Blog September 26, 2022

ASCO 2022 – Part 2: Vanishing dMMR Rectal Cancer; Predicting Cytokine Release Syndrome Risk

In our previous post, we discussed exciting news from the 2022 American Society for Clinical Oncology (ASCO) Annual Meeting pertaining to breast cancer and findings from a Phase 3 trial of trastuzumab-deruxtecan that expands treatment options for patients with low HER2 expression. In this post, we turn our attention to two further topics that caught our attention. The first is an unprecedented, although early stage, clinical result showing that treatment with dostarlimab-gxly (GlaxoSmithKline’s anti-PD-1 antagonist Jemperli) may spare certain patients with colorectal cancer from the potentially harmful consequences of chemo and radiation therapy, while still achieving a positive outcome. The second is the discovery by Medidata Acorn AI of biomarkers easily measured in blood that can predict which CAR-T treated patients are at risk of severe cytokine release syndrome (CRS).

Unprecedented Clinical Results in dMMR Rectal Cancer Patients

The DNA mismatch repair pathway is involved in maintaining genomic stability, correcting mistakes made during DNA replication and recombination. Mismatch repair deficient cells (dMMR) typically accumulate many mutations that can result in a predisposition to certain types of cancer (including colorectal cancers) and resistance to chemotherapy. In August 2021, the FDA granted dostarlimab-gxly an accelerated approval for the treatment of adult patients with recurrent or advanced dMMR solid tumors of any type that have progressed during or after treatment, and who have no satisfactory alternative treatment options.

Rectal cancers are typically treated with surgery, chemotherapy and/or radiation. The cure rate is high, but patients undergoing surgery and/or radiation can experience significant morbidities: infertility, bladder dysfunction or potentially, permanent colostomy. About 5-10% of the surgically treated patients have dMMR tumors against which chemotherapy is not very effective.  

A study of dostarlimab on dMMR rectal cancer patients was presented at ASCO

At ASCO, investigators from Memorial Sloan Kettering presented interim results from an 18-person Phase 2 study of patients with early stage dMMR rectal cancer who were treated with dostarlimab. The patients were infused with the PD-1 blocker every three weeks for six months, which was to be followed by chemotherapy and radiation if any cancer was left. The investigators were amazed to find that at six months every patient’s cancer had vanished. An additional four patients who were enrolled later in the trial also responded, one within three months of starting the treatment. At a median follow-up of 6.8 months, none of those treated had their cancers return, and no serious adverse events were reported. Most of the patients in the trial had large bulky tumors and would have otherwise undergone all three treatments of chemo, radiation, and surgery, according to the investigators.

While exciting, it is still too early to say whether this very positive response will equate to a cure. Rectal tumors have been known to regrow in some individuals two years after neoadjuvant therapy. The trial is expected to report on the sustained 12-month response and overall response rate in March 2023. However, given dostarlimab’s tumor-agnostic approval, the results to date suggest it carries the potential to eliminate the need for chemotherapy, radiation and surgery in the dMMR type of cancers, which are approximately 3-4% of all cancers.

Could dostarlimab potentially yield similar results in dMMR tumor types beyond colorectal cancer?  

Predicting Risk of Severe CRS 

Cytokine release syndrome (CRS) is an adverse reaction that frequently occurs after treatment with CAR-T and some other immunotherapies. Most cases are relatively mild, with flu-like symptoms. However, in about 18.5% of cases, CRS causes severe, life-threatening systemic reactions, which can include low blood pressure, capillary leakage, disseminated vascular coagulation, respiratory distress, and multi-organ failure. CRS events have reportedly led to the failure of at least 15 clinical trials of CAR-T therapies since 2016. Roche’s IL-6 inhibitor tocilizumab (Actemra) is currently the only FDA-approved treatment for CRS. Successful treatment depends on early diagnosis and intervention. However, until now it has been difficult to determine the risk of severe CRS events; CAR-T trials tend to involve only small numbers of patients and so data on CRS events from individual trials are limited.

At ASCO, Medidata’s Acorn AI presented the results of a new multi-study analysis that links the risk of severe CRS associated with CAR-T therapy to the presence of common biomarkers that are easily measured in ordinary lab tests like complete blood counts. The study pooled data from 542 patients across multiple clinical trials of a variety of CAR-T products. The researchers found variances in biomarkers such as platelet and neutrophil counts, serum albumin concentrations, and creatinine levels that differentiated between CAR-T treated patients who had experienced severe CRS and those who didn’t.

Medidata has recommended that the biomarkers be incorporated into Risk Evaluation and Mitigation Strategies (REMS)– detailed use plans that are frequently developed for medicines that pose serious safety concerns – for both approved uses and clinical trials of CAR-T treatments. Understanding and identifying the warning signs of CRS risk in individual patients offers advantages for both the clinical use of CAR-T therapies and the improved design of clinical trials. The biomarkers could be employed to better select patients for therapy and aid in early diagnosis and intervention in CRS-related events. They could also help CAR-T developers design safer trials and better understand and avoid trial failures.