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Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Helena A. Yu, MD, has disclosed that she has received funds for research support paid to her institution from AstraZeneca, Cullinan Oncology, Daiichi Sankyo, Novartis, and Pfizer; and consulting fees from AstraZeneca, Blueprint, Daiichi Sankyo, and Janssen Oncology.
Antibody–drug conjugates (ADCs) represent a novel approach to personalizing targeted therapy for patients with non-small-cell lung cancer (NSCLC) without actionable driver oncogenes. By linking a cytotoxic payload to a modifiable antibody directed against HER2, HER3, TROP-2, or CEACAM5, ADCs can selectively deliver chemotherapy to cancer cells expressing these unique biomarkers. Below, I share my thoughts on identifying patients eligible for key ongoing trials evaluating ADCs as single agents or in combination in NSCLC, managing ADC-associated interstitial lung disease (ILD), and future directions.
Biomarker Testing Considerations
How can we identify patients with NSCLC most likely to benefit from ADCs? An illustrative example is biomarker testing for HER2 status to select those most likely to benefit from HER2‑directed ADCs. Standard approaches include using next-generation sequencing (NGS) to identify activating HER2 mutations; fluorescence in situ hybridization or NGS to quantify HER2 amplification (defined as a gene copy number ≥2.0 compared with a control gene, typically CEP17); or immunohistochemistry (IHC) to assess for higher HER2 protein levels (defined as IHC2+/3+).
Key Ongoing Trials of ADCs in NSCLC
Patient Identification for Key Ongoing Trials of ADCs in Advanced NSCLC
A promising ADC under investigation in NSCLC is the HER2-directed ADC trastuzumab deruxtecan, which is already approved by the FDA for use in breast cancer. The phase II DESTINY‑Lung01 trial is assessing trastuzumab deruxtecan in patients with previously treated advanced NSCLC that is either HER2 overexpressing (IHC2+/3+ without known HER2 mutation; cohort 1) or HER2 mutated (cohort 2). Interim analyses reported that trastuzumab deruxtecan has activity in both HER2-mutant (overall response rate [ORR]: 61.9%) and HER2-overexpressing (ORR: 24.5%) NSCLC. This trial prescreens for HER2 overexpression using locally archived tissue followed by central confirmation—a good approach because IHC results can vary depending on the anti-HER2 antibody used.
Currently, HER2 protein as biomarker is not routinely assessed in community practice for patients with lung cancer. Up to 20% of patients with NSCLC have some degree of HER2 overexpression, with high expression (IHC3+) in fewer than 5%. My suggestions for community practitioners are, first, to consider referring patients lacking a known driver oncogene for a clinical trial once they have exhausted standard treatment options. The trial site would then handle prescreening for different trials. Second, keep in mind that HER2 gene amplification frequently overlaps with overexpression, but not vice versa. Routine NGS includes copy number changes, so if NGS identifies HER2 amplification, that patient is likely to be eligible for a trial requiring HER2 overexpression (eg, KEYNOTE-797; NCT04042701). However, the lack of HER2 gene mutation or amplification does not mean the patient will not have HER2 expression.
Progressive EGFR-Mutated NSCLC
The ADC patritumab deruxtecan (U3-1402) targets HER3, a biomarker overlooked by most practitioners because it is very uncommon for patients with NSCLC to have HER3 mutations. Indeed, patritumab deruxtecan is in clinical development for EGFR‑mutant NSCLC, which has a higher frequency of HER3 expression and also where there is an unmet need for treatments after standard EGFR tyrosine kinase inhibitor (TKI) failure.
At WCLC 2020, my colleagues and I presented phase I data on patritumab deruxtecan in patients with EGFR‑mutant NSCLC with diverse resistance mechanisms to EGFR TKI therapy. A preplanned analysis assessed HER3 expression to determine if there could be further biomarker selection. Of interest, patritumab deruxtecan was associated with antitumor activity in patients with diverse mechanisms of resistance, including those with acquired EGFR alterations like EGFR C797S, bypass signaling alterations like MET amplification and HER2 amplification, and BRAF fusions. We still await data as to whether higher HER3 expression is associated with improved response—an important observation that could inform how to sequence treatment with this agent. After EGFR TKI failure, the standard approach—assuming no clinical trial access—is platinum-doublet chemotherapy, which has response rates of approximately 30% to 35%. Thus, in which line of treatment to use this ADC would depend on whether it has a higher or lower response rate vs standard chemotherapy in that setting. My recommendation to community practitioners would be to consider this phase I trial of patritumab deruxtecan for patients with EGFR-mutant NSCLC failing EGFR TKIs (NCT04619004).
The phase III TROPION-Lung01 trial (NCT04656652) is comparing datopotamab deruxtecan, an ADC directed against TROP-2, a transmembrane glycoprotein highly expressed in many malignancies, vs docetaxel. This trial is enrolling patients with progressive advanced NSCLC lacking actionable genomic alterations regardless of TROP-2 expression following standard platinum chemotherapy and immunotherapy. Thus, this trial is an option for many patients readily identifiable in community practice.
CARMEN‑LC03: Study Design
The phase III CARMEN-LC03 trial is comparing the CEACAM5-directed ADC SAR408701 vs docetaxel in patients with metastatic nonsquamous NSCLC previously treated with platinum chemotherapy and immunotherapy. Patients must have high expression (IHC ≥50% of tumor cells) of CEACAM5, a surface glycoprotein highly expressed in multiple cancers; an initial analysis of this trial found that SAR408701 was most efficacious in those with high expression. I would recommend having a patient’s tumor screened for CEACAM5 expression after chemotherapy and immunotherapy; if CEACAM5 expression is high, patients could be eligible for this trial.
Many anticancer drugs, from chemotherapy to immunotherapy to targeted agents, are associated with a risk of pneumonitis and ILD. ADCs are no exception, and ILD can occur in approximately 5% to 16% of patients treated with these novel agents.
If you have any suspicion of ILD, it is important to stop the ADC immediately and perform workup. Steroids are the backbone of ILD treatment. I would consider restarting the drug for a grade 1 pneumonitis likely unrelated to the ADC (eg, the patient improved with antibiotics). For drug-related cases of ILD, regardless of grade, I would recommend against restarting the ADC.
The rational next step in the development of ADCs is to try combining them with other agents to improve efficacy. For example, a phase I trial (NCT04676477) is evaluating patritumab deruxtecan plus osimertinib; by continuing the targeted therapy and adding the HER3-directed ADC, responses may improve in this oncogene-addicted population. Other ongoing combination trials are assessing ADCs against HER2 (DESTINY-Lung03, KEYNOTE-797, TRAEMOS), TROP-2 (TROPION-Lung04, TROPION-Lung02, Morpheus-Lung), and CEACAM5 (CARMEN-LC05, CARMEN-LC04).
I find ADCs particularly exciting because these are efficacious, personalized drugs in a population historically lacking targeted therapies. In the future, I anticipate performing multiplex protein expression screens to identify patients eligible for ADCs. The more options we have that are tailored to an individual’s specific lung cancer, the more likely they are to have better outcomes.
How do you anticipate integrating ADCs into care of your patients with NSCLC? Please answer the polling question and join the conversation by posting a comment in the discussion section below.