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Pembrolizumab in Microsatellite Instability–High or Deficient Mismatch Repair Solid Tumors: The First FDA Approval for a Tissue-/Site-Agnostic Indication

Jane E. Rogers, PharmD BCOP
Clinical Pharmacy Specialist in Gastrointestinal Medical Oncology
Pharmacy Clinical Services
University of Texas
MD Anderson Cancer Center
Houston, TX

The concept of using the host’s immune system in the fight against cancer surfaced in the 19th century.1,2 Historically, however, limited strides have been made in stimulating T-cell immune responses via vaccination or cytokine treatment (interleukin-2 or interferon-alpha).1-5 Recently, cancer immunotherapy has reemerged in the forefront of oncology investigation, leading to a surge of immune modulation agents approved by the U.S. Food and Drug Administration (FDA).6-10 The resurgence in oncology care resulted from an investigative shift in targeting tumor immune inhibitory mechanisms, with the identification of key immune checkpoint receptors, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1).1-5

Since 2014, five monoclonal antibodies (mAbs) that target the immune checkpoint PD-1 pathway have been approved by the FDA.4-8 These agents have shown rapid growth in approval accompanied by a vast array of solid tumor indications. Further breakthroughs with these agents are expected, given the substantial number of trials recruiting subjects (a search for “PD-1” revealed 236 recruiting studies, and a “PD-L1” search showed 166 recruiting studies).11-12 PD-1 and its respective ligands, programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2), when bound cause T-cell exhaustion.1-5 Tumor cells have an upregulation of PD-L1, allowing these cells to suppress the immune system and avoid elimination. Blocking PD-1/PD-L1 via PD-1 or PD-L1 mAbs allows for T-cell activation. Pembrolizumab, an IgG4 PD-1 mAb, is among these agents.

On May 23, 2017, pembrolizumab achieved a milestone in oncology care when it obtained accelerated FDA approval for a biomarker-specific indication regardless of tumor site origin.6,13 The tissue-/site-agnostic indication is for the treatment of microsatellite instability–high (MSI-H) or deficient mismatch repair (dMMR) adult and pediatric patients with unresectable or metastatic solid tumors. Patients with solid tumors must have had disease progression following prior treatment and have no satisfactory alternative treatment options; metastatic colorectal cancer (mCRC) patients, specifically, are candidates for pembrolizumab only after disease progression on fluoropyrimidine, oxaliplatin, and irinotecan. The accelerated approval was based on tumor response and the duration of response seen in a pooled analysis, with continued approval contingent upon a confirmatory trial. The prescribing information limits use in pediatric patients with MSI-H central nervous system cancers because safety and efficacy in this population have not been established. Dosing is 200 mg flat dose (adults) or 2 mg/kg (pediatric patients) intravenous (IV) every 3 weeks.

Microsatellites are repetitive sequences of deoxyribonucleic acid (DNA) susceptible to errors during replication.14-16 The mismatch repair system functions to correct these insertion or deletion errors; however, when a deficient mismatch repair system is present, this leads to microsatellite instability and causes a highly mutated state. MSI-H tumors can be sporadic or can be associated with hereditary nonpolyposis colorectal cancer (HNPCC), known commonly as Lynch syndrome. Lynch syndrome is characterized by inherited defects in MMR proteins (MLH1, MSH2, MSH6, PMS2).14-17 MSI-H tumors are seen more in the sporadic setting resulting from somatic hypermethylation of the MLH1 promotor (often associated with BRAFV600E mutation in mCRC). MSI-H/dMMR status is tested either by polymerase chain reaction (PCR) DNA testing or via immunohistochemical (IHC) staining to detect the loss of one or more of the mismatch repair proteins.14-16 A variety of malignancies are associated with MSI-H. Colorectal cancer (15%–20%), endometrial cancer (20%–30%), and gastric cancer (8%–22%) are more frequently reported, but this tumor phenotype can be seen to a lesser degree in many malignancies, including cholangiocarcinoma, pancreatic, esophageal, prostate, small-bowel, thyroid, melanoma, ovarian, cervical, head and neck, and renal cell carcinoma.14

