T-Cell(Baylor College of Medicine)

As Bristol Myers Squibb weighs how to proceed with its triplet, Iovance Biotherapeutics has moved its Amtagvi-Keytruda regimen into phase 3. Over the years, melanoma has become a popular testing ground for researchers to explore new immuno-oncology approaches. With prior approvals in the skin cancer, Bristol Myers Squibb and Iovance Biotherapeutics are now showcasing early clinical data for their respective novel combinations. For the first time, investigators have revealed clinical trial performance for a triplet containing BMS’ PD-1/LAG-3 combo Opdualag and the CTLA4 inhibitor Yervoy in advanced melanoma. The three-drug regimen shrank tumors in 27 of 46 first-line melanoma patients. The 59% overall response rate, including a 17% rate of complete responders, came after a 49.4-month median follow-up of a cohort in the phase 1/2 RELATIVITY-048 trial. The results will be presented in detail at the upcoming American Society of Clinical Oncology (ASCO) 2024 annual meeting. Separately, researchers will present updated data showing that the pairing of Iovance’s newly FDA-approved cell therapy Amtagvi and Merck & Co.’s Keytruda delivered a 65.2% response rate in front-line advanced melanoma, including a 30.4% rate of complete responses. The result came from 23 patients after a median follow-up of 21.7 months of cohort 1A in the phase 2 IOV-COM-202 trial. Both research teams called the findings encouraging. And for Iovance, its immunotherapy doublet met a high efficacy bar previously set by Leerink Partners analysts in first-line melanoma.   Triplet versus doublet   For BMS' triplet approach, the company tried to find out whether the three-drug trio can perform better than its existing offerings in melanoma. BMS' Opdivo and Yervoy monotherapy, a combination of the two meds, and Opdualag, which is a combination of Opdivo and the LAG-3 antibody relatlimab, have each been approved in melanoma. Opdualag induced a response in 43.7% of first-line melanoma patients, versus 33.7% for Opdivo alone, according to an update of the phase 3 RELATIVITY-047 trial set to be presented at ASCO 2024. That result came after a median follow-up of 33.8 months. A progression-free survival win from the study previously earned Opdualag its first-line melanoma approval in 2022. Separately, the Opdivo-Yervoy combo’s response rate has been reported at 58% in the phase 3 CheckMate-067 trial. Despite better efficacy, the PD-1/CTLA4 pairing was not able to capture the entire first-line melanoma immunotherapy market because of a worse safety profile. In the triplet’s RELATIVITY-048 study, 72% of patients who took the BMS trio were still alive after two years. The two-year survival rates were 64% and 59% for Opdivo-Yervoy and Opdivo alone, respectively, as reported in CheckMate-067. The numbers were 63.7% and 58.3% for Opdualag and Opdivo alone, respectively, in RELATIVITY-047. In a statement to Fierce Pharma, a BMS spokesperson argued that cross-trial comparisons are problematic as the studies were conducted at different times, among different patient populations and with different lengths of follow-up. Patient characteristics such as tumor PD-L1 expression, BRAF mutations and prior exposure to adjuvant therapy after surgery could each affect a melanoma drug’s response rate. With the caveats of cross-trial comparisons in mind, the triplet’s efficacy was barely an improvement over the Opdivo-Yervoy doublet, raising a question about the necessity of adding a third agent into the mix. That's not to mention safety: In the triplet trial, two patients died from treatment-related adverse events, one with rectal hemorrhage and dyspnea and the other immune-mediated myositis. All told, 39% of patients experienced a grade 3 or 4 treatment-related side effect, and no new safety signals were observed with the triplet. The study’s sample size is too small to reach any conclusions, and it was not designed for regulatory filings. Larger studies are needed to confirm the efficacy and safety of the triplet combination in this setting, the BMS spokesperson said, adding that the company will review the data in depth and work with investigators to share any additional results.   "Paradigm-shifting" response rates   Unlike BMS, Iovance doesn’t have to prove its Amtagvi’s combination with Keytruda is better than BMS’ existing immunotherapy doublet. Nevertheless, for the Iovance regimen to be competitive, Leerink Partners analysts recently said they would like to see an overall response rate above 65% in a large patient group, ideally with more than 50 patients. The 65.3% response rate cleared that bar, but the number of patients involved wasn’t even half of what the Leerink team laid out in their ideal situation. In an email interview, Friedrich Graf Finckenstein, M.D., Iovance’s chief medical officer, called the trial’s response rates “paradigm-changing” and “unprecedented,” particularly for the 30.4% rate of complete responses. Previously, in RELATIVITY-047, Opdualag recorded a complete response rate of 16.3% after a median follow-up of 19.3 months. Opdivo and Yervoy posted a 19% rate on the same metric in CheckMate-067 after a median follow-up of 38 months. Again, Iovance’s results came from a very small trial population whose characteristics differ from patients in the BMS trials. The Iovance trial does not allow prior exposure to immune checkpoint inhibitors. In terms of duration of response, nearly all responses to the Amtagvi-Keytruda regimen were ongoing as of the data cutoff. By that time, eight of the 15 responders had been in remission for at least 12 months. As the Leerink team noted, the PD-1 monotherapy approach raises an “incredibly difficult bar” to clear for the new doublet in terms of duration of response. Previously in CheckMate-067, with a minimum of five years of follow-up, the median duration of response had still not been reached for either Opdivo-Yervoy or Opdivo alone. As for safety, high rates of grade 3 or above treatment-emergent adverse events were observed for thrombocytopenia, neutropenia and anemia. The triplet regimen’s safety profile was consistent with the underlying disease and known safety profiles of Keytruda, nonmyeloablative lymphodepletion and IL-2, the investigators wrote in an abstract. All things considered, Graf Finckenstein argued that the IOV-COM-202 results “strongly support” the company’s rationale behind running the phase 3 TILVANCE-301 trial, which is pitting Amtagvi-Keytruda against Keytruda alone in untreated advanced melanoma. Amtagvi was the first T-cell therapy greenlighted for a solid tumor. The FDA in February granted an accelerated approval to the one-time individualized therapy for post-PD-1 treatment of melanoma. Lymphodepletion and IL-2 are part of the treatment to prepare the body and to enhance the T cells. Graf Finckenstein suggested that an overall response rate readout from TILVANCE-301 could be used to support an accelerated approval in the front-line setting and to covert Amtagvi monotherapy’s post-PD-1 nod into a full approval. The phase 3 trial will then continue to potentially seek a full approval for the combo based on progression-free survival.

