One of the most talked about abstracts at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting is on a Phase II trial in neoadjuvant rectal cancer. In the investigator-led trial studying GSK’s immunotherapy Jemperli (dostarlimab-gxly), the first 14 out of 30 study participants with locally advanced mismatch repair-deficient (dMMR) rectal cancer reached clinical complete response.

“This was a complete surprise, there has never been a study with any anti-cancer drug that achieved 100% complete response,” says primary investigator Dr Luis Alberto Diaz, Jr, head of the solid tumour oncology division at the Memorial Sloan Kettering’s Department of Medicine.

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But what does this mean for rectal cancer clinical trials, and the treatment paradigm?

There is already high appetite for investigations in the neoadjuvant setting with chemotherapy and the Phase II data would likely further push interest of using immunotherapy in such patients, notes East and North Hertfordshire NHS Trust rectal and anal cancer clinical oncologist Dr Rob Glynne-Jones. He adds that in five to ten years, it is likely that immunotherapy would be standard of care in the neoadjuvant setting.

But with heightened mainstream media buzz, there might be the risk of overstating the weight of the Phase II data. Jemperli’s mechanism is logical in these very early-stage patients, which means the positive data is not a surprise, Glynne-Jones says. There is also the high likelihood of a class effect among immunotherapies that share the same approach, both experts say.

Further, only 5% of all rectal cancer patients are in the dMMR subgroup, with 95% of patients having MMR proficient tumours. “[But] I would think of this differently,” Diaz tells Clinical Trials Arena. “[The data] would apply to about 70,000 patients worldwide for rectal cancer. And, if you look at dMMR as a tumour agnostic marker, then the impact includes 4%–5% of all cancer patients.”

Immunotherapy logical in rectal cancer

Positive results from the Phase II trial (NCT04165772) are not unexpected due to dostarlimab’s mechanism as a PD-1 inhibitor, and that the trial targeted dMMR rectal cancer patients, says Glynne-Jones, who pitched a similar study several years ago but did not get support from relevant groups.

Patients with dMMR rectal cancers in the neoadjuvant setting have ‘very hot tumours’, Glynne-Jones tells this news service. Since neoadjuvant rectal cancer patients are yet to undergo surgery, they still have draining lymph nodes to do immune system-relevant work, which is pertinent because they create memory cells that attack cancer cells, he explains. This means that these patients are ideal for immunotherapy, which is already designed to boost the immune system to recognise cancer cells.

There are two notable subpopulations in dMMR rectal cancer: those with sporadic mutations and ones with Lynch syndrome. Between these two groups, patients with sporadic mutations do not respond to treatment as well, perhaps because they may have a relatively weaker immune system response, Glynne-Jones explains. Looking at the Phase II data, none of the patients have a BRAF mutation, which indicates most of the study participants have Lynch syndrome, he adds. All Phase II patients have BRAF V600E wild-type tumours

Immunotherapy class effect likely

There will likely be a class effect among most anti-PD-1 therapeutics in dMMR rectal cancer patients in the neoadjuvant setting, Diaz says. Glynne-Jones agrees, adding this is based on experience in colon cancer. The class effect may also apply with PD-L1 inhibitors, he adds. There may be minor differences among immunotherapies, but it is doubtful if Jemperli has distinguishing features that lead to the positive Phase II data, he notes.

There are 34 ongoing or planned Phase I-III rectal cancer trials in the neoadjuvant setting investigating an asset that inhibits the PD-1 or PD-L1 receptor, according to GlobalData’s Clinical Trial Database. These trials are either investigating an immunotherapy monotherapy or in combination with chemotherapy. GlobalData is the parent company of Clinical Trials Arena.

High chance of durable response

Nevertheless, the Phase II data is good news for patients within this subgroup. In fact, patients in the Phase II trial will likely experience long-term duration of response, Glynne-Jones says. So far, none of the Phase II patients have required chemoradiation or surgery during follow-up of up to 25 months.

Phase II patients are likely to have longer than three years durable response based on experience in colorectal cancer, Glynne-Jones says. In dMMR colorectal cancer patients with metastatic disease, approximately half of patients respond to treatment and 70% of these have durable response at three years, he says. Subsequently, neoadjuvant rectal cancer patients, who have not had surgery and still have their draining lymph nodes, may end up with better results.

The Phase II trial recruited Stage 2 and 3 patients. In Stage 2, they have a relatively low risk of recurrence because they have a robust immune system, Glynne-Jones adds. The same can be said with Stage 3, but they can be given adjuvant chemotherapy to reduce the risk of recurrence, he says.

With a likely shake-up in the neoadjuvant setting, should clinical trials in later-line therapy adjust their study designs accordingly? Probably, Glynne-Jones says, while underscoring the fact that the Phase II trial data is only relevant to the 5% of rectal cancer patients. “This is unless we find an efficient way of making the normal rectal cancers ‘hot’.”

Jemperli was first approved in April 2021 in recurrent or advanced dMMR endometrial cancer. It then received accelerated approval in adult patients with dMMR recurrent or advanced solid tumours in August 2021.