FDA approvals for mismatch repair deficiency in metastatic colorectal cancer and hepatocellular carcinoma: a next-generation oncology treatment based on biomarker expression

GI malignancies have been traditionally considered to be poorly immunogenic; however, increasing evidence now suggests that these tumors are recognized by the immune system. Immune checkpoint blockade is showing promising clinical activity in multiple GI tumors including colorectal cancers. In fact, one of the most significant achievements witnessed in the field of immunotherapy has been the success of immune checkpoint inhibitors (CPIs) in microsatellite instability-high colorectal and non-colorectal tumors. For this reason, the US FDA has granted accelerated approval to Pembrolizumab and Nivolumab as monotherapies and Nivolumab plus Ipilimumab as combined therapy. These new findings open the door to a next-generation oncology treatment based on biomarker expression. The average tumor displays dozens of mutations; however, tumors with DNA deficient mismatch repair (dMMR) may harbor thousands of them, especially in the regions of repetitive DNA known as microsatellites [1]. Tumors that are found to harbor mutations in select microsatellite sequences called microsatellite instability (MSI) regions are referred to as “microsatellite instability-high (MSI-H).” It is now understood that two distinct immunologic subtypes of cancer tumors exist according to the dMMR status, namely, MSI and microsatellite stable (MSS) subtypes, which are mutually exclusive [2, 3]. Recently, on May 23, 2017, the US Food and Drug Administration (FDA) granted accelerated approval to Pembrolizumab (Keytruda®, Merck & Co) for the treatment of non-hematological cancers in adult and pediatric patients with unrespectable or metastatic, MSI-high or dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-high or dMMR metastatic CRC (mCRC) following progression on a fluoropyridine, oxaliplatin and irinotecan regimen [4]. The approval was based on the data from 149 patients with MSI-H or dMMR cancers enrolled across five uncontrolled multi-cohort, multi-center, single-arm clinical trials Received: June 29, 2018; Accepted:December 16, 2018; Published: December 18, 2018 *Corresponding author: : Luis Mendoza, IQVIA, Oncology-Hematology Therapeutic Science & Strategy Unit, Pernerova 691/42, 186 00 Praha 8, Czech Republic; Email id: Luis.mendoza@iqvia.com (KEYNOTE-16, -164, -012, -028, and -158). Ninety patients had mCRC and the remaining 59 patients suffered from one of 14 other cancer types. The objective response rate (ORR) was 39.6 % (95% CI: 31.7, 47.9) including 11 (7.4 %) complete responses (CRs) and 48 (32.2 %) partial responses (PRs). On July 31, 2017, the FDA granted accelerated approval to another CPI, Nivolumab (Opdivo®, Bristol-Myers Squibb Company), for the treatment of patients aged 12 years and older with dMMR and MSI-H mCRC, and on September 22, 2017 the FDA approved Nivolumab for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib. The approval for mCRC was based on the data from study CHECKMATE-142, a multi-center, open-label study where 53 patients received Nivolumab 3 mg/kg by intravenous infusion every two weeks until unacceptable toxicity or radiographic progression. The ORR as assessed by an independent radiographic review committee was 28 % (n=15) (95% CI: 17, 42). Responses lasted six or more months for 67 % (95% CI: 38, 88) of the patients [5]. The approval for HCC patients who progressed on or were intolerant to sorafenib was based on the results from a subgroup of 154 patients enrolled in the phase I/II CHECKMATE-040 clinical trial. Patients received nivolumab 3 mg/kg by intravenous infusion every two weeks. The confirmed ORR, as assessed by blinded independent central review, was 14.3 % (95% CI: 9.2, 20.8), with three CRs and 19 PRs. The duration of response (DOR) ranged from 3.2 to 38.2+ months; 91 % of responders had responses lasting six months or longer and 55 % had responses lasting 12 months or longer [6]. Recently, on July 10, 2018 the FDA also granted an accelerated approval (July 10, 2018) to the combination of Nivolumab and Ipilimumab (Yervoy®, Bristol-Myers Squibb Company) for the treatment of adult and pediatric patients 12 years and older MSI-H or dMMR mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan combination. The approval is based on the results from a cohort of 119 patients with MSI-H or dMMR mCRC treated with the combination in the phase II CHECKMATE-142 study. The ORR was 46 % (95% CI, 35Page 2 of 3 Citation: Mendoza L (2018) FDA approvals for mismatch repair deficiency in metastatic colorectal cancer and hepatocellular carcinoma: a next-generation oncology treatment based on biomarker expression. Int J Hematol Blo Dis 3(4). 1-3 FDA approvals for mismatch repair deficiency in metastatic colorectal cancer and hepatocellular carcinoma: a next-generation oncology treatment based on biomarker expression Copyright: © 2018 Mendoza L. 58). Among the 38 responders, there were three CRs and 35 PRs. The DOR was not reached (range, 1.9-23.2+ months). Eighty-nine percent of the responders had a response of ≥6 months, with 21 % having response ≥12 months [7]. Table 1 shows detailed efficacy data from dMMR/MSI-H mCRC and HCC patients extracted from the studies used for the Pembrolizumab, Nivolumab and Ipilimumab approvals. The combination Nivolumab + Ipilimumab in 119 pretreated mCRC patients demonstrates superior efficacy results than the nivolumab monotherapy. Table 1: Efficacy data of CPIs in dMMR/MSI in mCRC and HCC Drug Name No. of subjects ORR CR PR SD PD NE/ND DCR Dose No. (%) (%) (%) (%) (%) (%) No. (%) Study name 95% CI 95% CI Study identifier dMMR/MSI mCRC Pembrolizumab 28 16 (57) 11 46 32 4 7 25 (89) 10 mg/kg Q2W 39 73 73 96 KEYNOTE-016 (NCT01876511)* Pembrolizumab 61 17 (28) 0 28 23 46 NA NA 200 mg Q3W 17 41 KEYNOTE-164 (NCT0260198)* Nivolumab 3 mg/kg 53 19 (36) 0 36 37 21 6 39 (74) CHECKMATE-142 (single arm) 23-50 60 -65 (NCT02060188)* Nivolumab 3 mg/kg + 119 65 (55) 3 51 31 12 3 95 (80) Ipilimumab 1 mg/kg 45 64 72 -87 CHECKMATE-142 (combination arm) (NCT02060188) dMMR/MSI HCC Nivolumab 3 mg/kg 154 14.3 2 12 CheckMate-040 (NCT01658878) CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE/ND, not evaluable/not determined; dMMR, deficient mismatch repair; MSI, microsatellite instability; MSS microsatellite stable; HCC, hepatocellular carcinoma; NA; not available. * Data supporting the Keytruda® and Opdivo® accelerated FDA approvals To date, three CPIs (two anti-PD-1 and one CTLA-4 inhibitors) have been approved based on the tumor biomarker regardless of the tumor original location. The regulatory approvals for Keytruda®, Opdivo® and Yervoy® for patients with MSI-H and dMMR tumors marked an important milestone for cancer treatment. The indication of the approvals is based on a common biomarker rather than the anatomic location (tissue or organ) in the body where the tumor originated. Recently, the National Comprehensive Cancer Network (NCCN) guidelines 2017 have incorporated the recommendation for universal testing for dMMR/MSI-H and the use of nivolumab or pembrolizumab in dMMR/MSI-H metastatic CRC after previous adjuvant FOLFOX/ CAPEOX within 12 months [8]. With increasing accessibility to genetic analysis tools such as next-generation sequencing, it may expect that identification of more dMMR/MSI-H patients will continue to grow. In addition, other CPIs are also being tested in clinical trials along with a new strategy combining CPI with other therapies in different tumor types.

