Summary:

HER3 is ubiquitously expressed in EGFR-mutant non–small cell lung cancer (NSCLC) irrespective of resistant mechanisms to EGFR tyrosine kinase inhibitors, thus garnering attention as a valuable therapeutic target. In this issue of Cancer Discovery, Jänne and colleagues highlight early clinical data supporting patritumab deruxtecan as a potentially appreciable agent for previously treated EGFR-mutant NSCLC.

See related article by Jänne et al., p. 74.

The last two decades witnessed the rapid advancement of the treatment landscape of non–small cell lung cancer (NSCLC). EGFR is the most common oncogenic mutation found in NSCLC, and EGFR exon 19 deletion or L858R point mutation in exon 21 is associated with response to EGFR tyrosine kinase inhibitors (EGFR-TKI; ref. 1). Osimertinib is regarded as a preferred first-line treatment option for advanced EGFR-mutated NSCLC, demonstrating significant overall survival benefit based on phase III FLAURA study in EGFR-mutated NSCLC (2). However, the emergence of acquired resistance to EGFR-TKIs is inevitable, underscoring the importance of a state-of-the-art approach for subsequent treatment. Given the limited benefit of salvage therapy in EGFR-mutant NSCLC after progression on EGFR-TKIs accompanied with diverse and heterogeneous resistance mechanisms, establishing the optimal treatment strategies for EGFR-TKI–resistant NSCLC is a highly unmet medical need that warrants further exploration.

Investigating molecular mechanisms driving resistance to EGFR-TKIs should be considered to guide subsequent therapeutic strategies (Fig. 1). Resistance to osimertinib can be categorized as on-target resistance, upregulation of bypass signaling pathways, and histologic transformations (3). For patients with on-target resistance mechanisms such as EGFR C797X mutation, which occurs in 10% to 20% of patients (4), osimertinib with gefitinib or necitumumab (an EGFR mAb) or fourth-generation EGFR-TKIs (e.g., BLU-945 or BBT-176) would be feasible options. In patients with bypass pathway activation, targeting the bypass pathway can be accomplished with combined use of osimertinib and other relevant targeted agents, as exemplified in the ORCHARD study. Specifically, MET amplification, which is the most frequent cause of bypass pathway activation, occurring in 10% to 25% of patients, can be targeted by combining osimertinib and MET-TKIs (e.g., savolitinib), as seen in the TATTON study (5). Likewise, targeting HER2 amplification, RAS–MAPK pathway activation, PI3K pathway activation, and oncogenic fusions with combination strategies is an emerging treatment option. Bispecific antibodies targeting EGFR and c-MET simultaneously, such as amivantamab, can be useful irrespective of acquired resistance mechanisms, occupying a unique position in the treatment landscape of EGFR-TKI resistance. Furthermore, several ongoing phase III studies are currently evaluating the efficacy of combination therapy with checkpoint blockade and chemotherapy in patients with EGFR-mutated NSCLC who progressed on previous TKIs (NCT02864251, NCT03515837, and NCT03924050).

HER3 is one of the four members of EGFR families and is responsible for eliciting oncogenic signaling pathways via heterodimerization with other EGFR family members (6). Activation of HER3 is associated with increased proliferation and progression of cancer cells, in response to its interactions with the PI3K/AKT/mTOR and JAK–STAT signaling pathways. Because HER3 expression is broadly observed in a wide range of patients with EGFR-mutated NSCLC, and genomic alterations in HER3 do not compose the resistance mechanisms to EGFR-TKIs, targeting HER3 can be considered a compelling approach to overcome intrinsic and acquired resistance to EGFR-TKIs. Currently, targeting HER3 with antibodies rather than small molecules is regarded as an optimal approach due to minimal kinase activity of HER3. Adding cytotoxic payload to HER3-directed mAb can be a promising strategy with enhanced target cell killing efficacy. Accordingly, patritumab deruxtecan [HER3-Dxd; an antibody–drug conjugate (ADC) consisting of a HER3 antibody and topoisomerase I inhibitor payload via tetrapeptide-based cleavable linker] has been developed to target previously regarded as “undruggable” catalytically defective receptor tyrosine kinase.

In this issue of Cancer Discovery, the safety and efficacy of patritumab deruxtecan for patients with EGFR-TKI–resistant EGFR-mutant NSCLC are presented (7). This study included a dose escalation and expansion cohort, most of the patients being previously treated with osimertinib (72/81, 89%). Among 57 patients treated with patritumab deruxtecan 5.6 mg/kg every 3 weeks (recommended dose for expansion), objective response was observed in 22 patients (39%) including one patient with complete response, and the median duration of response was 6.9 months. In addition, median progression-free survival was 8.2 months, and median overall survival was not reached, proving noteworthy activity. Considering the complexity and heterogeneity of cancer evolution upon the emergence of osimertinib resistance at the intra- and interpatient levels, patritumab deruxtecan is an appreciable treatment option to overcome a wide range of acquired resistance mechanisms simultaneously. This notion is supported by antitumor efficacy of patritumab deruxtecan spanning from on-target to bypass resistance mechanisms as well as in patients with tumor harboring multiple acquired resistance mechanisms. On the basis of the promising efficacy, phase II study exploring the safety and efficacy of patritumab deruxtecan as a single agent in EGFR-mutated NSCLC after progression on EGFR-TKIs has been initiated (NCT04619004). In addition, a multiarm phase I study testing patritumab deruxtecan in combination with osimertinib is ongoing in both treatment-naïve and previously treated patients with EGFR-mutant NSCLC (NCT04676477).

