The biotech world is often a rollercoaster of hype and disappointment. Yet, amidst the noise, sometimes a quiet giant stirs. Agenus Inc., a veteran player in the immunotherapy space, may be one such giant. While their Q1 2024 earnings call focused on the promise of their Botensilimab and Balstilimab (BOT/BAL) program in colorectal cancer (CRC), a closer examination of the transcript reveals an even more intriguing story: the potential for BOT/BAL to revolutionize cancer treatment by **sparing patients from debilitating surgeries**.

While surgery remains a cornerstone of cancer treatment, it often comes with significant downsides. Radical surgeries, like the removal of the rectum for lower colon tumors, can have a devastating impact on quality of life, particularly for younger patients. The prospect of a therapy that could eliminate the need for such invasive procedures is a game-changer, not just for patients but also for healthcare systems grappling with rising costs and an aging population.

Agenus's CEO, Garo Armen, alluded to this potential in the Q1 earnings call, revealing that at least one patient in the neoadjuvant CRC trial, after achieving a complete response with BOT/BAL, **refused surgery**. While this instance is anecdotal, it's a powerful illustration of the hope and empowerment that surgery-sparing therapies can offer.

The neoadjuvant setting, where treatment is given *before* surgery, is particularly exciting for BOT/BAL. Dr. Steven O'Day, Agenus's Chief Medical Officer, highlighted the remarkable results from an investigator-sponsored trial led by Dr. Pashtoon Kasi at Weill-Cornell Medical Center. In this trial, a single dose of BOT and two doses of BAL were given to 12 CRC patients before surgery. Remarkably, *all* three patients with MSI-high CRC had complete or near-complete pathologic responses, and six out of nine patients with MS-stable CRC had major pathologic responses, including **two complete pathologic responses** – all within just four weeks of treatment.

Furthermore, none of the 12 patients experienced tumor growth during the treatment interval, and no surgeries were delayed due to immune-related toxicities. The safety profile was also encouraging, with only two instances of reversible Grade 3 treatment-related adverse events.

These findings are particularly striking for MS-stable CRC, a type of colon cancer that has historically been resistant to immunotherapy. The fact that BOT/BAL could induce such profound responses in this challenging patient population within a short four-week window is groundbreaking.

Agenus is now expanding the neoadjuvant trial, extending the treatment period to six to eight weeks, a timeframe more typical of traditional neoadjuvant studies. This longer treatment duration is likely to further deepen responses, potentially pushing the percentage of complete pathologic responses even higher.

Response Rates in Neoadjuvant CRC Trial (4-week treatment)

Reference: https://seekingalpha.com/symbol/AGEN

While the company is understandably focused on securing accelerated approval for BOT/BAL in refractory MSS-CRC, the neoadjuvant setting could offer a faster path to market, particularly if the expanded trial continues to yield impressive results.

The potential for surgery-sparing treatment isn't limited to CRC. Agenus has reported encouraging data from smaller cohorts in other cancer types, including pancreatic and lung cancer. If these initial findings are confirmed in larger trials, BOT/BAL could become a transformative therapy across multiple solid tumors.

Hypothesis:

The neoadjuvant CRC trial data suggests that BOT/BAL, given for six to eight weeks, could achieve a complete pathologic response rate exceeding 50% in MS-stable CRC. This hypothesis is based on:

1. **The remarkable response rate observed in the initial four-week trial.** Extending the treatment duration is likely to further increase the depth of response. 2. **The mechanism of action of BOT/BAL.** As immuno-oncology agents, BOT/BAL activate the immune system to attack cancer cells. Longer treatment could allow for a more sustained and comprehensive immune response, leading to greater tumor destruction.

Potential Implications:

If the hypothesis holds true, Agenus could:

1. **Secure accelerated approval for BOT/BAL in the neoadjuvant setting for MS-stable CRC.** This would be a major milestone, offering patients a less invasive and potentially curative treatment option. 2. **Expand the use of BOT/BAL in the neoadjuvant setting across multiple tumor types.** This could revolutionize cancer treatment, sparing countless patients from debilitating surgeries and improving their quality of life.

While Agenus's future hinges on clinical data and regulatory decisions, the potential for BOT/BAL to become a cornerstone of surgery-sparing cancer treatment is undeniably exciting. If the company can successfully navigate the path ahead, they may well be the quiet giant that awakens, transforming the lives of cancer patients worldwide.

"Fun Fact: The human immune system is incredibly complex, containing trillions of cells that work together to defend the body against disease. Immunotherapy harnesses the power of this system to fight cancer."