Immuno-Oncology at a Crossroads: The Search for the Next Breakthrough

The immuno-oncology (IO) field, which revolutionized cancer treatment over a decade ago, finds itself at a critical juncture. As the industry seeks to build upon the success of checkpoint inhibitors like Merck's Keytruda and Bristol Myers Squibb's Yervoy, researchers are exploring novel targets, combination therapies, and even pre-emptive immunization strategies to usher in the next wave of IO innovation.

The Checkpoint Inhibitor Legacy and Current Challenges

More than ten years after the seminal approval of Keytruda, the IO landscape has dramatically evolved. The FDA has approved 11 checkpoint inhibitors targeting immune checkpoint proteins such as PD-1, PD-L1, CTLA-4, and LAG-3. However, despite these advancements, IO treatment response rates have plateaued at around 30%, leaving a significant unmet need for the remaining 70% of patients who do not respond to these therapies.

Graig Suvannavejh, senior biopharmaceuticals and biotechnology equity research analyst at Mizuho Americas, notes that the IO space "continues to be quite disappointing" as the industry searches for the next great IO target. The challenge lies in identifying novel targets that work effectively and can be developed into successful therapies.

Emerging Targets and Combination Approaches

The TIGIT Rollercoaster

One of the most closely watched targets in recent years has been TIGIT. After initial excitement sparked by Roche's promising Phase II CITYSCAPE study results in 2021, subsequent setbacks have tempered expectations. Both Roche's tiragolumab and Merck's vibostolimab failed to meet primary endpoints in advanced studies for non-small cell lung cancer (NSCLC).

However, recent Phase II results from iTeos and GSK have reignited interest in the TIGIT pathway. Their anti-TIGIT candidate belrestotug, in combination with GSK's anti-PD-1 therapy Jemperli, showed a 30% better confirmed objective response rate compared to Jemperli alone in NSCLC patients. This has led to the initiation of a Phase III trial studying the combination as a first-line therapy for NSCLC.

Beyond TIGIT: Novel Targets and Approaches

The industry is also focusing on other promising targets and approaches:

1. Ivonescimab: This PD-1/VEGF bispecific antibody, developed by Summit Therapeutics, has shown superiority to PD-1 inhibition alone in Phase III trials for NSCLC. It reduced the risk of disease progression or death by nearly 50% compared to Keytruda in first-line advanced NSCLC.

2. PRAME and RAS pathway: Suvannavejh highlights preferentially expressed antigen of melanoma (PRAME) and the RAS pathway, including the commonly mutated KRAS, as targets of particular interest. Companies like Amgen, BMS, and Revolution Medicines are actively developing drugs targeting these pathways.

3. Novel checkpoint discovery: Companies like Compugen are using artificial intelligence and machine learning to identify previously unknown checkpoint proteins. Compugen's COM701, targeting the newly discovered PVRIG checkpoint, is currently in trials for various cancers.

The Future of Immuno-Oncology

As the field evolves, experts are emphasizing several key areas for future development:

1. Combination therapies: Jeremy Levin, CEO of Ovid Therapeutics, stresses the importance of combination approaches in addressing complex diseases like cancer.

2. Pre-emptive immunization: Levin suggests that the ultimate goal of IO is to engage the human body to defeat cancer cells before they proliferate, potentially through pre-emptive immunization strategies.

3. Novel target identification: The use of advanced technologies like AI and machine learning may uncover new targets and pathways for IO therapies.

4. Overcoming development challenges: Christiana Bardon, co-managing partner of MPM BioImpact, notes that the development path for new checkpoint inhibitors is particularly challenging, often requiring combination studies with existing PD-1 drugs.

As the immuno-oncology field continues to evolve, the search for the next breakthrough remains intense. With a market projected to be worth more than $17 billion by 2032, the stakes are high for companies looking to capture a share of this lucrative space. The coming years will likely see a continued focus on novel targets, innovative combination approaches, and potentially paradigm-shifting strategies like pre-emptive immunization in the ongoing battle against cancer.