Regeneron, Immutep Talk LAG-3 as ESMO Highlights New I-O Approaches

The March approval of Bristol Myers Squibb’s Opdualag (relatlimab and nivolumab) to treat unresectable or metastatic melanoma validated the newest checkpoint in the immuno-oncology arsenal. Since then, Regeneron, Merck, Immutep S.A. and more have been working hard to develop the next successful lymphocyte activation gene-3 (LAG-3) inhibitor. 

At the European Society of Medical Oncology (ESMO) Congress, Regeneron presented data from a combination of Libtayo (cemiplimab) and fianlimab, a LAG-3 inhibitor, in advanced melanoma.

The Phase III study pits the combo against Merck’s Keytruda (pembrolizumab), with progression-free survival (PFS) as the primary endpoint. 

In two independent patient cohorts, the IO duo demonstrated greater than 60% response rates. One cohort saw a 62.5% overall response rate, six complete responses and 19 partial responses. The second had a 65% ORR with one CR and 25 PRs.

Israel Lowy, M.D., Ph.D., SVP, translational and clinical sciences, oncology at Regeneron, spoke about the meaning of these data.

“Combining LAG-3 and PD-1 inhibition has shown promise in advanced melanoma but achieving response rates above 50% has been challenging,” he said in a statement. A Phase III trial in first-line metastatic melanoma is currently enrolling, and Lowy said Regeneron “[looks] forward to opening additional trials with this combination in the near future.”

Dr. Omid Hamid M.D., chief of research/immuno-oncology at The Angeles Clinic & Research Institute and primary investigator on the trial, referred to the consistency of the results.

“With greater numbers of patients treated, we continue to see the same remarkable response rate of 63.8%,” he told BioSpace, adding that a LAG-3 dose 100x higher was still tolerable. No novel toxicities were seen and there were durable responses to therapy, he noted.

In New Jersey, Merck is always looking for ways to augment the success of Keytruda. One of these is combining the blockbuster drug with favezelimab, its own anti-LAG-3 antibody. The tag-team is being studied in a Phase III trial versus standard of care in patients with previously treated metastatic PD-L1 positive colorectal cancer.

And BMS is working just as hard to stay on top. The company is currently studying Opdualag in a Phase II trial for non-small cell lung cancer. Data from the NEOpredict-Lung trial were presented at ESMO. The winning melanoma combo showed early signs of efficacy in NSCLC, according to the abstract presented by principal investigator Dr. Martin Schuler of the University Hospital, Essen.        

Immutep is Building on LAG-3 Innovation

Meanwhile, Immutep, founded by Frédéric Triebel, M.D., Ph.D., who discovered the LAG-3 immune control mechanism in 1990, is well on its way to presenting a host of data at upcoming cancer conferences.

Immutep is developing eftilagimod alpha (efti) across a range of oncology and autoimmune indications, including metastatic breast cancer, NSCLC and head and neck squamous cell carcinoma (HNSCC).

A combination of efti and Keytruda is being assessed in the Phase II TACTI-002 trial in first-line NSCLC. Results presented at ESMO’s s European Lung Cancer Congress 2022 showed the duo led to an ORR of 6% and a disease control rate of 36%. The ORR was even stronger at 38.6%.

In an interview with BioSpace, CEO Marc Voigt said these results “doubled or tripled” those seen with Keytruda monotherapy. “This opens the door for late-stage development,” he said. Immutep expects additional data from the trial in the fourth quarter of this year.

At ESMO’s Breast Cancer Congress in May, the company presented “significant data” from the Phase IIb AIPAC trial, made up of 227 patients with HER2-negative/HR-positive metastatic breast cancer.

Immutep reported a statistically significant increase in innate and adaptive immune response biomarkers, monocyte and CD8 T cell counts and serum CXCL10 levels. Absolute lymphocyte count was demonstrated in the efti group, but not the placebo cohort.

Voigt shared that Immutep has “the chance to move forward” to Phase III in both NSCLC and metastatic breast cancer.

PD-1 inhibitors like Keytruda and Opdivo (nivolumab) have shown formidable success since the mid-2010s. LAG-3, an MHC class II ligand structurally and genetically related to CD4, is generating excitement because the inhibition of this gene can enable them to work in more patients.

A Unique Mechanism of Action

While BMS, Merck and Regeneron are focused on blocking LAG-3 on the T cell to keep it active, Voigt said Immutep is putting a different spin on it. 

“We are touching the other side of the interaction in MHC class II,” he said. “We activate the antigen-presenting cells to boost the immune system on a broader scale.” While Keytruda boosts the T cell response, “we are working on the antigen-presenting cells which are involved in generating more CD8 and CD4 T cells and more NK cells,” he explained.

In this way, Voigt continued, there are “potentially more targets for anti-PD-1 to work on.”

Aside from Merck, Immutep has programs partnered with Pfizer and GSK and has out-licensed an antagonist antibody targeting LAG-3, LAG525, to Novartis.

Efti has also attracted the attention of the Maria Skłodowska-Curie National Research Institute in Warsaw, Poland. On Sept. 6, Immutep announced an investigator-initiated Phase II trial assessing efti in combination with Keytruda and radiotherapy in the neoadjuvant setting in up to 40 patients with select soft tissue sarcoma (STS). Immutep expects to dose the first patient in the first half of 2023 with initial interim data expected in Q4 2024.

This trial will be efti’s first test in the neoadjuvant setting, Triebel told BioSpace.

“The current successes of efti plus pembro (Keytruda) in the first- and second-line metastatic disease settings encourage us to ‘climb the ladder’ and test the same combo in early disease,” he said.

Triebel added that “immunotherapeutic approaches should be used at the earliest possible stage of the disease” in STS.

LAG-3: The Possibilities

Hamid concurred, saying he sees LAG-3 combinations "moving into the adjuvant and the neoadjuvant field quickly to show response and benefit.” 

He also discussed the potential of the LAG-3/PD-1 combination to improve two other immunotherapy approaches: Tumor-infiltrating lymphocytes (TIL) therapy and immune-mobilizing monoclonal TCRs against cancer (ImmTAC).

Hamid pointed to Immunocore’s IMC-F106C, a PRAME×CD3 ImmTAC therapy, as an example. Immunocore presented data at ESMO demonstrating doses of the drug were clinically active and showed “consistent and robust interferon gamma induction” – a specific marker of T cell activation.

Durable responses were observed in two of six patients with cutaneous melanoma; two of four patients with ovarian cancer; and three of six patients with tebentafusp-naïve uveal melanoma. 

Hamid said LAG-3 “is the best backbone to future triplet trials in melanoma.”