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ASCO: Bristol Myers unveils I-O triplet data in melanoma as Iovance touts 'paradigm-changing' combo result
23 May 2024
Clinical ResultPhase 3ASCOCell TherapyImmunotherapy
As Bristol Myers Squibb weighs how to proceed with its triplet, Iovance Biotherapeutics has moved its Amtagvi-Keytruda regimen into phase 3.
OveBristol Myers Squibba has become a popular testing ground forIovance Biotherapeutics new immuno-oncAmtagvi-Keytruda. 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 timelanomastigators have revealed clinical trial performance for a triplet containing BMS’ PD-1/LAG-3 combo Opdualag and the CTLA4 inhskin canceroyBristol Myers Squibba. ThIovance Biotherapeuticsrank 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 Opdualagn the phaCTLA42 RELATIVITY-048 triaadvanced melanomall be presented in detail at thetumorsing American Society of melanoma 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 immuIovancepy doublet met a high efficacy bar Amtagvisly sMerck & Co.nk Keytruda analysts in first-line melanoma.advanced melanoma
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 phasmelanomaTIVITY-Opdivoial sYervoybe presented at ASCO 2024. That result came afterOpdualagn follow-up of 33.8 months. Opdivoression-free survival wirelatlimab study previously earned Opdumelanoma first-line melanoma approval in 2022.
In the triplet’sOpdivo-Yervoy48 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, amelanomaed 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 Opdivo-Yervoyient Opdivotions and with different lengths of follow-up. Patient characteristics such as tumor PD-LOpdualagsion,Opdivomutations 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, tumoraPD-L1s died from tBRAFment-related adverse events, one with rectal hemorrhage and dyspnea and the other immelanomaiated myositis.
All told, 39% of patients experienced a grade 3 or 4 treatment-related side effect, and no new safety signals wOpdivo-Yervoywith the triplet.rectal hemorrhagedyspneaimmune-mediated myositis
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.
In an email interview, Friedrich Graf Finckenstein, M.D., Iovance’s chief medical officer, called the trialLeerinkonse rates “paradigm-changing” and “unprecedented,” particularly for the 30.4% rate of complete responses.
Previously, in RELATIVITY-047, Opdualag recorded a completIovancense 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 fOpdualagry 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 termIovanceration of response, nearly all responses to the Amtagvi-Keytruda regimen were ongoing as of the data cutoff. By that Iovanceight of the 15 responders had been in reimmune checkpoint inhibitorsimmune checkpoint inhibitorsimmune checkpoint inhibitorshs.
As the Leerink team noted, the PD-1 monotherapy approach raiseAmtagvi-Keytruda 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 Leerink high rates of grPD-13 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-Opdivo-YervoyigatOpdivoote in an abstract.
All things considered, Graf Finckenstein argued that the IOV-COM-202 results “strongly support” ththrombocytopeniaonneutropeniarunnianemia phase 3 TILVANCE-301 trial, which is pitting Amtagvi-Keytruda against Keytruda alone in untreated advanced melKeytruda
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 melanKeytrudaphodepletKeytrudaIL-2 are part of theadvanced melanomapare the body and to enhance the T cells.
Amtagvinckenstein suggT-cellthat an overall response ratsolid tumorrom TIFDANCE-301 could be used to support an accelerated approval in the front-line setting and to covPD-1Amtagvi monothmelanomapost-PD-1 nod into a fIL-2approval. The phase 3 trial will then continue to potentially seek a full approval for the combo based on progression-free survival.
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