Differences between CRC MSI-H/dMMR tumors and microsatellite stable/proficient mismatch repair (MSS/pMMR) CRC tumors have emerged—in clinicopathological features, prediction of immunotherapy response, and prognoses.18-19 National guidelines recommend MSI or MMR testing for all mCRC patients, given the clear distinction in responses shown with immunotherapy in these two subsets.18 The immunotherapy response differences in mCRC were identified by two phase-2 studies with PD-1 inhibitors. Le and colleagues revealed an objective response rate (ORR) of 40%, with 78% progression-free survival (PFS) rate at 12 weeks in the MSI-H/dMMR group who received pembrolizumab compared to 0% ORR and 11% PFS rate in the MSS/pMMR group.20 Updated results continue to show benefit in only MSI-H/dMMR mCRC patients, with ORR of 50% compared to 0% in the MSS/pMMR group.21 Disease control was 89% for MSI-H/dMMR mCRC compared to 16% in the MSS/pMMR group. Overman and colleagues studied nivolumab alone or in combination with ipilimumab (a CTLA-4 inhibitor). Preliminary results showed that nivolumab alone resulted in a 27% versus 0% ORR in MSI-H/dMMR and MSS/pMMR, respectively.22 A recent update on the current results of the nivolumab-alone arm in the MSI-H/dMMR mCRC group showed a 31% ORR and 69% disease control.23 Diaz and colleagues reported the results of MSI-H/dMMR non-CRC patients from a phase-2 independent tumor histology trial design.24 Twenty-nine patients (with mostly endometrial, pancreatic, and ampullary cancer) received pembrolizumab. The ORR was 48%, with a disease control rate of 72%. Median overall survival and PFS were not reached at 21 months.

Pembrolizumab’s recent tissue-/site-agnostic approval was based on a pooled analysis of five uncontrolled open-label multicenter single-arm trials (KEYNOTE-016, KEYNOTE-164, KEYNOTE-028, KEYNOTE-012, and KEYNOTE-158).6 Trial design and patient population information is included in (Table 1 – see PDF). There were 149 total MSI-H/dMMR patients with a median age of 55 years. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Almost all patients (98%) had metastatic disease. Patients had a median of two prior treatments. Sixty percent had mCRC, with the remainder involving a variety of non-CRC tumors (Table 2 – see PDF). MSI or MMR status was determined via local PCR, local IHC, or central PCR. Patients received either 200 mg IV pembrolizumab every 3 weeks or 10 mg/kg IV every 2 weeks. From the pooled analysis the ORR was 39.6% (majority partial response 32.2%), with a duration of response at 6 months of 78%. The rationale for the positive outcomes in MSI-H/dMMR subset compared to MSS/pMMR patients is the concept that MSI-H/dMMR status contains a hypermutated state, increased tumor neoantigens (non-self-recognition by the immune system), and tumor-infiltrating T-cell lymphocytes making MSI-H/dMMR tumors more susceptible to immunotherapy modulating agents.

Pembrolizumab’s approval for a tissue-agnostic indication represents an exciting step in oncology care, particularly for rare tumors or entities, which often lack investigational focus and standard-of-care treatment options. MSI-H/dMMR is a rare entity among malignancies. MSI and MMR testing requires tissue; therefore, status determination may present a dilemma for additional testing in rare tumors with a low incidence of MSI-H/dMMR. Regardless of additional testing or biopsy, this pooled analysis allowed for outcomes to be reviewed faster than in traditional tissue-specific trials and was evaluated in patients with refractory cancer who had limited treatment options. Careful considerations and challenges remain, however, in expanding approvals or trial designs based on a targeted characteristic. There remain nonresponders to PD-1 inhibitor monotherapy in MSI-H/dMMR (responses ~ 30%–50%). Future investigation in this tissue-agnostic subset presents a challenge when one is considering immunotherapy-refractory disease and combination therapy trial design because antineoplastics differ in effectiveness across malignancies. Further, oncology investigators must be cautious when extrapolating targeted characteristics across malignancies, as is evident in the study of BRAF inhibition. BRAF inhibitor outcomes were shown to be vastly different among varying BRAF mutated tumors (minimal response in mCRC compared to metastatic melanoma). Targeted therapy and molecular tumor characterization have greatly expanded the way we understand the heterogeneous nature of cancer; however, more steps remain in understanding these targets across malignancies and even in tumor types with the same origin.  


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