Exercise-Based Regimen Shows Efficacy Promise in CRC

Nicholas J. Hornstein, MD, PhD, highlighted results from the phase 3 ATOMIC and CHALLENGE trials in CRC presented at the 2025 ASCO.

The 2025 American Society of Clinical Oncology (ASCO) Annual Meeting gave great insights into gastrointestinal oncology. Specifically in colorectal cancer (CRC), the phase 3 ATOMIC trial (NCT02912559) and the phase 3 CHALLENGE trial (NCT00819208) assessed a therapeutic and holistic approach to managing the disease, respectively.

Nicholas James Hornstein, MD, PhD, an assistant professor at the Donald and Barbara Zucker School of Medicine of Hofstra University and Northwell Health, spoke with CancerNetwork® and focused on these 2 studies because they impact the standard of care and how clinicians choose to treat patients with CRC.

In the ATOMIC trial, the primary end point of disease-free survival (DFS) was met with 86.4% in the modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus atezolizumab (Tecentriq) arm vs 76.6% in the mFOLFOX6 arm alone (HR, 0.50; 95% CI, 0.34-0.72; P <.0001).¹

Additionally, Hornstein highlighted that results from the CHALLENGE study, which is an exercise-based trial, showed improved DFS with the structured exercise program vs the health education material cohorts, respectively (HR, 0.72; 95% CI, 0.55-0.94; P = .017).² The trial also noted that for every 16 people, exercise prevented 1 person from having recurrent cancer or developing a new cancer.

Are you able to provide background on the ATOMIC trial?

Coming out of ASCO, a lot of people have been going over the data for ATOMIC and discussing how to incorporate [the regimen] best in their clinical practice. As a brief refresher, these were patients in the adjuvant setting who had stage III colon cancer, meaning nodal involvement, who were deficient mismatch repair [dMMR] or microsatellite instability [MSI]-high, and they were treated with either standard of care, which was mFOLFOX6 chemotherapy [alone], or with atezolizumab, which is a PD-L1 inhibitor. The study showed that there was a significant survival and DFS benefit with the addition of atezolizumab, and this has, overnight, become a new standard of care for our patients with stage III CRC that’s MSI-high.

There are still a few questions about this [regimen] that remain, especially in the community setting. One is, should every patient get mFOLFOX6 in addition to atezolizumab? Should some patients get a PD-L1 [inhibitor] alone? Should any patients get chemotherapy alone without immunotherapy? Breaking that down, first thing first, very few patients with dMMR tumors should be [getting] chemotherapy alone. There needs to be a compelling rationale. Maybe there is a pre-existing autoimmune condition that could be life-threatening if it were exacerbated, or something else like that in their medical history. For run-of-the-mill osteoarthritis or rheumatoid arthritis—things that don’t require biologics that are under good control—I would still push more towards incorporating immunotherapy into this paradigm.

The next question is, should some patients avoid chemotherapy with dMMR tumors? We don’t have good data in the adjuvant setting to suggest that it is a standard of care practice. I have already had some patients that I’ve seen. These are older patients, maybe they’re in their 80s, and it’s a question of, should we not give any adjuvant [therapy], or should we potentially hold the chemotherapy and give immunotherapy alone? That’s something that's going to need to be discussed on a case-by-case basis, bearing in mind that the FDA approval and the indication are with chemotherapy plus immunotherapy. For any criticisms levied against [this trial], it’s important to remember when this study was put together, which was many years ago before there was clinical equipoise to recommend immunotherapy alone for this patient population. As time evolves, we’ll see the conversation evolve as well, but it’s nice to have this for our patients now.

What advice would you put forth to clinicians about the safety profile observed in this analysis?

We know chemotherapy can be toxic, and we see those same toxicities in the interventional arm. With the addition of immunotherapy, we also see the same [adverse] effects that you can expect out of PD-L1 single-agent inhibition. It doesn’t seem to work together with chemotherapy in the sense that the toxicity is worse, but you still have to watch out for things like pneumonitis, colitis, and hypothyroidism; those are the big 3. We see some skin toxicities, usually at the start; it’s a nice sign that things might be working, but overall, a very safe and effective addition to conventional chemotherapy for these patients. The toxicity profile isn’t anything that we haven’t seen in things like non–small cell lung cancer or melanoma, where this has been a strategy we’ve used for many years.

Do you have any final thoughts about this analysis?