On July 31, 2017, the FDA granted accelerated approval to another CPI, Nivolumab (Opdivo®, Bristol-Myers Squibb Company), for the treatment of patients aged 12 years and older with dMMR and MSI-H mCRC, and on September 22, 2017 the FDA approved Nivolumab for patients with hepatocellular carcinoma (HCC) previously treated with sorafenib.The approval for mCRC was based on the data from study CHECKMATE-142, a multi-center, open-label study where 53 patients received Nivolumab 3 mg/kg by intravenous infusion every two weeks until unacceptable toxicity or radiographic progression.The ORR as assessed by an independent radiographic review committee was 28 % (n=15) (95% CI: 17, 42).Responses lasted six or more months for 67 % (95% CI: 38, 88) of the patients [5].The approval for HCC patients who progressed on or were intolerant to sorafenib was based on the results from a subgroup of 154 patients enrolled in the phase I/II CHECKMATE-040 clinical trial.Patients received nivolumab 3 mg/kg by intravenous infusion every two weeks.The confirmed ORR, as assessed by blinded independent central review, was 14.3 % (95% CI: 9.2, 20.8), with three CRs and 19 PRs.The duration of response (DOR) ranged from 3.2 to 38.2+ months; 91 % of responders had responses lasting six months or longer and 55 % had responses lasting 12 months or longer [6].
Recently, on July 10, 2018 the FDA also granted an accelerated approval (July 10, 2018) to the combination of Nivolumab and Ipilimumab (Yervoy®, Bristol-Myers Squibb Company) for the treatment of adult and pediatric patients 12 years and older MSI-H or dMMR mCRC following progression on a fluoropyrimidine, oxaliplatin, and irinotecan combination.The approval is based on the results from a cohort of 119 patients with MSI-H or dMMR mCRC treated with the combination in the phase II CHECKMATE-142 study.The ORR was 46 % (95% CI, 35carcinoma: a next-generation oncology treatment based on biomarker expression.Int J Hematol Blo Dis 3(4).1-3

FDA approvals for mismatch repair deficiency in metastatic colorectal cancer and hepatocellular carcinoma: a next-generation oncology treatment based on biomarker expression
Copyright: © 2018 Mendoza L. 58).Among the 38 responders, there were three CRs and 35 PRs.The DOR was not reached (range, 1.9-23.2+months).Eighty-nine percent of the responders had a response of ≥6 months, with 21 % having response ≥12 months [7].
Table 1 shows detailed efficacy data from dMMR/MSI-H mCRC and HCC patients extracted from the studies used for the Pembrolizumab, Nivolumab and Ipilimumab approvals.The combination Nivolumab + Ipilimumab in 119 pretreated mCRC patients demonstrates superior efficacy results than the nivolumab monotherapy.To date, three CPIs (two anti-PD-1 and one CTLA-4 inhibitors) have been approved based on the tumor biomarker regardless of the tumor original location.The regulatory approvals for Keytruda®, Opdivo® and Yervoy® for patients with MSI-H and dMMR tumors marked an important milestone for cancer treatment.The indication of the approvals is based on a common biomarker rather than the anatomic location (tissue or organ) in the body where the tumor originated.Recently, the National Comprehensive Cancer Network (NCCN) guidelines 2017 have incorporated the recommendation for universal testing for dMMR/MSI-H and the use of nivolumab or pembrolizumab in dMMR/MSI-H metastatic CRC after previous adjuvant FOLFOX/ CAPEOX within 12 months [8].With increasing accessibility to genetic analysis tools such as next-generation sequencing, it may expect that identification of more dMMR/MSI-H patients will continue to grow.In addition, other CPIs are also being tested in clinical trials along with a new strategy combining CPI with other therapies in different tumor types.

Table 1 :
Efficacy data of CPIs in dMMR/MSI in mCRC and HCC