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Combos for EGFR Acquired Resistance
Rational Combination Strategies in the Treatment of EGFR-Mutated NSCLC With Acquired Resistance to EGFR TKI Therapy: Updates From ASCO 2022

Released: July 13, 2022

Expiration: July 12, 2023

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Breaking research in lung cancer was presented at the 2022 American Society of Clinical Oncology Annual Meeting (ASCO 2022), including noteworthy studies reporting advances in the treatment of patients with EGFR-mutated non-small-cell lung cancer (NSCLC) and resistance to EGFR tyrosine kinase inhibitor (TKI) therapy. In this commentary, I will discuss data on rational combination regimens with third-generation EGFR TKIs, EGFR monoclonal antibodies, bispecific antibodies, and antibody–drug conjugates (ADCs) that target common resistance pathways to EGFR TKIs, such as MET.

Necitumumab, an EGFR Monoclonal Antibody, in Combination With Osimertinib
In a phase I trial from the ETCTN California Consortium (NCT02496663), which I presented the final results for at ASCO 2022 (abstract 9014), osimertinib plus the EGFR monoclonal antibody necitumumab was evaluated in 101 patients with EGFR-mutated NSCLC and resistance to a first-, second-, or third-generation EGFR TKI, with a primary endpoint of ≥3/18 patients with a confirmed partial response by Response Evaluation Criteria in Solid Tumors in each cohort in select settings of EGFR TKI resistance. This study was developed as a dose-escalation/dose-expansion study before osimertinib became the first-line standard of care based on the FLAURA study, which showed a substantial improvement in median progression-free survival (PFS) and overall survival (OS) vs earlier-generation EGFR TKIs.

Expansion cohorts in the ETCTN study focused on different settings of EGFR TKI resistance. The initial cohort in the dose-escalation phase included patients who were negative for an EGFR T790M mutation by tissue biopsy after progression on the early-generation EGFR TKIs erlotinib, gefitinib, or afatinib. In that setting, response rates are typically approximately 10% with second-line osimertinib in contrast to the 71% response rate reported for T790M-positive disease, which led to the original second-line indication for osimertinib. However, in ETCTN, the addition of necitumumab to osimertinib achieved a response rate of 22% with a median PFS of 3.9 months in T790M-negative disease, with the trial meeting its primary efficacy endpoint for that cohort.

In the next phase of the trial, we expanded the cohorts to include patients who had progressed on mostly second-line osimertinib stratified by T790M status (positive or negative), as well as those with EGFR exon 20 insertions after progression on platinum-based chemotherapy. When osimertinib became the first-line standard of care, we included another cohort of patients after progression on first-line osimertinib. In the dose-expansion phase, the primary efficacy endpoint was met for 3 of 5 cohorts: 4 of 18 patients with T790M-negative NSCLC after progression on a first- or second-generation EGFR TKI (cohort A) had a partial response and a median PFS of 3.9 months (90% CI: 1.3-5.7); 4 of 18 patients with an EGFR exon 20 insertion and progressive disease after chemotherapy (cohort D) had a partial response and a median PFS of 6.9 months (90% CI: 4.1-11.4); and 3 of 18 patients with progression after first-line osimertinib (cohort E)—a common contemporary scenario—had a partial response with a median PFS of 2.3 months (90% CI: 1.4-not available). With these results, the trial met its primary efficacy endpoints, which were prespecified as a signal for future clinical development.

Amivantamab, a Bispecific EGFR-MET Antibody, in Combination With Lazertinib, a Third-Generation EGFR TKI
In the ETCTN trial, we observed minimal clinical activity with combination EGFR blockade in patients who had MET amplification or other bypass-tract mechanisms to first-line osimertinib. MET amplification is the predominant mechanism of resistance to third-generation EGFR TKIs (approximately one quarter for osimertinib) when given in the frontline setting for the treatment of EGFR-mutated advanced NSCLC. The new bispecific antibody amivantamab, which has activity for both EGFR and MET, provides an opportunity for rational combination therapy in the treatment of these patients.

