Ono Pharmaceutical Co...announced that Ono Pharma Korea Co., Ltd. (“OPKR”), a South Korean subsidiary of ONO, received the following approvals of Opdivo (nivolumab) Intravenous Infusion ("Opdivo"), a human anti-human PD-1 monoclonal antibody, on February 14 from the Ministry of Food and Drug Safety (MFDS) in South Korea for two adjuvant treatments and for three combination treatments...In combination with ipilimumab, in adult patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

...nivolumab (Opdivo®) is accepted for use within NHSScotland...in combination with ipilimumab for the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer after prior fluoropyrimidine-based combination chemotherapy.

Bristol Myers Squibb...announced that the European Commission (EC) has approved Opdivo (nivolumab) plus Yervoy (ipilimumab) for the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) after prior fluoropyrimidine-based combination chemotherapy. The EC’s decision is based on results from the Phase 2 CheckMate -142 trial.

Ono Pharmaceutical Co., Ltd. (Osaka, Japan; President, Representative Director, Gyo Sagara; “ONO”) and Bristol-Myers Squibb K.K. (Shinjuku, Tokyo; President, Jean-Christophe Barland; “BMSKK”) announced today that the companies have received approval for combination therapy of Opdivo® (generic name: nivolumab) Intravenous Infusion (“Opdivo”), a human anti-human programmed cell death-1 (PD-1) monoclonal antibody, and Yervoy® (generic name: ipilimumab) Injection (“Yervoy”), a human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), in Japan to expand the combination use for the treatment of microsatellite instability high (MSI-High) unresectable advanced or recurrent colorectal cancer that has progressed following chemotherapy, for a partial change in approved items of the manufacturing and marketing approval.

OPDIVO is a programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of...adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, as a single agent or in combination with ipilimumab.

For dMMR/MSI-H tumours progressing after first-line ChT, ipilimumab–nivolumab is recommended…

Nivolumab plus ipilimumab is recommended, within its marketing authorisation, as an option for treating metastatic colorectal cancer with high microsatellite instability (MSI) or mismatch repair (MMR) deficiency after fluoropyrimidine-based combination chemotherapy.

...NICE has recommended Opdivo (nivolumab) plus Yervoy (ipilimumab) for advanced bowel cancer patients with the rare high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) mutations...with MSI-H or dMMR mCRC that has progressed following prior chemotherapy treatment.

..the panel considers pembrolizumab or nivolumab, as amonotherapy or in combination with ipilimumab, as options for neoadjuvant theapy of resectable dMMR/MSI-H mCRC.

Bristol Myers Squibb Announces Phase 3 CheckMate -8HW Trial Evaluating Opdivo (nivolumab) Plus Yervoy (ipilimumab) Compared to Chemotherapy in Microsatellite Instability–High or Mismatch Repair Deficient Metastatic Colorectal Cancer Meets Primary…The dual immunotherapy combination of Opdivo plus Yervoy demonstrated a statistically significant and clinically meaningful improvement in PFS compared to chemotherapy. The safety profile for the combination of Opdivo plus Yervoy remained consistent with previously reported data and was manageable with established protocols, with no new safety signals identified.

...Objective response rate (ORR) in all MSI-High and non-MSI-High subjects as determined by Investigators...

...Objective response rate (ORR) in all MSI-High and non-MSI-High subjects as determined by Investigators...

...• Phase 1: Subjects with advanced or metastatic cervical cancer, endometrial cancer, gastric cancer (including stomach, esophageal, and GEJ), HCC, melanoma (mucosal or cutaneous), Merkel cell carcinoma, mesothelioma, MSI-H CRC, NSCLC, ovarian cancer, SCCHN, SCLC, RCC, TNBC, and urothelial carcinoma (or alternative tumor types with medical monitor approval). ...

Pts with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W...At 64-mo follow-up, NIVO + IPI continued to demonstrate clinically meaningful survival and durable responses, with mPFS, mOS, and mDOR still not reached, suggesting the potential for long-term clinical benefit.

