Small study yields potentially game-changing results for rectal cancer

In what has been dubbed as ‘a small but mighty study’ at ASCO 2022, a phase II trial spearheaded by investigators from Memorial Sloan Kettering Cancer Center in New York, US heralded the remarkable efficacy and safety of the monoclonal antibody dostarlimab for the treatment of locally advanced mismatch repair-deficient (dMMR) rectal cancer.

“We were obviously beyond thrilled,” said Dr Andrea Cercek, study lead investigator, in a press release. “We have now treated a total of 14 patients, and all – 100 percent – have had a clinical complete response (cCR) to dostarlimab alone.” Moreover, there were no grade 3 or 4 adverse events nor disease recurrences. [ASCO 2022, abstract LBA5]

After a median follow-up of 12 months (range, 6–25 months), there was no evidence of tumour on MRI, ¹⁸F-fluorodeoxyglucose PET, endoscopic evaluation, digital rectal examination, or biopsy. [N Engl J Med 2022;doi:10.1056/NEJMoa2201445]

“I think everyone in this room will agree that the results are clinically meaningful. The 100-percent cCR rate is unprecedented in rectal cancer, and the potential to decrease morbidity by eliminating pelvic radiation and surgery for our patients is huge,” said invited discussant Associate Professor Kimmie Ng from Harvard Medical School, Boston, Massachusetts, US, at ASCO 2022.

“[T]he majority of these patients had big bulky tumours, and 94 percent were node-positive. The standard of care for these patients would have very likely required all three modalities of chemotherapy, radiation, and surgery,” said Cercek. Yet, at the time of reporting, none have required any of these treatments.

“Surgery and radiation have permanent effects on fertility, sexual health, and bowel and bladder function,” she continued. “The implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential. As the incidence of rectal cancer is rising in young adults, this approach can have a major impact.”

The results were compelling, especially for a subset of stage II/III rectal cancer patients with a rare mutation that is relatively resistant to chemotherapy. Nonetheless, Cercek was quick to point out that further studies are warranted to ascertain the durability of treatment.

 

A revolutionary treatment shift

“Very little is known about the duration of time needed to find out whether a cCR to dostarlimab equates to cure,” wrote Dr Hanna Sanoff from the University of North Carolina, Chapel Hill, North Carolina, US, in an accompanying editorial. “[Nonetheless,] these results are cause for great optimism.” [N Engl J Med 2022;doi:10.1056/NEJMe2204282]

“[The investigators] and their patients who agreed to forego standard treatment for a promising but unknown future with immunotherapy have provided what may be an early glimpse of a revolutionary treatment shift,” she continued. “[I]f immunotherapy can be a curative treatment for rectal cancer, eligible patients may no longer have to accept functional compromise … to be cured.”

 

Promising, but not there yet

While a 100-percent cCR rate seems promising, a small cohort with a specific genetic signature from a single institution, the single-arm design, and short treatment duration underpin the need for more in-depth evaluations involving larger, randomized cohorts with longer follow-ups.

Clinicians who were unaffiliated with the study echoed these sentiments as news made its rounds.

“This definitely needs a larger trial because it’s fabulous stuff. But we [are not] there yet,” said Professor Graham Newstead from Bowel Cancer Australia, North Sydney, New South Wales, Australia. “It’s exciting. We’re obviously hoping for our patients to get the best outcome, which is a cure. But it is early data. [It] needs to be evaluated properly with bigger studies,” echoed Dr Satish Warrier from Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. [www.abc.net.au/news/health/2022-06-10/cancer-drug-immunotherapy-rectal-dostarlimab-treatment-remission/101142596]

To date, 18 patients were enrolled. Dostarlimab 500 mg was given intravenously Q3W for 6 months. The other four patients have received at least one dose and are continuing to receive treatment.

Data on the other primary endpoint (duration of CR) shall be reported once available to shed light on the possibility of sparing all or most dostarlimab recipients from surgical resection in the long term.

 

Going beyond rectal cancer

Dostarlimab was given the FDA nod in early 2021 for dMMR recurrent or advanced solid tumours in adults. [www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approvals-jemperli-dostarlimab-gxly-patients-mismatch-repair-deficient]

Whether dostarlimab can fit into the treatment landscape of other cancers with a dMMR mutation remains to be seen. “As these data mature, we envision that PD-1 blockade will be evaluated in other dMMR tumours, such as localized pancreatic, gastric, and prostate cancers, in the context of neoadjuvant treatment; this could open the door for an immuno-ablative approach involving a variety of tumour types akin to MMR deficiency in patients with metastatic disease,” wrote Cercek and colleagues.

“It’s really the concept of being able to match a tumour, and the genomics of what’s driving it, with a therapy … Because we can move this beyond just this subset of rectal cancer,” commented Dr Julie Gralow, ASCO Chief Medical Officer and Executive Vice President, in another news release. “I’m excited when you see such a dramatic response … It gives me hope we can find such a dramatic match for other cancers, too.” [www.washingtonpost.com/health/2022/06/10/experimental-cancer-drug]