BIO is asking biopharma companies to quantify the time it would take to switch their contracts with Chinese CDMOs to other vendors, as well as the number of patients that would be impacted by a disruption to those services. It’s no secret that U.S. biopharma companies rely on Chinese contractors to provide lab research and drug manufacturing services. However, the exact size of this intersection is relatively unclear. Facing a push for China-U.S. decoupling from Washington, the industry trade group Biotechnology Innovation Organization (BIO) now wants to quantify the U.S.’s dependence on Chinese CDMOs through a survey titled “Understanding Key Elements of the Biopharma Supply Chain.” In a member’s communication that Fierce Pharma obtained, BIO Chief Science Officer Cartier Esham, Ph.D., said the organization wants to use this “broad-based industry survey” to quantify the U.S.’s reliance on Chinese CDMOs and to “understand and begin to quantify the magnitude of effort and time required to potentially decouple links to China-CDMOs.” A BIO spokesperson confirmed the survey to Fierce Pharma. “The goal of the survey is to better educate and inform policymakers about how the biopharma supply chain operates and to ensure that patients continue to have access to the medicines they need,” the spokesperson said. The survey comes as bipartisan U.S. lawmakers in both parts of Congress are advancing the BIOSECURE Act, which aims to block certain “biotechnology companies of concern” from receiving federal funding based on national security reasons. The bill would forbid federal agencies from contracting with drugmakers that use biotechnology equipment or services provided by a company of concern. Because Medicare and Medicaid are considered a type of federal contracting, the draft bill, if enacted in its current form, could effectively cut those firms out of the U.S. market. WuXi AppTec, the largest Chinese contract research and manufacturing organization, is among four companies initially being targeted by the bill, which includes a clause to potentially expand to more companies from China, Russia, Iran and North Korea. BIO has backed the bill, with its CEO John Crowley calling biotechnology a “national security imperative.” As the tension escalates, WuXi AppTec has exited BIO.   So far, the characterization of the U.S.’s dependence on Chinese CDMOs has mainly been descriptive or anecdotal.   In 2023, WuXi AppTec counted 65% of its 26.1 billion yuan ($3.6 billion) revenue from customers in the U.S. Its sister CDMO, WuXi Biologics, had about 47% of its 17 billion yuan ($2.4 billion) revenue last year from North America. WuXi AppTec is also reportedly the manufacturer of the active ingredient used in Eli Lilly’s popular diabetes and weight loss drugs Mounajro and Zepbound, according to Bloomberg. Its subsidiary WuXi Advanced Therapies also helps make Iovance’s Amtagvi, which in February became the first T-cell therapy approved by the FDA for a solid tumor. However, the WuXi companies are only a piece of the Chinese puzzle in the U.S. drug supply chain. Now, the BIO survey is asking companies about the number of programs they have with any Chinese CDMO and the percentage of those contracts in either their commercial portfolio or preclinical and clinical pipelines. Companies are also asked to quantify the time it would take to switch those contracts to another vendor, as well as the number of patients that would be impacted by a disruption to those services. The survey is expected to close by the end of business on May 3. Once BIO has the results, it will share them publicly, the spokesperson said. In parallel to the survey, BIO is conducting “a series of detailed interviews/case studies with select member companies” to capture the impact of any potential decoupling with Chinese CDMOs, Esham’s letter shows. “BIO is advocating for policies that support global biopharma supply chains that do not put the health of patients or information about U.S. patients (particularly genetic information) at risk,” Esham said in her message to members. “BIO will continue to engage with federal law and policymakers through its advocacy to inform them regarding both the complexities of supply chain operation and the potential patient impact (particularly the risk of drug shortages) of this proposed legislation,” she added. The impact of a potential decoupling is expected to be heaviest on small biotechs versus large pharma companies. Even as the BIOSECURE Act is still working its way through the U.S. legislative process, Novartis is already working on mitigation plans to cut ties with Chinese contractors, CFO Harry Kirsch said during a press call last week. Novartis has “a little bit of connections” to Chinese contractors, he said, adding that the impact from the biosecurity crackdown is “very manageable” for Novartis. Similarly, Roche said its pharma business faces a “fairly minimal impact” from the proposed law, the company’s pharma head, Teresa Graham said on a separate call with reporters last week. She touted the Swiss company as having “one of the largest and most resilient manufacturing footprints” in the industry. Bristol Myers Squibb is also drafting plans to “protect the continuity of supply” of its medicines, CFO David Elkins recently told the Financial Times. The three large pharmas and their U.S. subsidiaries are all members of BIO.