Regeneron is back with long-term follow-up for its LAG-3 inhibitor and PD-1 inhibitor combo in advanced melanoma, phase 1 findings that have prompted the company to launch four phase 3 programs with the intent to rival Bristol Myers Squibb's approved Opdualag.
“We are confident that we're cooking with gas here, and that we are en route to potentially having much better data than what's out there already with the BMS Opdualag,” Israel Lowy, M.D., Ph.D., Regeneron’s SVP of translational and clinical sciences in oncology, told Fierce Biotech.
Regeneron previously presented data on the LAG-3 inhibitor fianlimab at 2023’s American Society of Clinical Oncology annual meeting. The investigational monoclonal antibody is designed to target the immune checkpoint receptor LAG-3 on T cells and is being studied in combination with the company’s PD-1 blocker Libtayo. For the phase 1 trial, three separate groups of adults with unresectable or metastatic melanoma received 1,600 mg of fianlimab and 350 mg of Libtayo for 12 months.
At a median follow-up of 23 months, Regeneron’s treatment showcased a 57% overall response rate (ORR) among 98 patients, according to data presented at this year’s European Society for Medical Oncology conference in Barcelona. For the same timestamp, Regeneron reported a complete response rate (CR) of 25% and a median progression-free survival (PFS) of 24 months.
This compares to a 43% ORR among 355 patients who received BMS’s rival anti-PD1 and LAG-3 blocking antibody combo, dubbed Opdualag, at 19.3 months of follow-up. The combination gained FDA approval in March 2022, ushering in the first LAG-3-blocking antibody for patients with melanoma.
While cross-trial comparisons carry inherent flaws, they're often used by industry watchers to determine how therapies might stack up. Regeneron's LAG-3/PD-1 prospect and BMS' Opdualag are currently being studied in a head-to-head trial.
The new Regeneron data slice also compares to its own previously reported data at a median of 12.6 months, when the combo demonstrated a 61% ORR, a 12% CR rate and a median PFS of 15 months.
“We're seeing remarkable durability,” Mark Salvati, Regeneron’s vice president and fianlimab global program head, told Fierce Biotech. “And now this transformation of CRs over time from 12% to 25%—almost unprecedented in this space—and that's translated into a PFS of 24 months.”
Discontinuations and adverse events
In the earlier data, a significant portion of patients had discontinued treatment in the study—a number that continued to rise as time progressed.
The initial findings revealed that 64% (63) of patients discontinued treatment. The top reason cited for discontinuation was disease progression, reported by 52% (33) of patients who stopped treatment.
The most recent data cut reveals 78% (76) of patients discontinued fianlimab. The main reason for discontinuation was still disease progression, as reported by 47% (36) of patients stopping treatment. The second most common reason for discontinuation was treatment-emergent adverse events (TEAEs), as reported by 22% (17) of patients who discontinued. So, among the entire trial population, 17% of patients discontinued treatment because of TEAEs. No specific breakdown was provided on how many of the TEAEs that caused the discontinuations were drug-related.
“Yes, the discontinuation rate is high, but it's the initial patients who are refractory patients,” Salvati explained. “Those who do respond stay in very durable responses even after they discontinue therapy. And this is not uncommon with other immune therapies.”
The discontinuation rates compare to 65.8% at a median 13 months of follow-up in RELATIVITY-047, BMS’ phase 2/3 trial that underpinned the FDA approval of Opdualag, according to results published in the New England Journal of Medicine.
For Regeneron's therapy, 31% of patients completed one year of treatment, while 4% of patients completed two years.
“The second year of therapy was optional—we only see 4% of the patients had that,” Salvati said. “There's a variety of reasons why they stopped the therapy under a year. The net result, however, is that these patients are remaining in deep and durable responses even after discontinuing therapy.”
Most of the discontinuations aren’t related to toxicity, Lowy emphasized.
