OPTIONS & TOOLS
DOI: 10.1200/JCO.22.02564 Journal of Clinical Oncology - published online before print January 9, 2023
Immunotherapy in Localized Microsatellite Instability–High/Mismatch Repair Deficient Solid Tumors: Are We Ready for a New Standard of Care?
The hallmark of mismatch repair deficiency is the inability to repair spontaneous mutations during DNA replication, resulting in high tumor mutational burden levels and altered DNA microsatellite sequences or microsatellite instability (MSI).1-3 Although initially this feature was identified as a preliminary screening test for hereditary cancer syndromes such as Lynch syndrome,4 mismatch repair deficiency and MSI have now been recognized as critical predictive biomarkers and define a therapeutic strategy in cancer as well.
In the article that accompanies this editorial, Ludford et al20 investigate the potential safety, utility, and efficacy of neoadjuvant pembrolizumab for patients with localized mismatch repair deficient/microsatellite instability-high solid tumors. Although excellent safety and efficacy signals were seen in this study of neoadjuvant immunotherapy, more data are needed before this therapeutic approach is established as a ubiquitous standard of care for all patients with localized mismatch repair deficient/microsatellite instability-high solid tumors.
Early studies investigating programmed death 1 (PD-1) blockade demonstrated remarkable responses in patients with mismatch repair deficient (dMMR) or MSI-high (MSI-H) solid tumors.5-7 In a pivotal phase II study, patients with treatment-refractory metastatic solid tumors were treated with pembrolizumab.7 Objective response rates in the dMMR groups were markedly higher (40% in dMMR metastatic colorectal cancer [mCRC], 71% in dMMR metastatic noncolorectal cancer) relative to the mismatch repair proficient mCRC group (0%), and prolonged durable responses were observed in the dMMR/MSI-H groups. As a result, this study was expanded to enroll patients with dMMR cancers across 12 different tumor types, independent of the tissue of origin.8 In this cohort, objective responses were seen in 53% (46 of 86) of patients, with 21% (n = 18) achieving a radiographic complete response (CR). On May 23, 2017, the US Food and Drug Administration granted accelerated approval to pembrolizumab for adult and pediatric patients with unresectable or metastatic, MSI-H/dMMR solid tumors whose disease had progressed after prior treatment, marking the US Food and Drug Administration's first tissue/site-agnostic approval.
On the basis of these excellent outcomes in patients with treatment-refractory dMMR/MSI-H solid tumors, PD-1 blockade was tested earlier in the treatment course of patients with dMMR/MSI-H mCRC. KEYNOTE-177 was a randomized phase III study of first-line pembrolizumab versus chemotherapy in patients with MSI-H/dMMR mCRC.9 In this trial, pembrolizumab was superior to chemotherapy with respect to progression-free survival (PFS; median PFS, 16.5 v 8.2 months); although median overall survival was not improved, this was attributed to the 60% crossover rate to immunotherapy in patients assigned to upfront chemotherapy.10 Among patients with response to pembrolizumab, 83% had ongoing tumor response at 24 months, with a subset achieving a likely cure of their disease. Similarly, the nonrandomized phase II CheckMate 142 trial demonstrated the combination of the PD-1 inhibitor, nivolumab, and the cytotoxic T-lymphocyte antigen-4 inhibitor, ipilimumab, to be very effective, with an overall response rate of 69% and median duration of response, PFS, and overall survival not yet reached.11
How prevalent is MSI-H/dMMR in solid tumors, and does it vary by stage? Early estimates of the incidence of MSI-H/dMMR demonstrated a higher prevalence in earlier stage tumors and variability among tumor types.8,12 A more recent analysis of 16,065 evaluable colorectal adenocarcinoma biopsy specimens observed an overall dMMR prevalence of 13.4% and only 2.7% within the rectal cancer subset,13 consistent with known enrichment of right-sided colon cancers for dMMR.
Given this increased prevalence of dMMR/MSI-H in earlier stage tumors, as well as initial promising data using immunotherapy in patients with advanced disease with dMMR/MSI-H, it was hypothesized that immunotherapy could be successfully used in localized dMMR/MSI-H solid tumors also. The specific hypothesis is that the intact primary tumor provides a source of antigens for immune priming and expansion of activated tumor-specific T cells.14,15 Several studies have now explored this hypothesis with very encouraging results. A single-institution phase II study by Cercek et al16 is enrolling patients with MSI-H/dMMR locally advanced rectal cancer to six months of neoadjuvant therapy with the anti–PD-1 antibody dostarlimab. In early results, 100% of 12 consecutive patients have achieved a clinical CR to single-agent dostarlimab therapy. To specifically note, none of these patients have required chemotherapy, radiation, or surgical resection as part of their therapy to date. The median follow-up for this study is still short at 12 months, so it remains to be seen if this approach will lead to durable cancer control and be a viable long-term organ preservation option for this subset of patients.
In a similar vein, the NICHE-1 trial demonstrated that a short course of dual immune checkpoint blockade with nivolumab and ipilimumab led to a 100% pathologic RR and a 60% pathologic CR rate in patients with nonmetastatic dMMR colon cancer.17 These results led to the larger NICHE-2 study, recently presented by Chalabi et al18 at European Society for Medical Oncology 2022. In the nonrandomized NICHE-2 study, 112 patients with dMMR/MSI-H localized colon cancer (T3 and/or node-positive radiographically) received a cycle of nivolumab and ipilimumab, followed by another dose of nivolumab, before surgical resection of their primary tumor. All patients underwent surgery, with a 100% R0 resection rate, 95% major pathologic response (defined as 10% or less residual viable tumor) rate, and a 67% pathologic CR rate. Although this study needs longer follow-up, the results are very encouraging and lend further support to organ-sparing strategies and chemotherapy-free paradigms in dMMR/MSI-H colorectal cancer.
