Despite Progress, ADCs Still Stalled in Non-Small Cell Lung Cancer

With antibody-drug conjugates well established in liquid tumors, companies are pivoting their focus to treating solid tumors, such as those of the breast, prostate and lung. If ADCs can be a viable treatment option for non-small cell lung cancer (NSCLC), which is particularly challenging given its resistance to chemotherapy and radiation, it could be a significant treatment advance with huge market potential.

In August 2022, AstraZeneca and Daiichi Sankyo’s ADC Enhertu won FDA approval as the first antibody-drug conjugate (ADC) to treat patients with HER2-mutated metastatic NSCLC, and several more programs involving ADCs for lung cancer are moving forward.

In December 2023, the FDA accepted the Biologics License Application (BLA) for Daiichi Sankyo and Merck’s patritumab deruxtecan (HER3-DXd) for the third-line treatment of NSCLC and set a PDUFA date of June 26, 2024. Then, in February, the regulator accepted the Biologics License Application for datopotamab deruxtecan (Dato-DXd), co-developed by Daiichi Sankyo and AstraZeneca, for the second-line treatment of NSCLC, setting an action date of Dec. 20.

“We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace.

But a major challenge in developing ADCs for NSCLC is that unlike many cancers, lung cancer isn’t typically treated with antibody therapies, Christiana Bardon, co-managing partner at MPM BioImpact, told BioSpace. “The early data was not that positive.”

Bardon said she believes ADCs will stall in lung cancer for the same reason: until compelling surface targets for lung cancer are developed that have good rates of internalization, there are no good markers to ensure sufficient payload delivery.

But treatments like Dato-DXd could be making inroads. Results from the Phase III Tropion-Lung01 trial showed that Dato-DXd, which is directed at the TROP2 receptor, reduced the risk of disease progression or death by 25% in the overall trial population and by 37% in patients with non-squamous tumors when compared to chemotherapy. High-level overall survival results from the trial reported Monday numerically favored Dato-DXd, showing clinically meaningful improvement in a prespecified subgroup of patients. However, survival results did not reach statistical significance in the overall trial population.

Bardon said TROP2 is one of the few targets where “good progress” has been made, “but the data hasn’t been that impressive” in NSCLC. Patients treated with Dato-DXd in the TROPION-Lung01 trial showed a progression-free survival (PFS) of only 4.4 median months vs. 3.7 with chemotherapy. “That’s not super exciting,” Bardon said, adding that Dato-DXd has not generated much excitement among lung cancer doctors.

The PFS bare minimum hurdle for something to generate excitement in the field of lung cancer would be about six months, she said. Right now, chemotherapy provides about a 20% response rate, with a PFS of six months, Bardon noted, saying this is the low bar to meet with treatments for lung cancer.

Another ADC targeting the TROP2 receptor is Gilead Sciences’ Trodelvy, which is FDA-approved to treat breast cancer. However, the company announced in January that the drug did not meet the primary endpoint of overall survival in a Phase III study in NSCLC. Gilead did observe a more than three-month difference in median overall survival in a subgroup of patients, so the company plans to continue researching effectiveness in these patients.

“We will work to further identify the metastatic NSCLC patient populations that may benefit from Trodelvy,” Gilead Chief Medical Officer Merdad Parsey said in a statement.

Rutstein is bullish on the potential of ADCs targeting TROP2 in NSCLC. “We haven’t seen the data yet, but [Gilead] described some evidence of benefit, despite a negative trial,” Rutstein said. “Overall, if you take the totality of the data with TROP2 antibody drug conjugates in NSCLC, we think there’s an important potential for patients,” he said.

Beyond TROP2, there are several other ADCs in development for NSCLC targeting HER2, HER3, c-MET, EGFR, NaPi2b and more.

Mythic Therapeutics is studying MYTX-011, an ADC targeting the c-MET receptor, in Phase I, and emerging ADC player Tubulis has TUB-040, which targets NaPi2b, a highly overexpressed antigen in lung and ovarian cancers, in preclinical studies.

Data showed that TUB-040 led to complete eradication of tumors with a low-dose single treatment in multiple ovarian cancer mouse models. Additionally, repeat-dose toxicology studies in nonhuman primates demonstrated that TUB-040 was well tolerated with minor and reversible adverse effects.

“The novel technology we use in TUB-040 aims to address one of the current main challenges of ADC treatments: to ensure long-term delivery of the payload to the tumor site in order to improve the durability of anti-tumor responses and ultimately clinical outcomes,” Tubulis CEO and Cofounder Dominik Schumacher told BioSpace in an email. This will ultimately improve clinical outcomes, he said, adding that the asset will soon advance to Phase I clinical trials.

But some analysts are not convinced that ADCs are ready to make a substantive difference in lung cancer.

Thanks largely to the available targets of other cancers such as breast, ovarian and prostate cancers, ADCs are “much bigger” in these areas, Bardon said.

ADCs need good antibody targets so they can bind to something on the tumor to deliver the payload, Bardon explained, adding that in breast cancer, that target is HER2. Indeed, Enhertu, which targets HER2, was approved for breast cancer the week before it got the green light for HER2-low metastatic NSCLC.

“We have a good antibody that addresses that good target,” Bardon said. “Therefore, it’s easy to innovate on the payloads, and that’s why we’ve gotten more sophisticated with our ability to treat breast cancer with ADCs.”

But no established treatments for lung cancer are antibody dependent, and that’s why there hasn’t been much progress developing mature ADCs in this area, she noted.

That’s not to say they’re totally obsolete. Once ADCs are developed, Bardon sees the future of lung cancer treatment as a cocktail of therapies working together.

“We’re just starting to get all the different ingredients of chemo, [immuno-oncology], targeted therapies, and in the future ADCs, and then we’ll combine and mix and match these for the first, second and third line.”

Mollie Barnes is a freelance science writer. Reach her at mollie@100yearsco.com. Follow her on Threads and Instagram @shejustlikedtogo or LinkedIn. See more of her work at molliebarnes.contently.com.