Median OS was not reached (95% CI, not reached) in patients receiving nivolumab + low-dose ipilimumab versus 20.0 months (95% CI, 7.5–32.6) in patients receiving SOC, with a hazard ratio of 0.36 (95% CI, 0.17–0.80)….This study provides supportive evidence for the effectiveness of nivolumab + low-dose ipilimumab for patients with MSI-H/dMMR mCRC in the 2L+ setting relative to SOC.

The results confirm long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC.

Nivolumab plus ipilimumab demonstrated significant clinical benefit and was well tolerated in patients with MSI-H mCRC.

The 48-mo PFS rates were 36%, 54%, and 51% and 48-mo OS rates were 49%, 71%, and 72% in C1, C2, and C3, respectively...With extended follow-up of ~5 years, NIVO ± IPI continued to demonstrate durable OS and PFS benefit...These updated data further support current treatment recommendations for 2L+ NIVO ± IPI and 1L NIVO + IPI for pts with MSI-H/dMMR mCRC.

Here, we present a case series of three patients with dMMR/MSI-H mCRC, where a favorable, durable and ongoing response to nivolumab with ipilimumab was achieved after initial progression on pembrolizumab monotherapy….All three patients progressed on pembrolizumab and then were given nivolumab with ipilimumab (‘CTLA-4 rescue’).

One, 2, and 3-year PFS rates were respectively 75.4% (95% CI 62.0-84.6), 70.0% (95% CI 56.2-80.1), and 70.0% (95% CI 56.2-80.1). One, 2, and 3-year OS rates were 84.1 (95% CI 71.7-91.4), 78.4% (95% CI 65.1-87.1), and 73.1% (95% CI 58.4-83.4), respectively. 42/57 pts were progression-free and alive at 1 year....Nivolumab plus ipilimumab with a fixed duration of 1 year continued to show durable activity in pts with chemoresistant MSI/dMMR mCRC after 3 years of follow-up.

Patients with no prior treatment in the metastatic setting for MSI-H/dMMR CRC were treated with nivolumab every 2 weeks plus low-dose ipilimumab every 6 weeks until disease progression….Objective response rate and disease control rate were 69% (95% CI, 53 to 82) and 84% (95% CI, 70.5 to 93.5), respectively, with 13% complete response rate. Median duration of response was not reached; 74% of responders had ongoing responses at data cutoff....Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated as a first-line treatment for MSI-H/dMMR mCRC.

Bristol Myers Squibb (NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended approval of Opdivo (nivolumab) in combination with Yervoy (ipilimumab) for the treatment of adult patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) after prior fluoropyrimidine-based combination chemotherapy. The opinion was based on data from the Phase 2 CheckMate -142 trial.

NIVO + low-dose IPI demonstrated robust, durable clinical benefit...and was consistent in evaluated subgroups in 1L MSI-H/dMMR mCRC.

Patients (pts) with MSI-H/dMMR mCRC and no prior treatment for metastatic disease received NIVO 3 mg/kg Q2W + low-dose IPI 1 mg/kg Q6W until disease progression or discontinuation....The concordance rate of INV and blinded independent central review was 89%. Median duration of response (DOR) was not reached (Table). Median progression-free survival (PFS) and overall survival (OS) were not reached, and 24-mo rates were 74% and 79%, respectively.

 Patients with MSI-H/dMMR mCRC...Nivolumab plus low-dose ipilimumab demonstrated robust and durable clinical benefit and was well tolerated.

At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%.

This case report highlights the course of a heavily pretreated patient with MSI-H mCRC….After four cycles of ipilimumab and nivolumab followed by nivolumab-maintenance he achieved a long-lasting disease control of 22 months….Re-exposition with ipilimumab is a potential option to restore immune-mediated-disease-control in patients with preceding long-lasting response to ipilimumab/nivolumab and with dMMR-tumors.

A 33-year old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer...After MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment.

We report the case of a metastatic CRC (mCRC) patient with immunohistochemical and molecular heterogeneity in dMMR/microsatellite instability status in the primary tumour. The patient was treated with nivolumab plus ipilimumab and achieved a deep and lasting response with clear clinical benefit....The present case supports the efficacy of immune checkpoint inhibition in mCRC with heterogeneity in MMR/microsatellite instability status.