Although the use of the tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) is the preferred frontline approach in patients with non-small cell lung cancer (NSCLC) with classic EGFR mutations, acquired resistance mechanisms invariably develop.

“When we think about acquired resistance to TKIs, this is not limited to EGFR and ALK—it is a universal persistent challenge,” Jamie L. Schneider, MD, PhD, said during a presentation at the 21st Annual Winter Lung Cancer Conference, which was held February 2 to 4, 2024, in Hollywood, Florida, and was sponsored by Physicians’ Education Resource, LLC (PER). Schneider is a medical oncologist and assistant in medicine at Massachusetts General Hospital and an instructor in medicine at Harvard Medical School in Boston.

Acquired resistance is characterized by on-target and off-target mechanisms. “The clearest path for overcoming on-target resistance is to leverage a persistent oncogene dependency with an eye toward next-generation TKIs,” Schneider said. For off-target resistance which is more complex given its heterogeneity, solutions lie in bypass pathways, lineage change, and cellular phenotypic changes such as epithelial-mesenchymal transition.1

Resistance mechanisms after first- and second-line osimertinib are quite diverse but similar patterns do emerge. Results of retrospective studies have provided information about the distribution of resistance mechanisms: On-target resistance mechanisms include EGFR amplification and EGFR GT245; off-target resistance mechanisms can be KRAS mutation, MET amplification, BRAF or RET fusions; and transformation mechanisms include small cell, squamous, and pleiomorphic.

From a prospective standpoint, the phase 2 ELIOS trial (NCT03239340) characterized resistance mechanisms arising after first-line osimertinib.2 In the study, 154 patients were enrolled at a median age of 62 years (range, 35-87). At data cutoff patients had disease progression. Median progression-free survival (PFS) was 16.4 months (95% CI, 12.7-20.3).

The main acquired resistance mechanisms according to the investigators, were MET amplification (17%) and EGFR C797S (15%). “The findings underscored the importance of obtaining a biopsy after first-line osimertinib Schneider emphasized.

For off-target resistance, strategies to bypass pathway activation include MET amplification and acquisition of oncogenic fusions Schneider said.3 Specifically, clinical trials that combine EGFR and MET inhibition represent viable approaches. Clinicians can also consider off-label osimertinib plus crizotinib (Xalkori).

For RET fusions treatment options include compassionate access to osimertinib plus pralsetinib (Gavreto) or off-label osimertinib plus cabozantinib (Cabometyx). In ALK fusion, treatment options include an off-label EGFR TKI plus ALK TKI, and for ROS1 fusion clinicians can consider an off-label EGFR plus ROS1 TKI.3

"So the question that arises is how do we use biomarkers to guide treatment selection?" Schneider asked. With this diverse array of bypass pathways to consider, the phase ORCHARD trial (NCT03944772) may shed some light.4

ORCHARD investigators evaluated osimertinib plus savolitinib (Orpathys) in patients after disease progression on firstline osimertinib. Patients whose tumors harbor MET alterations were allocated to receive osimertinib plus savolitinib.

At the data cutoff patients were evaluable for confirmed response. Objective response rate (ORR) was (n = 7; 80% CI, 25-59). Seven patients (41%) had a partial response, 7 (41%) had stable disease, and 1 (6%) had disease progression as best response.

3D rendering of lung cancer

3D rendering of lung cancer

Investigators concluded that the safety profile for the combination was acceptable and consistent with known profiles of the agents individually.

Further exploration of the combination will continue in the phase trial 2 SAVANNAH (NCT03778229). The combination demonstrated an ORR of 49% (95% CI, 39.0%-59.0%) and a median PFS of 7 months in patients with EGFR-mutated NSCLC with high levels of MET overexpression and/or amplification.

“There have been chromosomal rearrangements detected in EGFR-mutant lung cancer resistance and these can involve BRAF, ALK, or NTRK," Schneider said. “These have been identified in the context of postemergent resistance, and so co-targeting fusion oncogenes and EGFR might represent an approach to overcome resistance in this context."

At the time of relapse the importance of biopsy can't be emphasized enough Schneider said. “I want to reiterate: if you don't look for these on- and off-target resistant mechanisms, you'll miss treatment opportunities for your patients," Schneider said.

