Progress Made, ADCs Still Stalled in NSCLC

Antibody-drug conjugates (ADCs) have shown promise in treating liquid tumors, prompting companies to explore their potential in solid tumors like those in the breast, prostate, and lung. A significant breakthrough could be the application of ADCs in non-small cell lung cancer (NSCLC), a notably challenging cancer due to its resistance to traditional treatments like chemotherapy and radiation.

In August 2022, AstraZeneca and Daiichi Sankyo’s ADC Enhertu received FDA approval to treat patients with HER2-mutated metastatic NSCLC, making it the first ADC to receive such an endorsement. Since then, several ADC programs targeting lung cancer have progressed. By December 2023, the FDA accepted a Biologics License Application (BLA) for patritumab deruxtecan (HER3-DXd) by Daiichi Sankyo and Merck for third-line treatment of NSCLC, with a set action date of June 26, 2024. Additionally, a BLA for datopotamab deruxtecan (Dato-DXd), co-developed by Daiichi Sankyo and Daiichi Sankyo, was accepted in February for second-line treatment, with an action date set for December 20.

Mark Rutstein, the Senior Vice President and head of global oncology clinical development at Daiichi Sankyo, expressed optimism about the potential of Dato-DXd for non-squamous NSCLC patients. However, developing ADCs for NSCLC poses unique challenges, as these cancers are not typically treated with antibody therapies. Christiana Bardon, co-managing partner at MPM BioImpact, noted that early data on ADCs for lung cancer was not encouraging due to the absence of compelling surface targets that ensure sufficient payload delivery.

Despite these challenges, some progress is being made with treatments like Dato-DXd, which targets the TROP2 receptor. Results from the Phase III Tropion-Lung01 trial demonstrated that Dato-DXd reduced the risk of disease progression or death by 25% in the overall trial population and by 37% in patients with non-squamous tumors compared to chemotherapy. However, high-level overall survival results did not reach statistical significance.

Bardon highlighted that TROP2 is one of the few targets with some progress, yet the data hasn't been particularly impressive for NSCLC. The progression-free survival (PFS) for patients treated with Dato-DXd was only 4.4 months, slightly better than 3.7 months with chemotherapy. To generate excitement in the field of lung cancer, Bardon stated that a PFS of about six months would be necessary.

Gilead Sciences’ ADC Trodelvy, approved for breast cancer, also targets the TROP2 receptor. Despite not meeting the primary endpoint of overall survival in a Phase III study for NSCLC, Gilead observed a notable difference in median overall survival in a specific patient subgroup, leading the company to continue research in these patients.

Beyond TROP2, several other ADCs are being developed for NSCLC, targeting a range of receptors such as HER2, HER3, c-MET, EGFR, and NaPi2b. Notably, Mythic Therapeutics is studying MYTX-011, an ADC targeting the c-MET receptor, and Tubulis is developing TUB-040, targeting NaPi2b, with promising preclinical results.

Dominik Schumacher, CEO and cofounder of Tubulis, emphasized that their novel technology aims to ensure long-term payload delivery to the tumor site, improving the durability of anti-tumor responses and clinical outcomes. TUB-040 is expected to advance to Phase I clinical trials soon.

Despite these efforts, some analysts remain skeptical about the immediate impact of ADCs on lung cancer treatment. Bardon pointed out that due to the lack of good antibody targets for lung cancer, progress in this area has been slower compared to cancers like breast and ovarian. She envisions the future of lung cancer treatment as a combination of therapies, including chemotherapy, immuno-oncology, targeted therapies, and eventually ADCs, tailored to different lines of treatment.

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