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, 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.
The phase 1/2 TARZAN trial1 exposed 18 patients with clinical stage ≤T3ab N0-1 distal-mid rectal tumors without mesorectal fascia involvement to 5×5 Gy RT, followed by three 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 participants. In addition, after a median follow-up of 20 months, 50% had not received TME surgery. In five patients who reached the primary endpoint, local excision was performed to achieve organ preservation; five 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 five of nine patients undergoing TME, including four anastomotic leaks and one abscess. An additional 20 patients will be evaluated in the phase 2 part of the trial.
Physician’s Weekly 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.
PW: What was the rationale for this study?
Dr. Chalabi: My research focus is neoadjuvant immunotherapy and GI cancers. In the case of 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 tumors, especially colorectal cancers, have gained a lot of attention recently with trials showing that if you give immunotherapy in the neoadjuvant setting in dMMR tumors, we can expect an almost 100% response rate.2,3
However, about 85% of patients with non-metastatic colorectal tumors 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 tumor is not going to recur and that patients can forego surgery. Keep in mind that rectal surgery has a very high rate of long-term morbidities. Patients often require stomas or colostomies. 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 are typically chemoradiation, just radiation therapy, or a combination of chemotherapy and chemoradiation. Considering my interest in neoadjuvant immunotherapy, I wanted to assess how can we use immunotherapy to achieve these responses in patients with rectal cancer who are not MMR proficient. We chose the patient population who had either an intermediate- or low-risk rectal cancer, because high-risk patients would immediately receive chemoradiation therapy or chemotherapy.
In TARZAN, we included patients when we took biopsies at baseline, and those samples will contribute to the translational work that is currently ongoing. And after that, we start with a cycle of bevacizumab, which is a VEGF inhibitor, for three cycles total. At cycle number two, we add atezolizumab, which is an anti-PD-L1, also for three cycles total. So, you have two combined cycles of bevacizumab with atezolizumab and two cycles of either bevacizumab or atezolizumab alone. The reason for combining bevacizumab and atezolizumab is because we have both pre-clinical and also strong clinical data, showing synergy between VEGF inhibition and checkpoint inhibition. Thus, there was rationale to combine these two treatments with radiation therapy, because, especially for the intermediate-risk tumors 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. The primary endpoint was the rate of clinical complete or near complete response rate at 10-12 weeks after start of radiation therapy.
What were your main findings?
We treated 18 patients. This is a two-stage design study, and the first part is 18 patients. More than three patients with a clinical complete or near complete response was the pre-determined threshold to proceed 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. At the 12-week point, we had clinical complete or near complete response in 56% of patients, easily meeting the primary endpoint of 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. We were happy to see that the responders were not just all the small T1 or T2 tumors that are lymph node-negative, and that the chances of having a complete response also after a short course of radiation therapy is higher.
In fact, among the responders, we had mostly T3 tumors, and one-third had lymph node-positive disease on MRI scan. Ultimately, of course, we want to know if these responses are durable—if these patients are 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 one patient who ultimately had to undergo a total mesorectal excision. Furthermore, we had a nearly 50% organ-sparing rate at this median follow-up of 22 months, or eight out of 18 patients, which is many more than the four patients we needed to achieve stage 1 clearance endpoints. Among those nine patients, four needed a local excision to remove some residual tumor, which was sufficient to radically remove all disease.
These 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 one patient, with increased liver enzymes.
In short, the data were very encouraging in terms of toxicity as a result of this neoadjuvant immunotherapy in combination with the radiation therapy. Patients who did require surgery had a high rate of surgery-related AEs, which was higher than expected, and even widened the gap between the intervention arm and comparator arm. Among nine patients who didn’t have complete response and underwent TME, four developed an anastomotic leak. Understanding this high AE rate in 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 finalize our conclusions. One intriguing observation from this study is, however, that patients who didn’t undergo surgery exhibited excellent tolerance of this immunotherapy treatment in addition to their high response rates with only the standard short course of radiation therapy, without the need for chemotherapy.
What are the next steps?
First, 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 seven clinical complete or near-complete responses out of 38 patients, but we already had nine meet those criteria in stage 1. It’s going to be a positive study. The question is how the surgery-related AEs are going to be when we have a full accrual of the study. We also want to understand how we can change the treatment to actually improve 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 and toxicity of the treatment. Assessing different sequencing of these treatments may also incrementally further improve these responses.
Did the tumors have to be PD-1L positive?
We haven’t looked at that yet, but it would be interesting to see if that might offer a means of patient selection. For colorectal cancer, PD-L1 doesn’t seem to be very predictive of response. But for these specific patients, it should be investigated.