“They have to do with either the treatment unfortunately not working or the treatment working really well in patients choosing to stop, or physicians choosing to stop,” Lowy explained. Seven patients (9%) stopped treatment due to a physician's decision, according to the data.
Regeneron’s 17% rate of patients stopping treatment due to a drug-emergent adverse event compares to 21% reported for Opdualag in the pivotal phase 2/3 trial, in which three treatment-related deaths were reported. The Opdaulag number includes 18% of cases that were directly related to treatment. Again, various factors could have played into the results from the separate trials.
For patients receiving Regeneron’s combo, grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 47% of patients. Grade 3 events are severe but not immediately life-threatening, while grade 4 events are life-threatening and grade 5 events are fatal. Of the 46 patients experiencing serious TEAEs, seven (15%) patients died.
When zeroing in on treatment-related adverse events (TRAEs), 19% of patients experienced serious events. TRAEs leading to death occurred in two patients: one experienced colitis and one experienced cardiac shock. The patient who experienced cardiac shock also had COVID-19 with pulmonary edema.
Overall, 39% of patients experienced treatment-related immune-mediated adverse events (imAEs), with 13% classified as serious events. The imAEs rate is similar to PD-1 monotherapy, according to Regeneron, except in adrenal insufficiency, in which it was 12% for all grades and occurred as a grade 3 or higher event in 5% of patients.
“If you look at the AE profile, with the exception of adrenal insufficiency, our rates are no different than a single agent PD-1, so the levels of discontinuation that you see reflect what you would see if you gave monotherapy,” Salvati said. “No patient with adrenal insufficiency went off therapy. So, the only AE that is substantially different didn't lead to treatment discontinuation.”
The ORR was 92% in the 12 patients experiencing drug-related adrenal insufficiency, according to Regeneron.
'Our next big thing'
For all 98 patients, disease control rate was 78%. The median overall survival duration was not reached. The combo showed “persistent high clinical activity” regardless of PD-L1 or LAG-3 status, according to Regeneron.
“In solid tumor oncology, this is our next big thing after Libtayo,” Lowy said.
The company is currently running a multi-study phase 3 program further evaluating fianlimab in melanoma.
This includes a phase 3 trial of fianlimab and Libtayo versus Keytruda in previously untreated unresectable locally advanced or metastatic melanoma that has an estimated enrollment of 1,590 patients and a primary completion date slated for 2026.
The company is also running a phase 3 study of fianlimab plus Libtayo up against Opdualag in unresectable or metastatic melanoma, with a primary completion date set in 2027.
That’s not all though—Regeneron has another ongoing phase 3. This one assesses the fianlimab-Libtayo combo compared to Keytruda in the adjuvant setting or among patients with completely resected high-risk melanoma.
Last but not least is the phase 2/3 trial of fianlimab and Libtayo compared with an anti-PD1 alone in peri-operative patients with resectable stage 3 and 4 melanoma.
“This really is the largest overall clinical development program in melanoma in history for ongoing phase 3 studies spanning across all the different stages of melanoma,” Salvati said. “It's a major commitment, and I think it reflects Regeneron’s desire to become a significant player in the oncology space, with melanoma fitting nicely with our existing skin franchise.”
The leaders see an opening in the European market for fianlimab as well.
“In Europe, the approval for Opdualag was confined to PD-L1 less than 1% because the benefit was not seen to be superior in the greater than 1%,” Lowy said. “But we're not seeing it. We're seeing a very strong [response] across the board, and if anything, it looks better.”
In Regeneron’s post-hoc analysis, the ORR was 50% in patients with less than 1% PD-L1 and 71% in patients with PD-L1 more or equal to 1%.
“We're seeing very strong efficacy regardless of the status of PD-L1 or LAG-3,” Salvati said. “We will look at both of these markers in the context of our larger phase 3 study.”
Regeneron is also studying fianlimab as a potential treatment in other solid tumors, such as non-small cell lung cancer, and advanced hematologic malignancies, according to the company’s pipeline.