At ASCO 2022, Shu and colleagues (abstract 9006) presented updated data for cohort A in the CHRYSALIS-2 trial, which evaluated the efficacy of amivantamab plus the third-generation EGFR TKI lazertinib in 162 patients with advanced NSCLC and an EGFR exon 19 deletion or exon 21 L858R mutation who were previously treated with osimertinib and platinum-based chemotherapy.

At a median follow-up of 10 months, the overall response rate with amivantamab plus lazertinib in this heavily pretreated population was 33% (95% CI: 26%-41%), with a median duration of response of 9.6 months (95% CI: 7.0-not estimable). That one third of patients responded and that many of the responses were durable makes this a noteworthy combination for future clinical development. The results from the CHRYSALIS-2 update also illustrate the principle of targeting not just EGFR, but also MET, a strategy that I think is going to be the key to overcoming resistance in select patients with EGFR-mutated advanced NSCLC who have MET-driven resistance to osimertinib. 

Telisotuzumab Vedotin, a cMET-targeting ADC, in Combination With Osimertinib
ADCs are an exciting new strategy in the treatment of advanced NSCLC. Proof of principle efficacy results with ADCs in the treatment of cancer come from the setting of breast cancer, including the HER2-targeting drugs trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd), which was featured in the plenary session at ASCO 2022, where it showed improved PFS and OS compared with T-DM1 (standard of care) in patients with previously treated low HER2–expressing metastatic breast cancer in the phase III DESTINY-Breast04 trial. Proof of ADC efficacy in lung cancer was recently shown in a phase II trial published by Li and colleagues where T-DXd achieved an objective response rate of 55% in patients with relapsed/refractory lung cancer and HER2 mutations, a median PFS of 8.2 months, and median OS of 17.8 months. 

At ASCO 2022, Goldman and colleagues (abstract 9013) presented noteworthy results from a phase I/Ib trial (NCT02099058) evaluating the MET-targeting ADC telisotuzumab vedotin (teliso-v) in advanced solid tumors. This presentation reported the safety and efficacy of teliso-v 1.6 mg/kg or 1.9 mg every 2 weeks plus osimertinib 80 mg once daily in a cohort of 25 patients with advanced, EGFR-mutated NSCLC with MET overexpression after failure on prior osimertinib treatment. As mentioned above, for EGFR-mutated NSCLC, it makes sense to target the MET pathway in combination with EGFR blockade. cMET expression was determined by immunohistochemistry, and patients with intermediate expression, defined as 25% to 49% of tumor cells with 3+ staining intensity, and high expression, defined as ≥50% of tumor cells with 3+ staining intensity, were enrolled. The primary endpoints were recommended phase II dose, safety, and pharmacokinetics.

The overall objective response rate with the combination of teliso-v plus osimertinib was 58% in 19 evaluable patients with resistance to osimertinib. All patients in this cohort experienced a treatment-emergent adverse event, with the most common being peripheral sensory neuropathy (36%), peripheral edema (24%), fatigue (20%), nausea (20%), and cough (20%). Although there were only a small number of patients in this trial, to me it appears that this ADC overcame resistance to osimertinib based on the robust preliminary response rate. I think this combination is deserving of further exploration in this setting in a larger trial with more patients, and these results also lend support to the promise of ADCs in the treatment of advanced NSCLC, of which multiple are being developed, including enapotamab vedotin, which targets AXL, patritumab deruxtecan, which targets HER3, and datopotamab deruxtecan, which targets TROP2.

Future Directions
Here, I have discussed 3 important studies from ASCO 2022 that showcase rational combination strategies to treat patients with EGFR-mutated NSCLC who have acquired resistance to first-line EGFR TKI therapy. Although these studies lay a good foundation, further clinical development is needed. One important factor for the future success of these regimens will be to understand when resistance is occurring, potentially by using circulating tumor DNA to detect resistance early, and what the mechanism is, as there is remarkable molecular heterogeneity in mechanisms of resistance to EGFR TKI therapy, even within the same patient, whether on‑target EGFR mutations, MET amplification, RET fusions, ALK fusions, or others. These advancements are exciting, and I look forward to seeing how the field continues to evolve.

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