Cancer Immunotherapy Month: Mismatch Repair Deficiency Shapes Tumor-Agnostic Use of Immunotherapy

In Partnership With City of Hope and Allegheny Health Network

Cancer immunotherapies have transformed the treatment landscape of many tumor types by stimulating the body’s mechanisms of targeting cancer cells. The efficacy of immune checkpoint inhibitors (ICIs) can vary widely between different tumor types based on immunogenicity and other factors—even patients with the same disease may respond very differently to treatment.

Multiple avenues are being explored to predict outcomes for immunotherapy so physicians can select the best treatment for their patients, including the use of molecular biomarkers. The mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) biomarker, which is found in multiple cancers, has proved to be strongly associated with response to immune checkpoint inhibitor therapy. This has led to one of the first pan-tumor indications for dMMR/MSI-H disease; patients whose cancer has this biomarker can receive pembrolizumab (Keytruda) without requiring an FDA study assessing its efficacy in the particular tumor.¹

“It's been a dramatic game changer in certain cancers: those cancers that have no other options or early on that are MSI-H,” said Nathan Bahary, MD, PhD, in an interview with Targeted Oncology^TM.

Biomarker testing can open up new options for patients outside the standard treatment paradigm, making it potentially valuable even when targetable alterations for a particular tumor type are not found.

The Origin of dMMR/MSI-H in Cancer Treatment

The discovery of dMMR/MSI-H came in the 1990s from research into patients with cancers related to hereditary Lynch syndrome, explains Bahary, division chief for medical oncology at Allegheny General Hospital at the Allegheny Health Network Cancer Institute. A flawed DNA repair mechanism leads to an accumulation of errors during cell division that contribute to cancer development, particularly in endometrial and colorectal cancers. MSI is the phenotype of a changed number of repeated DNA bases in a microsatellite that results from this deficiency.

This biomarker can be acquired as well as hereditary. “We found that you could have dMMR,…on a hereditary basis, such as Lynch syndrome, or what we call biallelic somatic.… About 20% of [patients with] endometrial cancers will have them, and colon cancers, about 15% [of patients] will have them,” Bahary explained.

Researchers analyzed whole exome data from 11,139 tumor-normal pair samples from 11,080 patients with 39 cancer types found MSI in 27 different cancers, including 31.37% of endometrial carcinomas and 19.72% of colon adenocarcinomas.²

When first investigated, ICIs initially were found to have efficacy in immunogenic tumors such as melanoma and renal cell carcinoma, said Bahary. When patients with colon cancer associated with Lynch syndrome responded to ICI therapy, dMMR/MSI-H was recognized as a predictive biomarker. Next-generation sequencing was able to identify other patients with dMMR/MSI-H who also responded to pembrolizumab.

Pembrolizumab received an accelerated approval in patients with all dMMR/MSI-H solid tumors who had progressed on prior therapy and had no satisfactory alternative in 2017; in March 2023, this was converted into a regular approval.^1,3 Another immunotherapy agent, dostarlimab-gxly (Jemperli) received an accelerated approval for recurrent or advanced solid tumors with dMMR in 2021.⁴

Significance of the dMMR/MSI-H Indication for Immunotherapy

Since then, the pan-tumor indication has made an impact on how oncologists approach treating various tumor types.

“It's become standard of care now across almost all tumor types to check for MMR status,” said Bahary. “Because pembrolizumab is available, because the responses can be incredibly durable, because they can be very deep, and they're much better tolerated.”

In cancers with specific indications for dMMR tumors, immunotherapy is a frontline option. “In stage IV colorectal cancer where these were studied, it beat out standard chemotherapy in terms of overall survival [with] better quality of life,” Bahary added. “In many places, that's used as the standard of care in the first line, though the FDA indication is in all the other tumors in the second line setting or beyond.”

Targeting dMMR has offered more flexibility in decision-making for many physicians.

“It's been phenomenal for us, because a number of our patients that we see with advanced gastric cancers [or] advanced colon cancer may exhibit both dMMR along with possibly other molecular biomarkers that can be targetable,” said Ajaz M. Khan, MD, chair of the department of medical oncology at City of Hope Atlanta, Chicago, and Phoenix, in an interview with Targeted Oncology.

Khan said that in some cases, he is able to end chemotherapy early for patients and in other cases, patients can receive immunotherapy as monotherapy. This provides a significant benefit to the patients in reducing acute and chronic toxicity chemotherapy-related toxicities, improving patients’ quality of life.

Bahary discussed seeing patients with tumors such as pancreatic adenocarcinoma, endometrial cancer, gastric cancers, and rectal cancers respond well to immunotherapy if patients tested positive for dMMR/MSI-H.

The opportunities presented by this biomarker make early testing crucial, according to Khan. “At the time of diagnosis, they need the evaluation done up front, whether it's by IHC [immunohistochemistry], by PCR [polymerase chain reaction], or even ultimately, by next-generation sequencing, because in those patients who are deficient, we certainly don't want them to lose the opportunity of obtaining treatment that could be lifesaving.”

In colorectal cancer, early screening for dMMR/MSI-H is showing a key role, Bahary explained. In patients with stage IIA cancer and MSI-H status who received 5-FU fluorouracil as adjuvant therapy had no improvement in disease-free survival and worse overall survival.⁵ “It’s incredibly important to find that out early,” he said. Bahary also noted that universal screening for dMMR/MSI-H is now done on precancerous polyps that are removed. This means patients can be diagnosed with Lynch syndrome and they and their families can be counseled appropriately.

