Innovating Time: At ESMO GI, Agenus reports remarkable results in MSS CRC
Sponsored by and Provided by Agenus
Despite significant progress in the screening, detection, and treatment of cancer, it remains the second leading cause of death in the United States, and 1 in 3 Americans will be diagnosed with the disease in their lifetime [1]. Colorectal cancer (CRC) is the third most common cancer diagnosis, and it is on the rise in people under the age of 50 [2]. A lack of early symptoms means CRC often goes undetected until an advanced stage, when it is much more difficult to treat. In 2022, an estimated 150,000 Americans will be diagnosed with CRC, and over 50,000 will die from their disease [3].
For patients receiving the news, a CRC diagnosis upends every aspect of their lives. Beginning an uncertain and strenuous treatment journey, they often wonder about one variable above all else: time.
Yet for patients with the most common genetic form of CRC, known as "MSS CRC," time is the one thing that no treatment has been able to offer. An initial course of cancer therapy is known as the first-line treatment; if it fails or is discontinued due to side effects, a patient moves to second-line options. Or third. In each round, the likelihood of success decreases, until a patient is classified as "heavily pretreated" – and left with very limited options. Time is especially of the essence for these patients.
In heavily pretreated MSS CRC, only 1-2% of patients respond to current standard-of-care drugs, and their expected survival is just 6-7 months [4] . These drugs are difficult to tolerate, often leading physicians to reduce or halt therapy, and decreasing quality of life in a patient's last months. Given this grim outlook, many patients and their doctors are instead turning to the experimental approaches offered by clinical trials. Patients, caregivers, and researchers are keenly seeking better options.
Each year, the medical world comes together at the ESMO World Congress on Gastrointestinal Cancer (ESMO GI) to discuss advances in this field. The 2022 meeting in Barcelona, Spain, drew more than 3,000 clinical experts from around the globe who spent 4 days exchanging information, resources, struggles—and hope.
In the weeks leading up to ESMO GI, researchers at Agenus, an immuno-oncology company based in Lexington, Massachusetts, sent an urgent message to conference organizers. Though the deadline for abstract submissions had passed, they believed they had something worth sharing.
Immunotherapy has revolutionized treatment in other forms of cancer, but has not made a large impact in MSS CRC. The data from a Phase I trial of an Agenus immunotherapy drug called botensilimab, given in combination with a second immunotherapy drug, Agenus' PD-1 inhibitor balstilimab, was different. It showed roughly a quarter of MSS CRC patients responding to therapy and exhibiting a durable response. The trial appeared to be offering heavily pretreated MSS CRC patients a lifeline [5].
Botensilimab was designed as an innate and adaptive immune activator, harnessing multiple facets of the body's immune system. It stands on the shoulders of a class of drugs known as first-generation CTLA-4 inhibitors, but was purpose-built to reach what cancer specialists refer to as "cold" tumors—the ones that don't respond to current immunotherapy. The results of Agenus' Phase I trial affirmed botensilimab's unique design. ESMO GI accepted the submission, and gave it prime presentation time in the conference's opening session on June 29th.
In Barcelona, Dr. Anthony El-Khoueiry, an investigator on the trial and Program Director at the USC Norris Comprehensive Cancer Center, Keck Medicine of USC, told the collective story of forty-one MSS CRC patients who received the combination of botensilimab and balstilimab. These individuals had previously undergone, on average, four previous regimens of cancer drugs, suffering the accompanying tribulations, disappointments, and exhaustion. Agenus' patients were men and women, young and old, and they had been treated with the botensilimab/balstilimab combination for up to two years.
The oncology experts in Dr. El-Khoueiry's audience were listening for several key terms in the CRC lexicon. One was the study's overall response rate, or ORR. This tracks how many patients' tumors shrank in response to therapy. A second was the disease control rate, or DCR. This combines those who responded with those whose tumors didn't grow. Both are proxies for whether a patient might be expected to live longer. Finally, clinicians wondered whether this combination would be well-tolerated; if the regimen led to significant side effects, patients would have to come off therapy, off-setting any potential medical gains.
Together, these figures would signify the duration of response: time.
Of the trial's forty-one patients, 24% saw their tumors shrink, and 73% saw lack of tumor growth. Of the patients who responded to therapy, the vast majority continue to see benefit; at the time of Agenus' data submission, eight out of ten patients who had responded were continuing to do so. Three patients had been followed for longer than a year, and one beyond two years [5].
In a disease setting where immunotherapy had never shown benefit—in hospital rooms where patients receive so much bad news—these results provided a breath of fresh, life-giving air.
Agenus plans to launch Phase II trials of botensilimab, alone and in combination with balstilimab, later this year, with studies in melanoma, pancreatic cancer, and CRC. The company bills itself as dedicated to "innovation and speed for cancer cures." For a group of people who previously had few options and even less time, the data presented at ESMO GI offers a glimmer of hope for life beyond an MSS CRC diagnosis. Agenus is pursuing the drug's potential as a combination agent in a multitude of other cancer therapies as well, following a truly innovative vision: one that is committed to seeking to develop agents that give patients better options and longer lives.
"We're looking for exponential growth. We aren't interested in improving the number of lives of patients impacted by a couple percentage points," said Agenus Chief Medical Officer Dr. Steven O'Day. "It comes down to addressing the unmet need in the clinic and hoping to witness patients' lives transformed."
[3] SEER
[4] Grothey et al. Lancet. 2013;381: 303-312.
Van Cutsem, et al. J Clin Oncol. 2012;30:15_suppl, 3502-3502.
Mayer et al. N Eng J Med. 2015;372:1909-1919.