ADCs couple the specificity of a mAb with the cytotoxic effects of chemotherapeutic agents to facilitate the targeted delivery of cytotoxic payloads directly to cancer cells (8). Currently, ADCs with customizable linkers and cytotoxic payloads with potency in the picomolar range have been successfully developed, overcoming the limitations of early ADCs. In NSCLC, increasing numbers of ADCs have been under development targeting various molecules. In the setting of emergent resistance to EGFR-TKIs, MET amplification is the most common bypass pathway in patients with EGFR-mutant NSCLC, representing MET as an attractive target for ADC development. Telisotuzumab vedotin (ABBV-399) is an ADC composed of the anti–c-MET mAb (ABT-700) coupled with microtubule inhibitor (monomethyl auristatin E). In a phase Ib single-arm study (NCT 02099058), 29 patients with advanced EGFR-mutant NSCLC with progression on prior EGFR-TKI treatment and with c-MET positivity received telisotuzumab vedotin 2.7 mg/kg every 3 weeks until disease progression. The objective response rate was 34%, and higher c-MET H-score (≥255) was associated with superior response and improved survival. In addition, 2% to 13% of patients showed HER2 amplification at the time of acquired resistance to EGFR-TKIs, revealing HER-2–directed ADCs as an appealing treatment option. For example, ado-trastuzumab emtansine (T-DM1) combined with osimertinib was explored in patients with EGFR-mutant NSCLC with HER2 bypass track activation (TRAEMOS; NCT03784599). Intriguingly, EGFR-directed ADCs have also been developed and tested in EGFR-mutated NSCLC progressed on standard treatment. MRG003 is an ADC composed of a human IgG1 anti-EGFR mAb conjugated to an monomethyl auristatin E payload via a protease-cleavable linker. A phase II study with MRG003 for EGFR-positive NSCLC is ongoing, addressing whether ADCs can overcome previous failure of mAb targeting EGFR in NSCLC.

Although ADCs are an innovative class of anticancer drugs and are expected to improve the outcome in a subset of patients, several concerns should be addressed. First, conceiving strategies to enrich patients who derive optimal benefit is especially challenging in the field of NSCLC. Theoretically, the expression of targets on the cell surface is necessary for ADCs to exert their activity. However, the heterogeneous nature of tumors as well as insufficient representativeness of small biopsy samples would hamper optimal estimation of target expression. Bystander properties of ADCs also add complexities of target molecule expression–based biomarker analysis. In line with this, there is a nonsignificant, but weak trend toward enrichment of response to patritumab deruxtecan in patients with higher baseline HER3 expression in this study. Promoting efficient internalization of ADCs through target modification can be a supplemental approach to broaden the benefit of ADCs. Recent preclinical study has demonstrated that EGFR inhibition through osimertinib can augment the antitumor activity of patritumab deruxtecan through upregulating membrane expression of HER3 and corresponding enhanced delivery of cytotoxic payload (9). In addition, safety profiles as well as unexpected toxicities would limit the clinical development and positioning of ADCs in earlier lines of treatment. Similarly, treatment-related interstitial lung disease occurred in 5% of patients and resulted in the discontinuation of patritumab deruxtecan in this study. Currently, expression of numerous target antigens exploited in ADC development is still poorly understood. To reduce on-target and off-target toxicities, several efforts are under way such as enhancing tumor-specific binding and minimizing leakage after cellular uptake. Unclear molecular mechanisms involved in the primary and acquired resistance would be another limitation of ADCs. Several resistance mechanisms including lysosomal proteolytic activity have been suggested, although largely unexplored (10). Development of linker chemistry or inhibition of drug efflux would hold a key to combat resistance mechanisms, which need further investigation.

In summary, ADCs are innovative and appealing therapeutic options for NSCLC as we witnessed in the case of patritumab deruxtecan in EGFR-TKI–resistant NSCLC. Currently, several ADCs are under investigation in early-phase clinical trials with promising results, and additional research efforts are ongoing, aimed at identifying novel target antigens and evaluating both rationally designed ADCs and new combinations with other anticancer drugs. Future studies should focus on identifying optimal biomarkers, broadening applicability, minimizing toxicities, and exploring resistance mechanisms of ADCs. With these efforts, ADC-based regimens would be incorporated into the treatment landscape of NSCLC either alone or in combination in the near future.

B.C. Cho reports grants from Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint medicines, Interpark Bio Convergence Corp.; personal fees from Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Janssen, Medpacto, Blueprint Medicines, TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, KANAPH Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp., KANAPH Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, Joseah Bio, Gencurix Inc, Interpark Bio Convergence Corp., Champions Oncology; and other support from DAAN Biotherapeutics outside the submitted work. S.M. Lim reports grants from Yuhan, Beigene, Boehringer Ingelheim, BridgeBio Therapeutics, Roche, GSK, Jiangsu Hengrui, AstraZeneca, Boehringer Ingelheim, Lilly, Takeda and J Ints. No disclosures were reported by the other authors.

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