Optimizing the Contribution of Immunotherapy

With better understanding of the molecular factors predicting where immune checkpoint inhibitors are most effective, clinical trials are investigating new roles for these treatments in colorectal cancers and beyond. In the neoadjuvant setting, dostarlimab showed a 100% complete response rate with no evidence of disease in 14 patients with MSI-H/dMMR rectal cancer.⁶

Khan emphasized that this trial highlights the benefit of a targeted approach compared with lower responses from neoadjuvant chemotherapy. “It boils down to the fact that…personalizing these cancer treatments for specific patients for their tumor-specific types makes the difference in terms of achieving the greatest possible response for them, particularly at surgery.”

According to Bahary, there is ongoing research comparing immunotherapy with chemotherapy as adjuvant therapy for patients with MSI-H colon cancer, but it is not yet the standard of care. He anticipates that immunotherapy may advance to the neoadjuvant setting in colon and gastroesophageal junction cancers. “I bet that you will see this stage migration in earlier treatment. As we become more facile with it, as we understand better [when] looking at the pathological indicators of response, [and] which ones of those might correlate with survival, then we can begin to try to bring them into the mainstream of treatment.”

Use of immune checkpoint inhibitors can come with certain toxicities requiring special attention, such as autoimmune colitis, pneumonitis, central nervous system events, and carditis. Bahary and Khan both stressed the importance of cardiac, pancreas, thyroid, and liver monitoring.

Generally, with a small number of approved immunotherapies in use, they are well tolerated, and toxicity is consistent across different indications. “I don't see any difference in tolerability between the different indications, meaning the non–MSI versus the MSI indications,” said Bahary. Regimens that add a CTLA-4 inhibitor such as ipilimumab (Yervoy) can be more toxic. However, Bahary added that in light of the successful 1-time dosing of tremelimumab (Imjudo) in combination with durvalumab (Imfinzi) in hepatocellular carcinoma, this combination approach is also being investigated in MSI-H cancers to reduce toxicities such as in the INFINITY trial (NCT04817826).

The decision to use a particular treatment can be influenced by the ease of administration as well. “Particularly at City of Hope, we have a lot of patients that travel on average…approximately 500 miles. We try to make that convenient for them as well,” said Khan. “If they can get treatment every 6 weeks or every 4 weeks, versus getting every 2 weeks, certainly makes it a little bit easier for them in terms of their travel and getting to treatment on time.” The dMMR/MSI-H indication for pembrolizumab allows administration on a schedule of every 3 weeks or every 6 weeks.⁷

Other Developing Treatment Approaches

Although dMMR/MSI-H is one of the most successful biomarkers for immunotherapy, others play a role in predicting outcomes for treatment, such as tumor mutational burden (TMB) and PD-L1 status. The FDA approved pembrolizumab for patients with a TMB of 10 mut/Mb.⁸ Bahary said that in patients with a DNA polymerase deficiency who had 600 to 1000 mut/Mb, he has observed responses comparable to those with dMMR/MSI-H. “It's also very clear that those dMMR patients that trend towards the higher TMB have the better response, but it's not 100%,” he added.

Pembrolizumab was also indicated for PD-L1 expression above 50% in patients with metastatic non–small cell lung cancer, and later expanded to patients with above 1% in stage III disease.⁹ Additionally, Bahary said that he has had patients with cholangiocarcinoma or other small bowel cancers and high PD-L1 expression who received immunotherapy after failing first-line systemic therapy, resulting in deep, durable responses. He stressed that although dMMR, TMB, and PD-L1 can be correlated, they are sometimes disassociated and there is more to learn about the relationship between these markers.

Other combination therapies and different agents are under investigation in a variety of disease settings, such as the anti–PD-1 antibody tislelizumab in a phase 2 trial (NCT03736889) of patients with advanced solid tumors. In the case of patients who do not respond adequately to immunotherapy, research is underway into vaccines and other methods of stimulating the body to respond to immune checkpoint inhibition.

“It will really be fascinating to see how we can go…and how we might more surgically be able to exorcise these tumors using the immune system,” said Bahary.

Selecting patients who will respond well to immunotherapy offers one of the best avenues for improving safety and efficacy outcomes.

“Patients are living longer, hopefully healthier, and more importantly without treatment-related toxicities moving forward,” said Khan.

_References:

_{1. FDA converts to full approval indication for KEYTRUDA® (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. News release. Merck. March 29, 2023. Accessed June 19, 2023. https://tinyurl.com/2p8p5r7m}

_{2. Gouda MA, Nelson BE, Buschhorn L, Wahida A, Subbiah V. Tumor-agnostic precision medicine from the AACR GENIE database: Clinical implications. Clin Cancer Res. 2023;CCR-23-0090. doi:10.1158/1078-0432.CCR-23-0090}

_{3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. News release. FDA. May 27, 2017. Accessed June 19, 2023. https://tinyurl.com/bdejrney}

_{4. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. News release. FDA. August 17, 2021. Accessed June 19, 2023. https://tinyurl.com/mr32c99x}

_{5. Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J Clin Oncol. 2010;28(20):3219-3226. doi:10.1200/JCO.2009.27.1825}

_{6. Cercek A, Lumish M, Sinopoli J, et al. PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer. N Engl J Med. 2022;386(25):2363-2376. doi:10.1056/NEJMoa2201445}

_{7. Keytruda. Prescribing information. Merck; 2022. Accessed June 19, 2023. https://tinyurl.com/yw2p25p4}

_{8. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 16, 2020. Accessed June 19, 2023. https://tinyurl.com/2kurmfye}

_{9. FDA expands pembrolizumab indication for first-line treatment of NSCLC (TPS ≥1%). News release. FDA. April 11, 2019. Accessed June 19, 2023. https://tinyurl.com/3fszta2b}