Second-Line Osimertinib

Guidelines suggest that upon systemic progression, osimertinib should be discontinued and platinum-based chemotherapy initiated. “But we now from various studies that some tumor cells remain osimertinib sensitive," Schneider said. “Continuing osimertinib treatment during chemotherapy might be beneficial many of us in practice are doing this."

The COMPEL study (NCT04765059)6 is an ongoing randomized phase 3 study evaluating the safety and efficacy of chemotherapy plus osimertinib vs chemotherapy plus placebo in patients with EGFR-mutant advanced NSCLC who experienced non central nervous system progression following first-line osimertinib therapy.

Patients in arm will receive pemetrexed (Alimta) plus cisplatin or carboplatin (plat-pem; investigators choice; cisplatin 75 mg/m2, carboplatin area under the curve, 500 pemetrexed mg/m2) plus osimertinib 80 mg followed by pemetrexed maintenance 500 mg/m2 and osimertinib 80 mg. Patients in arm will receive plat-pem plus placebo followed by pemetrexed maintenance and placebo. The first patients were enrolled in April 2021 and readouts are expected September 2024.

There is also evidence for novel combinations that target both EGFR and bypass pathways in the second line, Schneider said. The phase 3 MARIPOSA-2 trial (NCT04988295) demonstrated improved PFS vs chemotherapy after disease progression on osimertinib in patients with EGFR-mutated advanced NSCLC.7

In MARIPOSA-2, patients were randomly assigned to receive amivantamab-vmw (Rybrevant)/lazertinib/chemotherapy vs chemotherapy vs amivantamab plus chemotherapy.

At a median follow-up of 8.7 months, PFS was significantly improved with amivantamab plus chemotherapy (HR, 0.48; 95% CI, 0.36-0.64) and amivantamab/lazertinib/chemotherapy (HR, 0.44; 95% CI, 0.35-0.56) vs chemotherapy (median PFS, 6.3 and 8.3 vs 4.2 months, respectively; P <.001 for all). The ORR was 64% for amivantamab plus chemotherapy and 63% for amivantamab/lazertinib/chemotherapy vs 36% for chemotherapy (P <.001 for all). Interim overall survival was immature, with HR of 0.77 (95% CI, 0.49-1.21) for amivantamab plus chemotherapy vs chemotherapy and HR of 0.96 (95% CI, 0.67-1.35) for amivantamab/lazertinib/chemotherapy vs chemotherapy.

"The resistant mechanisms to EGFR inhibition are diverse and complicated. With continued use of next-generation EGFR inhibitors, we are seeing more off-target resistance as we hit EGFR harder," Schneider said. “Evaluation of EGFR-dependent and EGFR-independent mechanisms of resistance needs to be considered at the time of relapse."

1. Passaro A, Jänne PA, Mok T, Peters S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer. 2021;2(4):377-391. doi:10.1038/s43018-021-00195-8
2. Piotrowska Z, Ahn MJ, Pang YK, et al. ELIOS: a multicentre, molecular profiling study of patients (pts) with epidermal growth factor receptor-mutated (EGFRm) advanced NSCLC treated with first-line (1L) osimertinib. Ann Oncology. 2022;33(suppl 7):S1420-S1421. doi:10.1016/j. annonc.2022.08.055
3. Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging treatment paradigms for EGFR-mutant lung cancers progressing on osimertinib: a review. J Clin Oncol. Published online June 18, 2020. doi:10.1200/JCO.19.03123
4. Yu HA, Ambrose H, Baik C, et al. ORCHARD osimertinib¢+¢savolitinib interim analysis: a biomarker-directed phase II platform study in patients (pts) with advanced non-small cell lung cancer (NSCLC) whose disease has progressed on first-line (1L) osimertinib. Ann Oncol. 2021;32(suppl 5):S978-S979. doi:10.1016/j.annonc.2021.08.1844
5. Tagrisso plus savolitinib demonstrated 49% objective response rate in lung cancer patients with high levels of MET overexpression and/or amplification in SAVANNAH phase II trial. News release. August 8, 2022. Accessed February 16, 2024. h¦p://
6. Sequest LV, Peled N, Tufman A, et al. COMPEL: chemotherapy with/without osimertinib in patients with EGFRM advanced NSCLC and progression on first-line osimertinib. J Thor Oncol. 2021;16(10):S1101. doi:10.1016/j.jtho.2021.08.504
7. Passaro A, Cho BC, Wang Y, et al. Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(suppl 2):S1307. doi:10.1016/j.annonc.2023.10.063
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