Immunotherapy is the future of not just dMMR CRC, but also microsatellite-stable CRC. We still need to work on the keys to unlock its potential. Every day, there are more studies coming out. The phase 3 STELLAR-303 trial [NCT05425940] just had a press release, and it looks like their is survival benefit with the addition of zanzalintinib, which is a TKI, plus atezolizumab for patients with metastatic microsatellite stable CRC. We’re going to keep seeing that over and over again over the next few years.

What is the background of the CHALLENGE trial?

This was not a plenary session. This was an oral [session], and this study has gotten a lot of press. I’ve heard the saying, exercise is the best medicine, and this was explored in the clinical trial. This was a randomized trial taking patients who were status post-resection for localized colon cancer, and it put them into 2 buckets. One, you get a personal trainer and regimented exercise over the course of a week. The other was that you got [educated] about exercise. Somebody sat down and said, “Hey, exercise is great. You should think about it.” [They’re] very different interventions. A lot of people would have expected that this wouldn’t be that positive of a study, but when they randomized the data, the DFS in the group that did exercise as their intervention was drastically higher.

Comparing this with what we normally get, things like oxaliplatin and chemotherapy, there was a higher DFS benefit with exercise than there was with oxaliplatin. This is shocking in terms of the degree of benefit that was observed in this study. Most people would have said, “Oh, yeah, there probably is going to be some benefit to exercise”, but the fact that this is looking to be on the same level as one of our chemotherapy moieties is incredible. This was an interesting study. It is something that I am discussing with all my patients now in the adjuvant setting. I’ve even had some patients who have said, “Hey, can you write me a prescription for a gym pass membership? Can you see if we can get this covered?”, because, to them and me, this is something that needs to be incorporated into our daily practice now, and a lot of patients can benefit. It’s just nice to have a study to point to and say, “Exercise is worth it.”

Do you have a call to action or advice to offer colleagues about reinforcing the need to integrate exercise into a patient’s regimen? Perhaps also advice to the patient as well?

Most of my patients will ask me, “What did I do that caused this?” Usually, it’s nothing. More so, “What can I do to prevent this from coming back?” A few months ago, I might have said, “You can exercise, you can have a healthy diet.” It would be a quick conversation. Now, with this randomized control trial evidence, I can point to this and reinforce on the same level I do with, “Hey, we’re going to do chemotherapy, and this is the benefit, and this is what we'll see.” Now, I can do that with exercise. We need to reframe it, instead of just saying, “This could be helpful”, [and instead say] “This is as helpful as some of the chemotherapy we give. This is an important part of the regimen that you're going to be on,” if you’re treating somebody in the adjuvant setting. By doing that, it ramps up the importance of things like exercise. That’s how I would reframe it, and how I have reframed it for my patients. My patients are going to the gym. Over the last month or 2, they’ve been sticking with it. I hope that’s going to continue.

Do you have any final thoughts on this trial?

Kudos to the trial team for putting this together. This was a long-running study using an intervention that is not historically funded. This is not a drug. No one is going to be making money off this. It’s important to take that into context and think about that. Kudos to the study designers for being able to pull off a great study that adds to our compendium of knowledge.

Do you have any final thoughts about ASCO overall?

There are lots of other things that we could touch on in colon cancer coming out of ASCO. There was a lot of interesting data, things like anolitinib being put into the metastatic setting, and a few other studies that are, frankly, practice changing, but at the end of the day, things like immunotherapy for dMMR tumors in the adjuvant setting, exercise in the adjuvant setting, also acetylsalicylic acid [Aspirin] in the adjuvant setting, thanks to the phase 3 ALASCCA study [NCT02647099] that was originally presented at the ASCO Gastrointestinal Cancer Symposium earlier this year. These are all tools that we’re able to add to our armamentarium to decrease the burden of disease and to decrease relapse in our patient population. We’re getting closer to being able to ensure that patients don’t have recurrence. We still have our patients coming in that do recur, and I hope there’s going to be a day when that isn’t the case, but for right now, I’m just glad we have these additional tools to use.

References

1. Sinicrope F, Ou FS. Arnold D, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). J Clin Oncol. 2024;43(17):LBA1. doi:10.1200/JCO.2025.43.17_suppl.LBA1
2. Booth CM, Vardy JL, O’Callaghan CJ, et al. A randomized phase III trial of the impact of a structured exercise program on disease-free survival (DFS) in stage 3 or high-risk stage 2 colon cancer: Canadian Cancer Trials Group (CCTG) CO.21 (CHALLENGE). J Clin Oncol. 2025;43(17):LBA3510. doi:10.1200/JCO.2025.43.17_suppl.LBA3510