More than two years after an initial FDA approval in melanoma, Bristol Myers Squibb is moving its PD-1/LAG-3 combo Opdualag into registrational testing in one of the most important oncology disease areas—first-line non-small cell lung cancer (NSCLC).
The company has disclosed a phase 3 trial coded RELATIVITY1093 to evaluate Opdualag—a fixed combination of the PD-1 inhibitor Opdivo and the LAG-3 inhibitor relatlimab—plus chemotherapy in stage 4 or recurrent nonsquamous NSCLC cases with PD-L1 expression between 1% and 49%. The trial will adopt a higher dose of relatlimab than in Opdualag’s FDA-approved melanoma indication and will use Merck & Co.’s Keytruda and chemo as the comparator.
Separately, BMS plans to initiate another phase 3 trial next year for Opdualag in first-line nonsquamous NSCLC patients with PD-L1 expressions of at least 50%, Chief Medical Officer Samit Hirawat, M.D., told Fierce Pharma in an interview.
RELATIVITY1093 is ready to roll because “the signal is very clear” and the unmet medical need still exists in the PD-L1-low population, Hirawat said.
“We don’t believe that the current standard of care is giving you the benefit of [progression-free survival] and overall response rate as what we have seen in our clinical trial,” Hirawat said. “So that is squarely a place where we wanted to go and fit and start the study as soon as possible.”
In contrast, BMS is taking time to “do a little bit more homework” as it devises the exact design of its phase 3 for the PD-L1-high population, including on the utilization of chemotherapy, he said. When asked whether BMS is considering dividing the PD-L1-high population to focus on a subgroup based on eligibility for chemo, Hirawat said he’s “not ready to commit” to such an approach.
Development of Opdaulag has been “a slow march,” Hirawat acknowledged.
“We didn’t straight away jump into [a] phase 3 trial in non-small cell lung cancer after we saw the melanoma data, which used to happen in the prior I-O world, because we really need to define how LAG-3 works, what the combinations would be and what the indication should be.”
ESMO RELATIVITY-104 readout
BMS’ latest decision is based on results from the phase 2 RELATIVITY-104 trial conducted in patients with previously untreated stage 4 or recurrent NSCLC. The trial did not include any enrollment criteria around levels of PD-L1 present in patients’ tumors. The story refers to the combo as Opdualag even though the dosage strengths of nivolumab and relatlimab evaluated in the trial are different from those in Opdualag’s FDA-approved melanoma indication.
Among PD-L1-negative patients enrolled in the part 2 efficacy portion of the trial (see table below for detailed data), the addition of relatlimab—at the 360-mg dose as selected from part 1—to Opdivo and chemo led to a slightly higher overall response rate (ORR), but the LAG-3-containing regimen performed slightly worse on progression-free survival (PFS), according to results shared at the European Society of Medical Oncology Congress 2024. Similarly, in patients with squamous disease, the Opdualag regimen showed a higher ORR but a shorter median PFS time.
In terms of patients’ life expectancy, benefits of Opdualag were observed only in PD-L1-positive patients and in those with nonsquamous disease, Hirawat said.
In PD-L1-low patients, those who took Opdualag and chemo showed an ORR of 60.7% and a median PFS of 9.8 months, whereas the Opdivo-chemo group experienced an ORR of 30% and PFS of 5.5 months, according to Hirawat.
In PD-L1-high patients, Opdualag and chemo delivered an ORR of 54.5% and a median PFS of 13.8 months, versus 46.4% and 7.1 months for Opdivo and chemo.
Among nonsquamous patients with PD-L1-positive tumors, the median PFS was 11.6 months for the LAG-3 group and 6.9 months for control, translating into a 45% reduction in the risk of progression or death.
BMS took into consideration data from part 1 of the trial and also benchmarked all results with findings from other published trials, Hirawat said.
| Opdualag + chemo | Opdivo + chemo | |||
| ORR (%) | mPFS (mo) | ORR (%) | mPFS (mo) | |
| PD-L1-negative | 50 | 5.6 | 44.8 | 5.8 |
| PD-L1-low | 60.7 | 9.8 | 30 | 5.5 |
| PD-L1-high | 54.5 | 13.8 | 46.4 | 7.1 |
| Squamous | 60.8 | 5.6 | 55.3 | 5.8 |
| Nonsquamous | 46.7 | 8.3 | 38.5 | 6 |
Shifting lung cancer landscape
Previously, in the landmark KEYNOTE-189 trial conducted in first-line nonsquamous NSCLC. Keytruda and chemo led to a median PFS of 11.3 months in PD-L1-high patients and 9.4 months in PD-L1-low patients, according to an updated analysis published last year.
BMS is advancing Opdualag into phase 3 testing as the NSCLC ground rapidly shifts under its feet. In LAG-3 alone, a phase 2/3 study that’s comparing the addition of Regeneron’s fianlimab on top of the company’s PD-1 inhibitor Libtayo and chemotherapy in advanced NSCLC is currently underway in phase 2. Regeneron has some early data at ESMO24 suggesting fianlimab might be better than BMS’ relatlimab in melanoma and is determined to prove that with an ongoing head-to-head phase 3 trial.
Beyond the LAG-3 class, Akeso and Summit Therapeutics’ PD-1/VEGF bispecific antibody ivonescimab just beat Keytruda monotherapy in a head-to-head China phase 3 in first-line, PD-L1-positive NSCLC. Summit has already launched a phase 3 trial pitting ivonescimab and chemo against Keytruda and chemo in first-line squamous NSCLC.
Merck, AstraZeneca and Gilead Sciences are developing their TROP2 antibody-drug conjugates in first-line NSCLC, too.
BMS has recently in-licensed an EGFRxHER2 bispecific ADC from China’s SystImmune. The drug is being evaluated in NSCLC and breast cancer. On the flip side, the New Jersey pharma just terminated a deal for Agenus’ TIGITxCD96 bispecific antibody following multiple failures in the TIGIT class.
“Each and every clinical trial is a step forward, not a step backward,” Hirawat said, “because it gives us an insight into how the landscape is evolving and what is to be learned.”