Immunotherapy in CRC Depends on Identifying Predictive Biomarkers

Dung Thi Le, MD

Even as immunotherapy grows more popular as a treatment for solid tumors, physicians are racing to identify patients with the molecular subtypes, rather than the disease, who will derive the most benefit.

The goal is to develop a biomarker that works across histologies and create a tissue-agnostic treatment, said Dung Thi Le, MD, associate professor of medical oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. She explored biomarker possibilities for immunotherapies, such as pembrolizumab (Keytruda) and nivolumab (Opdivo), during a presentation at the 2nd Annual International Congress on Immunotherapies in Cancer™, hosted by Physicians’ Education Resource®, LLC, held December 16, 2017.

Le discussed these agents specifically in patients with colorectal cancer (CRC) with mismatch repair—deficient (dMMR) or microsatellite instability high (MSI-H) molecular subtypes. Tumors harboring a mismatch repair deficiency are the most common type of gastrointestinal cancer, representing 15% of colorectal carcinomas across all stages, although they are less common in advanced disease (4%).

Le was the lead investigator of a phase II study published in New England Journal of Medicine in 2015 that evaluated immune checkpoint blockade in patients whose tumors had or did not have mismatch repair deficiency.¹Le and her team recruited 32 patients with refractory progressive metastatic CRC from September 2013 through January 2015 and segregated them into cohorts A and B. Cohort A included 10 patients with dMMR CRC, while 18 patients with mismatch repair—proficient CRC made up Cohort B. Seven other previously-treated patients with dMMR solid tumors other than CRC were enrolled in cohort C. All patients were assigned to 10 mg/kg pembrolizumab every 14 days.

Patients in Cohort B did not respond, but the immune-related objective response rate (ORR) was 40% in Cohort A (95% CI, 12%-74%) and 71% in Cohort C (95% CI, 40%-97%). Immune-related progression-free survival (PFS) at 20 weeks was 78% in Cohort A and 67% in Cohort C.

Le said researchers did not set out to design a trial aimed at detecting tissue-agnostic development, but simply followed the data. “As we were developing this study, we asked, ‘If it works in colorectal cancer, why should we not test it in all tumor types?’ Histology should not matter.”

That supposition has borne out, as she detailed in results from the KEYNOTE-016, -164, and -158 trials, all of which were submitted as evidence when the FDA approved pembrolizumab for unresectable or metastatic, MSI-H, or dMMR solid tumors in May 2017.

In KEYNOTE-016, 40 patients with dMMR CRC (Cohort A) and 46 with dMMR non-CRC (Cohort C) were assigned to 200-mg pembrolizumab (10 mg/kg) every 2 weeks. As in the Le study, a third cohort of patients with mismatched repair—proficient CRC did not respond to treatment and were not included in the results.

In Cohort A, the complete response (CR) rate was 12% and the partial response (PR) rate was 40%. The ORR was 52%, and the disease control rate (DCR) was 82%. Two-year PFS was 59% and 2-year overall survival (OS) was 72%. Median PFS and OS were not reached.

In Cohort C, the rates were 28%, 26%, 54%, and 72% for CR, PR, ORR, and DCR, respectively. The 2-year PFS was 46%, and 2-year OS was 57%. The median PFS was 18.1 months, and the median OS had not yet been reached.

Across KEYNOTE-164 and -158 assessing pembrolizumab in patients with MSI-high or dMMR solid tumors, the ORR was 28% in CRC and 37% in non-CRC, including 4 CRs. The DCR was 51% in patients with CRC and 59% in patients with non-CRC.

“Mismatched repair—proficient patients did not respond and the mismatched repair–deficient patients did,” Le said.

“In earlier studies, although they were reported later, in PD-L1 selected colorectal cancer, regardless of [microsatellite instability (MSI)] status, PD-L1 is not a good selection marker for [patients with] colorectal cancer because in those studies, they also did not have a response rate, except for 1 patient with MSI-H colorectal cancer.”