In the noncolorectal area, the phase II GERCOR NEONIPIGA trial is investigating the use of neoadjuvant nivolumab and ipilimumab and adjuvant nivolumab in patients with localized dMMR/MSI-H gastric or gastroesophageal junction adenocarcinoma.19 In 29 patients with cT2-4NxM0 disease who underwent surgery after a total 12-week course of neoadjuvant dual immunotherapy combination, an encouraging 59% pathologic CR rate was observed. Given the promising initial results of these studies, there has been substantial interest in the potential adoption of neoadjuvant immunotherapy as definitive treatment for patients with dMMR/MSI-H solid tumors.
In the single-institution prospective phase II trial that accompanies this editorial, Ludford et al20 described outcomes from 35 patients who received neoadjuvant immunotherapy with pembrolizumab for locally unresectable or high-risk resectable dMMR/MSI-H tumors of various types. Although the majority of patients treated on this study had colorectal tumors (n = 27; 19 colon, eight rectal), the remainder had a mix of various tumor types (two pancreas, two duodenal, one gastric, one ampullary, one meningioma, and one endometrial). In addition to the tumor type heterogeneity, small sample size, and subjectivity of the eligibility criteria (particularly, the definition of locally advanced being a nonmetastatic primary cancer with at least a 20% chance of recurrence with surgical resection alone), the patients in this study underwent different treatment algorithms. A total of 17 patients (49%) underwent surgery, with a resultant pathologic CR rate of 65%. The remainder (51%) received nonoperative management with ongoing pembrolizumab of varying durations. The objective RR for 33 evaluable patients was an impressive 82%. Endoscopic responses were not assessed in all patients with luminal gastrointestinal cancers, although a complete endoscopic response was observed in 63% of evaluable patients, with a median time to response of 17 weeks.
Although this study is a valuable addition to our expanding experience with neoadjuvant immunotherapy for the treatment of patients with localized dMMR/MSI-H solid tumors, its details the many important questions in this space that have yet to be answered. Results from the available neoadjuvant studies described here and elsewhere indicate the potential for higher response rates and improved patient outcomes with the use of immunotherapy earlier in the disease course with plausible biological rationale. However, what duration of immunotherapy is necessitated for cure in this unique genomically selected subset of patients with solid tumor remains to be determined. Is PD-1 blockade sufficient or will combined PD-1 and cytotoxic T-lymphocyte antigen-4 inhibition with agents such as nivolumab and ipilimumab be required for successful nonoperative treatment approaches? As different solid tumor types have inherently different operative risks, morbidity, and surveillance challenges, it is possible that the value and benefit of using immunotherapy as a neoadjuvant approach may vary when compared with its associated risks. An inherent assumption is that patients prefer immunotherapy to other more traditional cancer treatment modalities; although this is likely often true, patient-reported outcomes will be a key data source to investigate this assumption more thoroughly. Can we truly spare patients the morbidity of our traditional cancer treatment modalities such as chemotherapy, radiation, and surgery, or are we just trading these known potential morbidities for an approach with different toxicities and an as yet uncertain long-term outcome?
In addition to longer follow-up and results that are pending from ongoing studies, translational efforts will be key to personalizing an immunotherapy approach for patients with dMMR/MSI-H solid tumors. Ludford et al20 provided select examples in an exploratory analysis of immune profiling in their study—namely that more CD15+ granulocytic cells within the tumor microenvironment with proximity to cytotoxic CD8+ T cells, as well as T-cell exhaustion, may predict for lack of (or loss of) treatment response. Results from additional ongoing studies of circulating tumor DNA dynamics, novel imaging techniques, and single-cell sequencing in these trials, among others, are eagerly awaited and will help us understand the mechanisms of primary and acquired resistance to immunotherapy.
Will neoadjuvant immunotherapy become the new standard of care for patients with localized dMMR/MSI-H solid tumors? Only more time will tell—but the collection of additional data from well-designed, prospective, multicenter studies will be essential to help answer these critical questions and guide our best treatment of patients with tumors that harbor this unique genomic signature.
See accompanying article doi: 10.1200/JCO.22.01351
Conception and design: Kristen K. Ciombor
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Kristen K. Ciombor
Consulting or Advisory Role: Merck, Pfizer, Lilly, Seattle Genetics, Replimune, Personalis, Incyte
Research Funding: Pfizer (Inst), Boston Biomedical (Inst), MedImmune (Inst), Onyx (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Bristol Myers Squibb (Inst), Merck (Inst), Novartis (Inst), Incyte (Inst), Amgen (Inst), Sanofi (Inst), Array BioPharma (Inst), Daiichi Sankyo (Inst), Nucana (Inst), AbbVie (Inst), Pfizer/Calithera (Inst), Genentech (Inst), Seattle Genetics (Inst)
Travel, Accommodations, Expenses: Array BioPharma, Incyte
Consulting or Advisory Role: GlaxoSmithKline, Bayer Health, Natera, Janssen Oncology, HalioDx
Research Funding: Hutchison China Meditech (Inst), Elevar Therapeutics (Inst)
Uncompensated Relationships: Pfizer (Inst), Merck (Inst)
No other potential conflicts of interest were reported.
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