Considering Targeted Therapies When Managing Young Patients With mCRC

According to Jennifer Y. Wo, MD, colorectal cancer is becoming more common in young adults. As a result, quality-of-life considerations and long-term survivorship are becoming increasingly important, and determining the best treatment options for patients is key.

“In this younger onset, given the rise of incidence within our younger population where the morbidity is so high with the need for sphincter removal with an APR, this is a patient population that is prioritizing quality-of-life and pushing the envelope of, can we move towards a non-operative approach? Then, the Memorial [Sloan Kettering] data adds to a growing bevy of data of how best to think about treatment, optimal treatment paradigms to achieve that end point, while not at the risk or cost of cancer outcomes, like distant metastases and overall survival,” said Wo, associate professor, radiation oncology at Harvard Medical School and clinical attending, radiation oncology at Massachusetts General Hospital, in an interview with Targeted Oncology^TM.

At the 2023 ASCO Gastrointestinal Cancers Symposium (ASCO GI), experts gathered to discuss some of the latest innovations, multidisciplinary approaches, and research for the treatment of patients with gastrointestinal cancers. Experts highlighted new treatment strategies, updates in clinical research, and new ways to care for patients, including in the CRC space.

Clinicians, including Wo, discussed and listened to presentations on emerging data for patients with mCRC which focused on how non-operative management plays a role in treatment, the toxicities and benefits that come with frontline EGFR treatment, and how the role of chemotherapy and radiotherapy has changed with targeted agents coming into the picture.

Through evaluating new targeted therapies and different treatment strategies at meetings like ASCO GI, determining the optimal treatment plan for each individual patient becomes clearer and well defined for experts.

In the interview, Wo highlighted some of the emerging discussions and data in the mCRC space, how targeted therapies are playing a role, and what the next steps for research include.

What topics are important now when discussing refining the management of metastatic colorectal cancer (mCRC)?

Wo: There's a lot of key topics that have emerged over the course of the ASCO GI that are timely and important. One is identification of oligometastatic disease, and in which patients is the cure obtainable? That's a whole spectrum of metastatic disease. We recognize, is it the number of lesions? Is it biology? Is it synchronous or metachronous? How much does biology play into it? How much does the site of metastasis play into it? Is it liver? Lung? How do both play into the ability of care? How do we define this, and how do we set up the best treatment paradigm for each individual patient?

I think that's where a lot of the emerging discussions and the multidisciplinary panels of trying to harness the resources we have, within our community at large. Involving interventional radiology, surgeons, medical oncologists, hepatologists, our GI specialists, and then radiation oncology, is critical in terms of sort of the discussions early on to sort of lay this groundwork and then try to plan proactively about what kind of treatment plan is optimal for each individual patient. That's 1 of the critical discussion points that we had at a GI ASCO session.

Can you talk about the use of frontline EGFR antibody therapy for unresectable metastatic disease that's RAS driven? What has been the efficacy and safety shown with these therapies?

There was a very compelling discussion between 2 of our experts, Kai-Keen Shiu, PhD, FRCP, and then Ardaman Shergill, MD, from the University of Chicago, highlighting emerging data when looking at frontline EGFR. While the studies suggest that there is a benefit, the question is, what is the toxicity that can be associated with that?

At the beginning, we did a poll, and it suggested that 80% of those in attendance upfront, based on just the data that exists, had voted in favor of frontline EGFR data by Dr. Shergill who argued against it because of financial toxicity and adverse effects and argued that perhaps delaying EGFR may just be as effective and pushing it to later lines of therapy may make sense and that was a reasonable approach too.

Ultimately, she was able to shift about 30% of the audience into her favor, once again, highlighting that for metastatic patients, we're thinking about overall survivals, we're thinking about efficacy, but we're also thinking about quality-of-life, toxicity, financial toxicity, and that has to be weighed into the overall picture of patients.

Considering that we now have targeted therapies for mCRC. What is the role of chemotherapy and radiotherapy now?

