Neoadjuvant Pembrolizumab Elicits High Response Among dMMR/MSI-H Solid Tumors

Kaysia Ludford, MD

Neoadjuvant pembrolizumab (Keytruda) elicited high clinical activity in patients with mismatch repair deficiency (dMMR)/microsatellite instability high (MSI-H) solid tumors and was well tolerated, according to data from a phase 2 study (NCT04082572) published in the Journal of Clinical Oncology. Patients who underwent nonoperative management demonstrated promising benefit from the treatment in addition to those who had surgical resection.¹

The primary end point of the study was pathological complete response (pCR) among those who received 3 doses of pembrolizumab prior to resection. Fifteen patients were evaluable for this end point and had a pCR rate of 67% (95% CI, 38%-88%). At the time of data cutoff, March 31, 2022, 17 patients (49%) underwent surgical resection—including 1 patient after cycle 1, and 1 patient after cycle 2—and achieved a pathological CR rate of 65%. Although the pCR rate of 65% was lower than the study goal of 80%, patients with colorectal cancer (n = 11/14) experienced a pCR rate of 79%.

Among all patients evaluable for radiographic response (n = 33) the overall response rate (ORR) was 82% with a complete response (CR) rate of 30%. Eighteen patients did not undergo surgical resection and either had nonoperative management after 1 year of pembrolizumab (n = 10) or received pembrolizumab for less than a year (n = 8). At median follow-up of approximately 9.5 months (range, 0-26), only 2 patients in the efficacy-evaluable nonoperative arm (n = 17) experienced progression events.

In the cohort of patients who received pembrolizumab for less than a year, 5 patients opted for nonoperative management, 3 patients achieved CRs, 2 experienced stable disease, 1 patient withdrew consent, and 2 patients died from causes unrelated to treatment. Additionally, both patients on the trial with pancreatic cancer (n = 2), experienced adaptive progression and did not achieve a pCR.

“One of the most intriguing findings from this prospective trial is the suggestion that neoadjuvant PD-1–based therapy may represent a definitive approach for dMMR solid tumors enabling organ preservation,” wrote lead study author Kaysia Ludford, MD, of The University of Texas MD Anderson Cancer Center, in Houston, TX, and colleagues, in the paper.

The investigator-initiated, open-label trial was conducted at The University of Texas MD Anderson Cancer Center in Houston and enrolled a total of 35 patients from October 31, 2019, to March 25, 2021. Most patients (77%) had colorectal adenocarcinomas, which included colon adenocarcinoma (54%), rectal adenocarcinoma (23%), pancreatic adenocarcinoma (6%), duodenal adenocarcinoma (6%), and other (11%).

Patients had unresectable cancer at a rate of 26%, with 74% of patients presenting with clinical stage 3 disease and 23% with stage 2 disease. Additionally, 74% of patients were not previously treated and 11% of patients had prior radiation, 9% surgery, and 6% chemotherapy.

The coprimary end points were safety and pCR. Key secondary end points included ORR and organ-sparing at 1 year for patients who declined surgery.

Pembrolizumab 200 mg was administered intravenously once every 3 weeks for 8 treatments followed by surgical resection. A nonsurgical management option included was for patients to receive pembrolizumab for 16 treatments followed by observation.

Eligible patients were at least 18 years of age with measurable disease by RECIST 1.1 with locally advanced, defined as a 20% chance or greater of recurrence with solely surgical resection, dMMR/MSI-H solid cancers. The median age was 62 years (range, 25-90) and more than half of patients were women (57%). Limitations of the study design included the small patient population, enrollment at only 1 institution, and the choice given to the patient and/or treating physician to decide whether to proceed with surgical resection.

Thirty patients (86%) in the trial had luminal gastrointestinal cancers. Additional findings from the study showed that among the 19 who were evaluable for endoscopic response, 63% experienced a CR and 37% had incomplete responses with a median time to response of 17 weeks (range, 6-31). Five patients who had a CR underwent surgical resection, all of whom achieved a pCR. Additionally, 3 of the patients who had incomplete responses underwent surgical resections with 2 experiencing a pCR and 1 residual disease.

Moreover, 19 patients had serial sample and detectable circulating tumor DNA (ctDNA) at baseline and 13 of 15 patients with ctDNA decrease had no progression. The study authors noted that an early decrease in ctDNA was predictive of no future progression events (P = .037).

No new safety signals were reported for pembrolizumab. Grade 1 or 2 adverse events (AEs) occurred in 37% of patients in the safety population (n = 35) and 6% experienced grade 3 AEs. No grade 4 AEs were reported. Out of the 17 patients who underwent surgery, 3 postoperative complications were experienced consisting of grade 3b surgical site abscess, grade 1 abdominal wall hematoma, and grade 2 diarrhea occurring.

Pembrolizumab was previously granted accelerated approval by the FDA on May 23, 2017, for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H/dMMR solid tumors whose disease had progressed after prior treatment.2 Additionally, the PD-1–targeted antibody gained a standard approval from the agency for the first-line treatment of patients with unresectable or metastatic MSI-H/dMMR colorectal cancer on June 29, 2020.³

MSI-H and dMMR tumors are most commonly found in colorectal, endometrial, and gastric cancers and are typically seen in the early-stage of disease. Although therapy for localized dMMR cancer is based on treatments for proficient MMR/microsatellite stable tumors which includes surgery, chemotherapy, and/or radiation, data have indicated that chemotherapy may not provide the same level of benefit for dMMR disease.¹

MSI-H tumors, regardless of PD-L1immunohistochemistry expression levels, have had greater responses to checkpoint blockades with PD-1 or PD-L1 inhibitors than microsatellite stable tumors.⁴ Additionally, dMMR tumors have a high prevalence in colorectal adenocarcinomas; an analysis of 16,065 evaluable biopsy specimens demonstrated an overall dMMR prevalence of 13.4% compared with only 2.7% within the rectal cancer subset.²

“When the immune profiles between progressors and nonprogressors were compared, progressors demonstrated a trend toward higher presence of granulocytic cell cluster and exhausted T cells…the presence of CD151 granulocytic cell types and their close proximity to CD81 T cells associate with progression in dMMR cancers,” study authors noted.

Future directions for this research include further investigating checkpoint inhibitors, which have established efficacy in this patient population, in the neoadjuvant space as well as enrolling larger studies on dMMR solid tumors to define duration of therapy. The best assessment to evaluate luminal tumors also requires more investigation according to the study authors.¹

References

1. Ludford K, Ho WJ, Thomas JV, et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J Clin Oncol. Published online January 9, 2023. doi:10.1200/JCO.22.01351
2. Ciombor KK, Eng C. Immunotherapy in localized microsatellite instability-high/mismatch repair deficient solid tumors: are we ready for a new standard of care? J Clin Oncol. Published online January 9, 2023. doi:10.1200/JCO.22.02564
3. FDA approves pembrolizumab for first-line treatment of MSI-H/dMMR colorectal cancer. FDA. Updated June 30, 2020. Accessed January 25, 2023. bit.ly/3XXORkO
4. Marginean EC, Melosky B. Is there a role for programmed death ligand-1 testing and immunotherapy in colorectal cancer with microsatellite instability? Part II-the challenge of programmed death ligand-1 testing and its role in microsatellite instability-high colorectal cancer. Arch Pathol Lab Med. 2018;142(1):26-34. doi:10.5858/arpa.2017-0041-RA