Results from the NCI-MATCH trial should provide another valuable step toward the development of a tissue-agnostic treatment and identifying the necessary biomarkers.²MATCH is the first national signal-finding trial to incorporate centralized national geodetic survey testing to put patients in molecularly targeted parallel phase II treatment arms.

Eligible patients have advanced or refractory solid tumors, lymphoma, or myeloma with a molecular abnormality believed to predict response. The most common tumor types accounted for 38.2% of the cancers screened and included CRC (15.4%), breast (12.8%), and lung (7.4%) cancers. Of the tumors screened, 18% were found to have a genetic mutation that matched the patient to 1 of the 30 treatment arms. As of July 2017, investigators used next-generation sequencing to screen 5963 tumor samples. The sequencing assay successfully yielded a result 93% of the time.

Thirty-four patients who were previously treated with anti—PD-1/PD-L1 antibodies or other immune checkpoint inhibitors for dMMR non-CRC were treated with 3 mg/ kg nivolumab every 2 weeks for four 28-day cycles.³After cycle 4, the dose was changed to 480 mg every 4 weeks. The ORR was 24% (95% CI, 11%-41%), exceeding the prespecified target of 16%, and consisted of 8 PRs. The DCR was 56%, and the 6-month PFS was 49% (95% CI, 32%-67%). Ten patients (29%) had progressive disease.

NCI-MATCH trial is using the Comprehensive Genomic Profiling Plus molecular testing service to assess DNA, RNA, and proteins, including MSI, total mutational load, and PD-L1 expression, to reveal a molecular blueprint to guide more precise and personalized treatment decisions.

Le mentioned 4 studies evaluating next-generation tools used to assess MSI expression: mSINGS, MSIsensor, MANTIS, and MOSAIC. She noted that in MANTIS, the assay detected MSI-H tumors across 3.8% of 11,139 tumor samples: from a high of

31.4% in endometrial cancers to a low of 0% in pancreatic adenocarcinoma.⁴MSI was highest among Lynch syndrome tumors, which has been consistent across multiple studies. Results from MANTIS were validated with polymerase chain reaction (PCR) of MSI samples.

As seen in results from MSIsensor, the MSK-IMPACT assay had a 99.4% concordance rate with PCR/immunohistochemistry.⁵The results showed that MSI-H status was not generally prognostic for survival, but did appear to be a predictor for positive outcomes in patients with CRC.

“We would like to start looking at PD-1 inhibitors in earlier lines of therapy,” Le said. “There are studies in the first line as well as the adjuvant setting, but we do not have data on those studies. We are starting to see broader testing of solid tumor types in mismatch repair by immunohistochemistry and polymerase chain reaction. We’re also starting to identify more of these patients as patients are getting more next-generation sequencing panels, and we hope to start developing immunotherapy as an option for other patients as well based on high mutation burdens that are microsatellite stable.”

References

1. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch- repair deficiency.N Engl J Med. 2015;372(26):2509-2520. doi: 10.1056/NEJMoa1500596.
2. Harris L, Chen A, O’Dwyer P, et al. Update on the NCI-Molecular Analysis for Therapy Choice (NCI-MATCH/EAY131) precision medicine trial. Presented at: the 2017 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA. Abstract B080. abstractsonline.com/pp8/#!/4557/presentation/400.
3. Azad N, Overman M, Gray R, et al. Nivolumab in mismatch-repair deficient (MMR-d) cancers: NCI-MATCH Trial (Molecular Analysis for Therapy Choice) arm Z1D preliminary results. Presented at: 2017 SITC Annual Meeting; November 9-12, 2017; National Harbor, MD. Abstract O37. jitc.biomedcentral.com/articles/10.1186/s40425-017-0297-3.
4. Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types [published online October 3, 2017].JCO Precision Oncology.2017. doi: 10.1200/PO.17.00073.
5. Middha S, Zhang L, Nafa K, et al. Reliable pan-cancer microsatellite instability assessment by using targeted next-generation sequencing data [published online October 3, 2017].JCO Precision Oncology.2017. doi: 10.1200/PO.17.00084.