The approval of relatlimab/nivolumab (Opdualag) is exciting because it represents a new immunotherapy combination for patients with unresectable or metastatic melanoma, according to Hussein A. Tawbi, MD, PhD.

However, the newly approved agent will not replace PD-1/CTLA-4 combination immunotherapy, he explained. Rather, the 2 will now co-exist in the treatment landscape, providing oncology care teams multiple therapeutically relevant treatment options to offer their patients.

The fixed-dose PD-1/LAG-3 inhibition regimen was 

 on the indication of unresectable or metastatic melanoma for adults of at least 12 years of age and who weigh at least 40 kg. Notably, the approval was based off findings from the RELATIVITY-047 study, which demonstrated the combination 

Tawbi, a professor of the Department of Melanoma Medical Oncology at The University of Texas MD Anderson Cancer Center, and principal investigator in the RELATIVITY-046 trial, recently met with 

todiscuss what this approval means for patients with unresectable or metastatic melanoma.

“It is a really important development for our patients,” he said. “We know that single agent PD-1 has been capable of curing almost 40% of our patients with unresectable or metastatic melanoma. We really think that this [agent] will add a significant proportion of [successfully treated patients].”

“The one thing that we will always need to be very clear about is that this study did not compare the combination [of nivolumab/relatlimab] to the combination of PD-1/CTLA-4 inhibition,” noted Tawbi.

“There will be decision making in the first-line setting, [we will ask ourselves], ‘can I rely on nivolumab/relatlimab or do I give nivolumab/ipilimumab [Yervoy] despite the toxicity?’ From my perspective, that combination of nivolumab/relatlimab will replace single-agent PD-1 inhibitors.”

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Hussein A. Tawbi, MD, PhD, principal investigator of the phase 2/3 RELATIVITY-046 trial, highlights the importance of relatlimab/nivolumab’s recent FDA approval in melanoma.          

Expert Talks Significance of Relatlimab/Nivolumab Approval for Metastatic Melanoma

The discovery of LAG-3 inhibition may represent the first checkpoint inhibitor in over a decade, explained Hussein A. Tawbi, MD, PhD.

®, Tawbi, who is a professor of melanoma medical oncology of The University of Texas MD Anderson Cancer Center, deputy chair of clinical research, co-director of MD Anderson Brain Metastases Clinic, discussed why the results of the RELATIVITY-047 trial (NCT03470922) are particularly exciting for oncologists working with immunotherapies. Tawbi is lead study author of RELATIVITY-047, which was published in the 

The trial findings revealed that a novel regimen of immune checkpoint inhibitors, relatlimab and nivolumab (Opdivo), yielded encouraging responses among patients with untreated, advanced melanoma, and did not exhibit any new safety signals. 

Specifically, patients who received the combination achieved a median progression-free survival (PFS) of 10.1 months (95% CI, 6.4-15.7) compared with 4.6 months (95% CI, 3.4-5.6) among patients who received nivolumab as monotherapy (HR, 0.75; 95% CI, 0.62-0.92; 

Tawbi explained that “LAG-3 is one of several checkpoint inhibitors that are expressed on immune cells—in this case specifically on activated exhausted T cells. As you know, the immune checkpoint inhibitors have revolutionized cancer in the last decade.”

“I really do want to highlight the fact that we're very excited that this is the third checkpoint inhibitor after PD-1 and CTLA-4 to show clinical activity,” he shared with 

®. “It has been about a 10-year wait to find the third checkpoint inhibitor, and now we have a new agent to consider combining in different patient populations.”

“I would also like to highlight the fact that participation in clinical trial has been a critical component to make this happen,” added Tawbi. “It was a very difficult study to run during the pandemic, as a good part of it happened during the pandemic. I'm very grateful for the patients who participated. [In light of] all of the challenges that were happening, we would just like to commend them for that, and make it another call to action for all patients to consider enrollment in clinical trials, because that is how we bring progress. That's how we will have, hopefully, a new agent in hand to treat all patients

LAG-3 represents a potentially relevant immune checkpoint pathway in melanoma treatment.

Expert Explains Significance of LAG-3 Inhibition in Novel Immunotherapies for Melanoma

LAG-3 represents a potentially relevant immune checkpoint pathway, according to Hussein A. Tawbi, MD, PhD.

®, Tawbi, who is a professor of melanoma medical oncology of The University of Texas MD Anderson Cancer Center, deputy chair of clinical research, co-director of MD Anderson Brain Metastases Clinic, as well as lead study author in a recent study published in the 

, discussed the results of the RELATIVITY-047 trial (NCT03470922), which found that the combination of the immune checkpoint inhibitors relatlimab and nivolumab (Opdivo) demonstrated safety and efficacy as a treatment for patients with untreated, advanced melanoma. 

Tawbi explained that “LAG-3 is one of several checkpoint inhibitors that are expressed on immune cells—in this case specifically on activated exhausted T cells. And as you know, you know, the immune checkpoint inhibitors have been you have revolutionized cancer in the last decade.”

“One of the challenges with the combination of PD-1 and CTLA-4 is that it's highly potent, highly effective, but it is also unfortunately highly toxic. We have about a 55% [rate of] grade 3/4 adverse events with that combination,” he explained. “Again, as we are looking for these checkpoints. There are several that are being studied. One of them is LAG-3; what we know about LAG-3 is that that is also co-expressed with PD-1 quite regularly on exhausted antigen specific exhausted T cells.”

“In preclinical models when you block PD-1 and you blocked LAG-3 with it that had shown quite a bit of synergy,” Tawbi continued. “The idea of being able to combine those in patients to improve their outcomes has been in study now for several years… there were definite durable response rates in patients that had already progressed on prior PD-1 or PD-1 and CTLA-4.”

“Based on that safety and clinical activity, RELATIVITY-047 was designed to study the same combination, but this time in patients with previously untreated metastatic melanoma: patients [who] are treatment naïve that have not experienced treatment with anti–PD-1 before.”

Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. 

 2022;386(1):24-34. doi: 10.1056/NEJMoa2109970

Dr. Hussein Tawbi, MD, PhD, explains the rationale behind the RELATIVITY-047 trial in melanoma and how the LAG-3 findings could further revolutionize immunotherapy. 



Hussein A. Tawbi, MD, PhD

Articles

Expert Talks Significance of Relatlimab/Nivolumab Approval for Metastatic Melanoma

Expert Explains Significance of LAG-3 Inhibition in Novel Immunotherapies for Melanoma

Expert Explains Rationale Behind RELATIVITY-047 in Melanoma