Novel regimen may avoid TME surgery in rectal cancer

In patients with rectal cancer, neoadjuvant radiotherapy (RT), followed by atezolizumab and bevacizumab resulted in an encouraging complete response rate. The findings of this phase 1 study, presented at the ASCO Gastrointestinal Cancers Symposium of 2023, held in San Francisco (CA, USA) from 19 to 21 January, demonstrate that total mesorectal excision (TME) may be prevented in a significant proportion of patients, increasing the chance of organ preservation and reducing the risk for long-term morbidity related to surgery. Medicom asked senior author and principal investigator Dr Myriam Chalabi (Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands) to talk us through the results and the clinical implications of the study.

The phase 1/2 TARZAN trial (NCT04017455) [1] exposed 18 patients with clinical stage ≤T3ab N0-1 distal-mid rectal tumours without mesorectal fascia involvement to 5x5 Gy RT, followed by 3 cycles of atezolizumab and bevacizumab, with the aim of avoiding TME and increasing the chance of organ preservation. The primary outcome was the clinical complete and near-complete response (CR) rate at 12 weeks after RT.

The primary endpoint was achieved by 56% (n=10) of the patients. In addition, after a median follow-up of 20 months, 50% of the patients had not received TME surgery. In 5 of the patients who reached the primary endpoint, local excision was performed to achieve organ preservation; 5 others displayed a clinical CR and did not need additional interventions. The regimen was well tolerated, with only one grade 3 study drug-related adverse event (AE). Surgery-related grade 3 AEs were reported in 5 out of 9 patients undergoing TME, including 4 anastomotic leaks and 1 abscess. An additional 20 patients will be evaluated in the phase 2 part of the trial.

MEDICOM interviewed Dr Chalabi to complement the data that was presented at the ASCO-GI cancers symposium of 2023.

MEDICOM: what was the rationale for this study?

Chalabi: “My research focus is neoadjuvant immunotherapy and GI cancers. And that's the common denominator across all of my studies. And in this case for the TARZAN study, it's neoadjuvant immunotherapy combined with anti-VEGF and also radiation therapy for patients with rectal cancer.

TARZAN is not for mismatch repair-deficient (dMMR) rectal cancers. The study was set up for MMR-proficient cancers. MMR-deficient tumours, especially colorectal cancers, have gained a lot of attention recently with trials showing that if you give immunotherapy in the neoadjuvant setting in dMMR tumours, we can expect an almost 100% response rate [2,3].

However, about 85% of patients with non-metastatic colorectal tumours are MMR proficient, reaching 95% or higher for rectal cancers. We need to find something for that patient population that hopefully works better than chemotherapy, or at least as well but with less toxicity.

That is what we set out to do in the TARZAN trial for rectal cancers. In general, wherever possible, we hope to help patients achieve a clinical complete response, avoiding or delaying surgery. Ideally we take an organ-sparing approach and hope that the tumour is not going to recur and that patients can forego surgery. Keep in mind that rectal surgery is often also a very morbid surgery and has a very high rate of long-term morbidities. Patients often have to have stomas, or colonostomies. For that reason there is increasing interest in organ-sparing approaches in rectal cancer, and I think it's becoming increasingly seen as the standard of care.

The normal modalities of neoadjuvant treatment in this setting is typically chemoradiation, or just radiation therapy, or a combination of chemotherapy and chemoradiation. Considering my interest in neoadjuvant immunotherapy, I wanted to ask how can we use immunotherapy to achieve these responses in rectal cancer patients that are not MMR proficient. We chose the patient population who had either an intermediate-risk rectal cancer or a low-risk rectal cancer because the patients with high-risk rectal cancers would immediately receive chemoradiation therapy or chemotherapy.

In TARZAN, we included patients when we take biopsies at baseline, and those samples will contribute to the translational work that is currently ongoing. And after that, we start with first a cycle of bevacizumab, which is a VEGF inhibitor, for 3 cycles total. At cycle number 2, we add atezolizumab, which is anti PD-L1, also for 3 cycles total. So you have 2 combined cycles of bevacizumab with atezolizumab, and 2 cycles of either bevacizumab or atezolizumab alone. The reason for combining bevacizumab and atezolizumab is because we have both pre-clinical, but also strong clinical data, showing synergy between VEGF inhibition and checkpoint inhibition. Thus, there was rationale to combine these 2 treatments, with radiation therapy because, especially for the intermediate risk tumours that normally would get it anyway, we don't want to give something that we have no data on in a neoadjuvant setting, which is potentially a curative setting. In addition, radiation therapy could induce neoantigens which in turn might increase responses to immunotherapy. So that's the rationale behind the design of the study, with the primary endpoint actually being the rate of clinical complete or near complete response rate at 10 to 12 weeks after start of radiation therapy.

