Dostarlimab shows efficacy as curative-intent treatment in rectal cancer subset
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CHICAGO — Dostarlimab, an anti-PD-1 monoclonal antibody, demonstrated a 100% clinical complete response rate among a small cohort of patients with mismatch repair-deficient locally advanced rectal cancer, phase 2 study results showed.
Longer follow-up is needed to examine the duration of treatment response in this patient population, according to researchers of the study, reported at ASCO Annual Meeting published simultaneously in The New England Journal of Medicine.
Rationale and methods
“Patients with mismatch repair-deficient, locally advanced rectal cancer are treated with standard-of-care chemotherapy, radiation and surgery. However, a fraction of these patients are resistant to chemotherapy, and the radiation and surgery, although effective, have significant short- and long-term toxicities, including bowel, bladder and sexual dysfunction,” Andrea Cercek, MD, medical oncologist, section head of colorectal cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers at Memorial Sloan Kettering Cancer Center, told Healio.
“Mismatch repair-deficient tumors are sensitive to checkpoint inhibitors," she added. "Thus, our hypothesis was that PD-1 blockade with dostarlimab [Jemperli, GlaxoSmithKline] could replace chemotherapy and potentially eliminate the need for radiation and surgery in these patients.”
Cercek and colleagues sought to assess whether locally advanced, mismatch repair-deficient rectal cancer is sensitive to checkpoint blockade and whether patients who receive it could skip chemoradiotherapy and surgery.
Fourteen patients (median age, 54 years; 67% women; 61% white) with mismatch repair-deficient stage II and stage III rectal adenocarcinoma received dostarlimab every 3 weeks for 6 months, followed by standard chemoradiation and surgery. However, those who achieved a complete response to treatment could omit chemoradiation and surgery.
Median follow-up was 6.8 months.
Key findings
At the time of presentation, 18 patients were enrolled on trial.
Results among the 14 patients with at least 6 months follow-up showed a complete response among all patients (95% CI, 74-100), with no evidence of tumor on biopsy, digital rectal exam, endoscopic visualization, fluorodeoxyglucose-PET or MRI. The other four patients are responding to treatment.
No patients experienced disease progression or recurrence, and no patients required chemoradiation or surgery. Moreover, researchers did not observe any serious grade 3 or higher adverse events.
Looking ahead
“Given the remarkable response of 100% treatment with PD-1 blockade, dostarlimab may replace the current standard of care for locally advanced rectal cancer,” Cercek said. “We are continuing this study in this patient population and are planning an expansion study. We are also studying the microenvironment in the samples collected in this trial to determine why we see such robust responses. Additionally, we are studying neoadjuvant PD-1 blockade in all microsatellite instability solid early-stage tumors, such as gastric cancer, pancreas cancer and bladder cancer.”
The results are cause for great optimism, but such an approach cannot yet supplant our current curative treatment approach, Hanna K. Sanoff, MD, MPH, researcher in the division of oncology at Lineberger Comprehensive Cancer Center at The University of North Carolina, wrote in an accompanying editorial.
“Cercek and colleagues and their patients who agreed to forgo standard treatment for a promising but unknown future with immunotherapy have provided what may be an early glimpse of a revolutionary treatment shift,” Sanoff wrote. “Although the incidence of severe toxic effects with PD-1 inhibitors is usually higher than that seen in this study — closer to 10% — lasting consequences are uncommon. Thus, if immunotherapy can be a curative treatment for rectal cancer, eligible patients may no longer have to accept functional compromise to be cured.”
References:
Cercek A, et al. Abstract LBA5. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
Cercek A, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2201445.
Sanoff HK. N Engl J Med. 2022;doi:10.1056/NEJMe2204282.
For more information:
Andrea Cercek, MD, can be reached at cerceka@mskcc.org.
Perspective
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Heinz-Josef Lenz, MD
The data reported by Cercek and colleagues are potentially practice-changing, as patients with stage II or stage III rectal cancer usually receive neoadjuvant chemoradiation therapy followed by surgery and, not in all cases, sphincter-sparing surgery.
In this study, patients who had mismatch repair-deficient tumors received the anti PD-1 antibody dostarlimab. If these data are confirmed in a larger cohort with longer follow up, it will be paradigm-changing. Immune checkpoint inhibitors are known to be effective in metastatic microsatellite instability-high tumors, with complete response reported in up to 20% of patients. However, this study has only localized disease and all patients had complete resolution of the disease, which might be a critical difference and important for development of immune therapies in the neoadjuvant setting for any microsatellite instability-high tumors.
Perspective
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Kimmie Ng, MD, MPH
The potential impact of these findings on patients is huge.
Neoadjuvant dostarlimab for 6 months represents a promising new treatment for this patient population. Larger, multicenter clinical trials with longer follow-up and DFS and OS endpoints are needed. It is going to be critical that we identify predictive biomarkers of pathologic complete response to help guide treatment for our patients.
Cercek and colleagues are attempting to replace every component of standard of care in favor of a biomarker-driven approach with an anti-PD-1 therapy alone among patients with mismatch repair-deficient, locally advanced rectal cancer. While this may appear bold at first, especially in a potentially curative setting, the study is supported by strong data showing efficacy of checkpoint blockade for treatment in this patient population.
This study adds to the literature about the potential efficacy of preoperative immunotherapy, with a 100% complete clinical response rate in 14 patients for whom no radiation has been given and no surgery has had to be performed. The responses appear to be durable, as well, although the median follow-up is only 6.8 months.
Putting these data into context, many will agree that these results are clinically meaningful. Because these life-altering morbidities are especially amplified in a young childbearing population, the potential impact of this study is particularly relevant as we have seen rectal cancer cases rise steadily in patients younger than age 50 years since the mid-1990s. Slightly challenging the interpretation of these findings is the lack of a control arm and lack of historical control data on the outcomes of this rare population, but what we do know is mismatch repair-deficient early-stage tumors are usually associated with very good prognosis. Another important point to make is that there is a high percentage of patients with Lynch syndrome in this patient population, with about 20% of these patients ultimately going on to develop other colonic primaries and extra colonic Lynch syndrome-associated malignancies.
Another relevant control data set to consider when assessing the clinical significance of the current study is the phase 2 OPRA trial, in which researchers randomly assigned patients to different strategies of total neoadjuvant therapy with a watch-and-wait approach offered to clinical responders. That study provided prospective benchmark data on clinical complete response and organ preservation rates to total neoadjuvant therapy. We do not yet have data on how many patients in OPRA are mismatch repair-deficient, but I suspect it is very low.
It is also important to note that there are no pathologic complete response data available in the study by Cercek and colleagues, but the possibility that the clinical complete responses may represent pathologic complete responses is supported by multiple published case reports among patients with mismatch repair-deficient rectal cancer who did receive preoperative immunotherapy and did proceed to surgery. We must also note that radiographic response does not seem to accurately predict pathologic complete response.
These study data are not yet practice changing for several reasons. First, the sample size is relatively small, the median follow-up is still extremely short and all patients were enrolled at a single institution that arguably has the most extensive expertise in the management of rectal cancer. In addition, the only endpoint available is overall response, with no data on survival or other clinically relevant outcomes.
Looking ahead, what we need to change the standard of care is a larger sample size, longer follow-up, data on other clinically relevant endpoints such as 3-year DFS and OS and importantly, multi-institution participation to confirm that the high clinical complete response rates can be replicated in all cancer care settings.
Reference:
Garcia-Aguilar J, et al. J Clin Oncol. 2020;doi:10.1200/JCO.2020.38.15_suppl.4008.
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Cercek A, et al. Abstract LBA5. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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