The Targeted Pulse: FDA Clears a Promising New ADC, Experts Examine Cabozantinib/Nivolumab’s Remarkable Effects in RCC, and More

FDA Clears IND for ZW191: A Possible Game Changer in Difficult-to-Treat Cancers

The FDA cleared the investigational new drug application for a novel antibody-drug conjugate (ADC) currently known as ZW191. This ADC functions as a topoisomerase I inhibitor and is designed to selectively target folate receptor alpha (FR⍺), a characteristic often observed in gynecologic cancers and non–small cell lung cancer. Zymeworks, the manufacturer of the agent, endeavors to initiate clinical development in 2024 and subsequent FDA approval.

“ZW191 is a differentiated product candidate in our pipeline that reflects the strength of our approach in developing best-in-class antibody-drug conjugates,” said Paul Moore, Phd, in a press release. “Developed to target FR⍺, which is expressed in several types of difficult-to-treat cancers, ZW191 incorporates a novel antibody and drug-linker that provides a unique combination of antibody-linker stability and payload potency, together with strong bystander activity, which could result in improved efficacy and enable targeting lower levels of FR⍺ compared with previously developed drug candidates.” Moore is the chief scientific officer of Zymeworks.

Cracking the Code on Immunotherapy’s Impact on Metastatic Angiosarcomas

The use of immunotherapy in metastatic angiosarcomas has produced mixed results, as demonstrated by data from the phase 2 AO91902 trial (NCT04339738). The first arm of the study showed that combining cabozantinib (Cabometyx) with nivolumab (Opdivo) resulted in significant anti-tumor effects and was well-tolerated among patients with advanced angiosarcoma who had previously received taxane treatment. However, in the second arm, the addition of nivolumab alone to paclitaxel did not significantly improve progression-free survival (PFS) compared with paclitaxel alone. Surprisingly, some benefit was observed specifically in scalp and face angiosarcoma.

“I think the most compelling data were presented at ASCO 2023 with cabozantinib/nivolumab. We are thinking more about platforms somewhat more analogous to that. The most promising data had a PFS of over 9 months. The question is where to go from here with that, probably moving that to [evaluation in randomized studies],” Juneko Grilley-Olson, MD, said in an interview discussing the varying data. Grilley-Olson is an associate professor in medicine at the Duke University School of Medicine and member of the Duke Cancer Institute.

Explaining Cabozantinib/Nivolumab’s Long-Term Survival Edge in RCC

Daniel George, MD, explores compelling treatment data involving the combination of cabozantinib and nivolumab in renal cell carcinoma (RCC), illustrated with a detailed case example. Drawing from the CheckMate 9ER study [NCT03141177] data, which compared the combination with sunitinib (Sutent), George explores the ideal treatment strategy for a 61-year-old man who has a history of low-volume, indolent metastatic clear cell RCC, having undergone left nephrectomy and adrenalectomy.

“There is a bit more elevation of rates of low-grade toxicities with sunitinib, [such as] fatigue, nausea, some of the inflammation, and some of the cytopenias. The cabozantinib/nivolumab [combination has] higher [rates of] hypothyroidism, diarrhea, liver function test [elevation]… Most of it is low grade, grade 1, and grade 2. If you look at grade 3 [and higher], they’re similar between the 2 arms,” George explained. George is the Eleanor Easley Distinguished Professor, professor of medicine and surgery at Duke University School of Medicine in Durham, North Carolina.

FDA’s Denial of Botensilimab/Balstilimab for mCRC Causes Agenus to Pivot

The FDA advised Agenus, the manufacturer for both botensilimab (AGEN1181) and balstilimab (AGEN2034), not to file for accelerated approval due to unfavorable objective response rates for survival from a phase 2 trial (NCT05608044). In the trial, investigators evaluated the efficacy of botensilimab plus balstilimab in patients with relapsed/refractory microsatellite stable metastatic colorectal cancer without liver metastases. After further discussion, the FDA and Agenus reached an agreement regarding the recommended dose of the combination for a phase 3 study.

“Based on the high level of enthusiasm from significant numbers of global clinical experts and the promising clinical activity we have seen in the phase 1 and 2 studies, our commitment to seek all possible pathways to make botensilimab/balstilimab available to patients is unwavering,” said Steven O’Day, MD, chief medical officer of Agenus, in a press release. “This includes exploring opportunities to partner in the United States to accomplish a successful phase 3 trial.”

PFS Rates Stagnate With Nivolumab/Tivozanib Combination For RCC

Data from the phase 3 TiNivo-2 trial (NCT04987203) showed that the addition of nivolumab to tivozanib (Fotivda) did not improve PFS for those with advanced metastatic RCC whose tumors had progressed following prior immune checkpoint inhibitor (ICI) treatment. In contrast, data from the control arm of the trial, with patients receiving tivozanib alone, demonstrated a clinically meaningful median PFS in the second line after treatment with an ICI combination.

“The PFS and safety results from the control arm support tivozanib as an effective and well-tolerated treatment option in the second-line following an ICI combination as prior systemic therapy,” said Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, the Jerome and Nancy Kohlberg Chair and professor of medicine at Harvard Medical School, and lead investigator, in a press release.

Thank you for joining us for this week’s Targeted Pulse. Look out for more recaps to come.

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