I think that minus the population of patients that perhaps have microsatellite, unstable disease where immunotherapy has found to have such high efficacy in that population, which we see the metastatic colorectal setting, but also interesting data published in the New England Journal suggesting that immunotherapy alone with the style of Mab may be able to achieve sort of clinical complete responses and patients who are MMR deficient. Short of that, chemotherapy still plays a significant role. The question is more in terms of, how do we integrate these targeted agents into our existing doublet or triplet chemotherapy regimens, whether that be with anti-angiogenic agents, or with more targeted therapies for EGFR wild-type or BRAF-mutant patients.

Where does radiation play a role? In general, as we improve our systemic efficacy, it sort of clarifies and defines more of a role of radiation, I would argue, as patients are living longer and we have improved outcomes. We have to think about how to integrate these local therapies to achieve different goals, perhaps time off of chemotherapy and tolerability and quality of life. In the setting of oligo progression, or oligo persistent disease, can we think about integration of radiation, buying time off of chemotherapy or systemic therapy, if we treat all known sites of disease? There are a lot of randomized trials in this space that are ongoing for different disease sites looking at this question. By taking patients off of systemic therapy, how does that impact quality-of-life and tolerability and resumption of chemotherapy?

I would also argue that in the setting of better controlled systemic disease, local recurrences are more important, and trying to control local recurrences, which is traditionally the role of radiation therapy, can only be more important as well. In the setting of metastatic rectal cancer, we've always appreciated that local control is critical and pelvic control is critical for quality-of-life for these patients, just because local recurrences are associated with such high morbidity. It's a worthwhile end point, even without overall survival, to have pelvic control. I think that's even more highlighted if patients are living longer. There are more lines of systemic therapy as we are gaining traction in distant MET control, and balancing all of these different outcomes are more important. The integration and that discussion at the beginning of involving your multidisciplinary tumor board early on and of spectrums of care are critical.

What unmet needs with metastatic CRC still exist?

There were a lot of different, interesting abstracts brought up at the meeting at large for colorectal cancer, not just in the metastatic space. I think 1 of the other critical and very interesting points is, unfortunately, that there are more and more young onset colorectal cancers. We have more patients in their 20s, 30s, and 40s, and that coincides with a lot more emerging data in terms of non-operative management and how that plays into things. There was a nice abstract presented by Memorial Sloan Kettering that looked at short course vs long course in the COVID era, where they shifted to short course, given concerns about frequency of visits within the institution to minimize contact during the height of the COVID era. [It] looked at the long course, which is 5 and a half weeks of radiation with concurrent capecitabine, vs the shorter course of radiation 5 Gy times 5 without capecitabine. In terms of achieving this non-operative management outcome, that was retrospective data, but it was provocative data because there showed no difference in distant MET outcomes.

There were disease-free survival or overall survival outcomes, but there did seem to be a suggestion of more patients getting non-operative management in patients that underwent long course chemoradiation vs short course, and higher rates of local regrowth in the short course arm. It brings 2 important topics. One is, in this younger onset, given the rise of incidence within our younger population where the morbidity is so high with the need for sphincter removal with an APR, this is a patient population that is prioritizing quality-of-life and pushing the envelope of, can we move towards a non-operative approach. Then, the Memorial data adds to a growing bevy of data of how best to think about treatment, optimal treatment paradigms to achieve that end point, while not at the risk or cost of cancer outcomes, like distant metastases and overall survival.

Looking forward, what do you think will be an important research topic for metastatic CRC?

As we learn more about targeted therapies, how to further integrate targeted therapies into the existing chemotherapies are going to be critical. A lot of research is looking at how you get a response in patients with metastatic colorectal cancer with immunotherapy that are proficient, so those without mismatch repair deficiency. I think we know and have established that for those who are MMR deficient, immunotherapy has changed the spectrum. We don't see that yet in MMR proficiency. There's a lot of literature looking at how we get these tumors responsive to immunotherapy. That's a huge question that's out there.

There's also a lot of emerging data suggesting that having liver metastases can further damage in response to immunotherapy. There are ways to integrate ablative therapy to the liver and within the setting of immunotherapy and other systemic therapies to enhance the impact of the systemic therapy targeting the liver with ablative techniques. I think how we can integrate all of our therapies and thinking not just digitally, like how do we just intensify chemo, how do we intensify radiation, but how do we optimize the impact and the systemic impact of radiation or ablative therapies in the setting of systemic therapies? Recognizing that liver metastases may be different from lung metastases is an exciting horizon.