MEDICOM: What were your main findings?

Chalabi: We treated 18 patients. This is a 2-stage design study, and the first part is 18 patients. The pre-determined threshold to proceed was if we have more than 3 patients with a clinical complete or near complete response, then that's enough to go into stage 2 and accrue more patients to ultimately have a total cohort of 38 patients.

Here we are showing the stage 1 results, and we are accruing for stage 2, so that fact gives away the results already. What we saw is that at the 12 week time point we had clinical complete or near complete response in 56% of patients, easily meeting the primary endpoint of the stage 1 of the study. That was very encouraging data, especially if you consider that one third of those patients had n-plus metastatic disease, being the higher risk tumours, of course. We were happy to see that the responders were not just all the small T1 or T2 tumours that are lymph node negative, and that the chances of having a complete response also after short course of radiation therapy is higher.

In fact, among the responders, we had mostly T3 tumours, and one third had lymph node positive disease on MRI scan. Within that population 56% of complete or near complete responses. Ultimately, of course, we want to know in the long run: are these responses durable? Are these patients going to have to undergo surgery anyway? And that actually wasn't the case with a median follow-up now of 22 months (range 14-33 months). We only had 1 patient who ultimately had to undergo a total mesorectal excision. Furthermore, we had nearly 50% organ-sparing rate at this median follow-up of 22 months, or 8 out of 18 patients, which is many more than the 4 patients that we needed to achieve stage 1 clearance endpoints. Among those 9 patients, 4 of them needed a local excision to remove some residual tumour, which was sufficient to radically remove all disease.

This results are really encouraging if you consider that many of these patients currently get chemoradiation, which is 5 weeks of daily radiation therapy with daily capecitabine, and is associated with many major side effects. The treatment that we tested here was very well tolerated. We only saw grade 3 adverse events (AEs) in 1 patient only, with increased liver enzymes.

In short, the data was very encouraging in terms of toxicity as a result of this neoadjuvant immunotherapy in combination with the radiation therapy. The patients who did require surgery had a high rate of surgery-related AEs in the patients, which was higher than expected, and even widened the gap between the intervention arm and comparator arm. Among the 9 patients who didn't have complete response and underwent TME, we had 4 patients who developed an anastomotic leak. Understanding this high AE rate in the patients who underwent surgery is always very difficult when you have very small cohorts. You have to wonder what is chance and what is possibly due to the treatment that you gave before? But again, the confidence interval here is very, very broad. No doubt we will need more data from the rest of the trial to see whether this trend holds up. We need more patients and more data to finalise our conclusions. One intriguing observation from this study is, however, that the patients who didn't undergo surgery exhibited excellent tolerance of this immunotherapy treatment and in addition to their high response rates with only the standard short course or radiation therapy, without the need for chemotherapy.

MEDICOM: What are the next steps?

Chalabi: Firstly, finishing stage 2. With the responses we have so far, we have already met the endpoint of the whole study. Because the prespecified threshold to consider the study successful was more than 7 clinical complete or near complete responses out of 38 patients, but we already had 9 patients meet those criteria in stage 1. It's going to be a positive study. The question is how are the surgery-related AEs going to be when we have a full accrual of the study? And also how can we change the treatment to actually even improve the responses even more? Should we be using dual checkpoint blockade, for example?

Looking at different combinations of different modalities, both immunotherapy targeted treatments, and radiation therapy, might also improve the response, as well as the toxicity of the treatment. Assessing different sequencing of these treatments may also incrementally further improve these responses.

MEDICOM: Did the tumours have to be PD-1L positive?

Chalabi: We haven't looked at that yet, but it would be interesting to see if that might offer a means of patient selection. However, for colorectal cancer, PD-L1 doesn't seem to be very predictive of response. But for these specific patients, it should be investigated.

References:

1. Verschoor YL, et al. Radiotherapy, atezolizumab, and bevacizumab in rectal cancers with the aim of organ preservation: The TARZAN study. Poster Session C: Cancers of the Colon, Rectum, and Anus, Abstract 158, 2023 ASCO GI Cancers Symposium, San Francisco, CA, USA, 19-21 January.
2. Chalabi M, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020 Apr;26(4):566-576.
3. André T, et al. KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020 Dec 3;383(23):2207-2218.

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Posted on 3 February, 202317 March, 2023