When it comes to immune-checkpoint inhibitors (ICIs), we cannot question the pervasiveness of already best-selling anti-PD1/PD-L1s such as Keytruda, Opdivo, Tecentriq, durvalumab, and others, leading the oncology sector for a decade. Undeniably, the development of ICIs has shaped the therapeutic landscape of various cancer types. Since the combination therapies in cancer research and development are evolving rapidly, key pharma companies are weaving newer and older ICIs to get the best results, ultimately increasing potential treatment options apart from enhancing their commercial value. Considering its benefits, data readouts related to the latest ICIs such as KRAS, LAG-3, and TIGIT are trending this ASCO 2021.
Concerning ASCO 2021 updates, DelveInsight has already published a detailed analysis on KRAS immunotherapy entitled “Amgen and Mirati – Leading Players with High Hopes for the Undruggable KRAS Mutation?” Now, it is time to shift attention toward LAG-3 (lymphocyte activation gene-3) immunotherapy, which is likely to steal the spotlight this upcoming conference.
BMS, already known for experimenting with a combination of ICIs to get the maximum, is currently pursuing its drug Opdivo (nivolumab) combined with relatlimab (LAG-3 blocking antibody) in a front-line setting for advanced resectable Stage III melanoma. The current standard of care for melanoma is mainly the combined dose of Opdivo-Yervoy and Opdivo monotherapy. However, with relatlimab, the company is planning to expand and occupy the remaining melanoma patient share. BMS’ RELATIVITY-047 study is the first randomized Phase III trial to evaluate this PD-1 and anti-LAG-3 antibody combination versus PD-1 alone in more than 700 patients. The fixed combination of Opdivo-Relatlimab achieved a median progression-free survival (mPFS) of 10.2 versus 4.63 months from Opdivo alone. Moreover, the company is also excited about the established safety and lower rates of adverse events than the Opdivo-Yervoy combination. Following the positive findings, we are assured that BMS has many talking points during the upcoming conference as relatlimab is the third distinct checkpoint inhibitor for the company with a promising opportunity to segment the melanoma treatment further and contribute to its growing share. The combination has also shown high pathologic complete response (pCR) and MPR rates with a favorable toxicity profile in the neoadjuvant and adjuvant settings.
Undoubtedly, BMS is ahead of the curve in recognizing the ability of LAG-3 immunotherapy, which holds considerable potential to boost responses and stop resistance, a common issue in many cancer treatments. However, we still need to hold on to our excitement as the company has only achieved the desired progression-free survival (PFS), while the overall survival data remain immature; full results will be presented during the conference on June 6, 2021.
Not just BMS, other players have understood the importance of enhanced immune responses when targeting the LAG-3 pathway in combination with PD-1 inhibition. BMS’s rival Merck is also evaluating an anti-LAG3 antibody, MK-4280, combined with Keytruda in the Phase I/II trial. Another drugmaker in the race is Immutep, a global leader evaluating eftilagimod alpha (Efti) in combination with Keytruda that has been driving strong responses and has the potential to expand keytruda’s patient population in large indications. The company will present the clinical data from its two Phase II trials (TACTI-002) evaluating Efti –Keytruda combination in patients with PD-L1 unselected metastatic second-line squamous head and neck carcinoma (HNSCC) and PD-L1 unselected metastatic non-small cell lung carcinoma (mNSCLC). The company has already disclosed that the combination is safe and shows encouraging antitumor activity and is also evaluating the Chemo-IO combination apart from IO-IO combinations. Immutep remains particular in differentiating Efti, an APC (antigen-presenting cells) activating soluble recombinant LAG-3 protein, which works oppositely compared to the other mentioned anti-LAG-3 therapies. The company has well-positioned Efti and is the only MHC II agonist being developed. Also, as clinical data continues to strengthen, Immutep is seemingly well situated for potential takeout or large deals. It is worthy of knowing that Immutep has out-licensed two of its antagonist antibodies to Novartis and GSK, which are being developed as leramilimab and GSK’781, respectively.
Next on the list is the drugmaker Innovent Biologics, which is evaluating IBI110 (LAG-3 blocking antibody) in Phase Ia/Ib dose-escalation study of IBI110 as a single agent and combined with sintilimab in patients with advanced solid tumors. IBI110 alone or plus sintilimab has acceptable toxicity and shows preliminary antitumor activity, whereas the company has planned to showcase the complete results in ASCO 2021.
Various other players are also a part of the race in LAG-3 immunotherapy evaluating multiple cancer indications; these include Macrogenics (tebotelimab), Regeneron (fianlimab), Roche (RO7247669), Incyte (NCAGN02385) and Symphoge (SYM022), where Regeneron is also set to present its Phase I data in the upcoming conference.