Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142

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1 Nivolumab in Patients With DNA Mismatch Repair Deficient/Microsatellite Instability High Metastatic Colorectal Cancer: Update From CheckMate 142 Abstract #519 Overman MJ, Lonardi S, Leone F, McDermott R, Morse MA, Wong KYM, Neyns B, Leach JL, Garcia-Alfono P, Lee JJ, Hill A, Lenz H-J, Desai J, Moss RA, Cao ZA, Ledeine J-M, Tang H, Kopetz S, Andre T

2 Introduction Globally, colorectal cancer (CRC) is the fourth leading cause of cancerrelated death 1 Approximately 4% of patients with metastatic CRC have a high degree of microsatellite instability (MSI-H) due to a deficiency in the DNA mismatch repair system (dmmr) 2,3 These patients may be less responsive to conventional chemotherapy than patients who are MMR proficient 3 dmmr/msi-h CRC is associated with elevated levels of tumor neoantigens and tumor-infiltrating lymphocytes and upregulated expression of checkpoint regulators in immune cells, including PD-1 and PD-L1 4,5 CheckMate 142 is a phase II study investigating the efficacy and safety of nivolumab ± ipilimumab in patients with metastatic dmmr/msi-h CRC 1. International Agency for Research on Cancer. GLOBOCAN Accessed January 24, Goldstein J, et al. Ann Oncol. 214;25(5): Venderbosch S, et al. Clin Cancer Res. 214;2(2): Giannakis M, et al. Cell Reports. 216;15(4): Llosa NJ, et al. Cancer Discov. 215;5(1): Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

3 Study Design Stage 1 a Stage 2 b Patients Histologically confirmed metastatic/recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy Nivolumab 3 mg/kg q2w Nivolumab 3 mg/kg q2w Stage 1 c Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w for 4 doses Then nivolumab 3 mg/kg q2w 74 patients were treated in monotherapy stages 1 and 2 (DBL Sept 216) Stage 2 d Nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w for 4 doses then nivolumab 3 mg/kg q2w Primary endpoint: ORR per investigator assessment Secondary endpoint: ORR per blinded independent central review (BICR) Other endpoints: PFS, OS, biomarkers, safety, and tolerability q2w, every 2 weeks; q3w, every 3 weeks a Enrollment complete; b Opened based on an adequate ORR (CR + PR) in patients with centrally confirmed MSI-H CRC treated in mstage 1; c Opened despite an adequate ORR in mstage 1 to proceed to mstage2; d Opened based on an adequate ORR in cstage 1 Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

4 Response assessment by blinded independent central review (BICR) and investigator Tumor assessments were performed using CT or MRI per RECIST v1.1 Evaluated: at baseline; q6w 24 weeks; q12w until disease progression or discontinuation Biomarker assessments: Methods PD-L1 expression was assessed using the Dako 28-8 pharmdx assay Evaluated: tumor cell PD-L1 expression ( 1% or <1%); abundance of tumor-associated immune cells expressing PD-L1 (rare, intermediate, or numerous) BRAF and KRAS mutation status was determined by investigators per local guidelines Characterization of Lynch syndrome was determined by investigators based on clinical records Patient-reported outcomes were evaluated by the EORTC QLQ-C3 and the EQ-5D EORTC, European Organisation for Research and Treatment of Cancer; q6w, every 6 weeks; q12w, every 12 weeks; RECIST, Response Evaluation Criteria In Solid Tumors Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

5 Patients, n (%) Baseline Characteristics dmmr/msi-h per Local Laboratory [n = 74] Median age (range), years 52.5 (26 79) Male, n (%) 44 (59.5) Race, n (%) White Black Other ECOG performance status, n (%) a 1 Disease stage at diagnosis I III IV Prior lines of therapy b (87.8) 7 (9.5) 2 (2.7) 32 (43.2) 42 (56.8) 41 (55.4) 33 (44.6) 1 (1.4) 11 (14.9) 22 (29.7) 4 (54.1) Prior radiotherapy 27 (36.5) Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

6 Baseline Characteristics Patients, n (%) Clinical history of Lynch syndrome, n (%) Yes No Unknown Mutation status BRAF/KRAS wildtype BRAF mutated KRAS mutated Tumor PD-L1 expression quantifiable at baseline a 1% <1% Abundance of PD-L1 expressing tumor-associated immune cells a Rare Intermediate Numerous dmmr/msi-h per Local Laboratory [n = 74] 23 (31.1) 26 (35.1) 25 (33.8) 28 (37.8) 12 (16.2) 26 (35.1) n = (28.4) 45 (6.8) n = (34.8) 2 (3.3) 23 (34.8) a PD-L1 status was not evaluable in 8 patients. Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

7 Exposure and Disposition Patients, n (%) dmmr/msi-h per Local Laboratory [n = 74] Median follow-up (range), months 7.4 ( ) Median number of doses (range) 13 (1 54) Continuing treatment 4 (54.1) Discontinued treatment 34 (45.9) Reasons for discontinuing treatment Disease progression Treatment-related toxicity Maximum clinical benefit Patient decision Withdrawn consent 27 (36.5) 4 (5.4) 1 (1.4) 1 (1.4) 1 (1.4) Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

8 Response and Disease Control dmmr/msi-h per Local Laboratory [n = 74] dmmr/msi-h per Central Laboratory [n = 53] Patients, n (%) ORR, n (%) 95% CI Investigator BICR Investigator BICR 23 (31.1) 2.8, (27.) 17.4, (35.8) 23.1, (32.1) 19.9, 46.3 Best overall response, n (%) CR PR SD PD Unable to determine 23 (31.1) 29 (39.2) 18 (24.3) 4 (5.4) 2 (2.7) 18 (24.3) 28 (37.8) 2 (27.) 6 (11.1) 19 (35.8) 21 (39.6) 1 (18.9) 3 (5.7) 1 (1.9) 16 (3.2) 21 (39.6) 12 (22.6) 3 (5.7) Disease control for 12 weeks, n (%) a 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8) BICR, blinded independent central review a Patients with CR, PR, or SD for 12 weeks Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

9 Change in Tumor Burden a On treatment Off treatment CR or PR First occurrence of new lesion Change truncated to 1% a Patients evaluated as dmmr/msi-h by local laboratory. Tumor evaluations by investigator assessment. Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

10 Characterization of Response and Stable Disease Patients With Response (n = 23) a Investigator Assessed Median TTR: 2.8 months Median DOR: not reached 83% (19/23) responses ongoing Patients With Stable Disease (n = 29) a Censored Last dose when patient off treatment First response Death Weeks Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

11 Progression-Free Survival Probability of PFS, % a PFS per Investigator Median [95% CI], months 9.6 [4.3, NE] 12-month rate [95% CI], % 48.4 [33.6, 61.7] PFS per BICR 12-month rate [95% CI], % 45.6 [32.2, 58.1] No. at risk Months BICR, blinded independent central review; NE, not estimable a Investigator assessed dmmr/msi-h by local laboratory Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

12 Overall Survival Probability of Survival, % a No. at risk Median OS [95% CI], months 12-month OS rate [95% CI], % Months NR [17.1, NE] 73.8 [59.8, 83.5] NR, not reached a dmmr/msi-h assessed by local laboratory Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

13 Reduction in Target Lesions Regardless of PD-L1 Expression Investigator-Assessed Best Change in Target Lesion Size, % Tumor PD-L1 Expression 1% <1% + Confirmed CR/PR Investigator-Assessed Best Change in Target Lesion Size, % Abundance of PD-L1 Expressing Tumor-Associated Immune Cells Rare Intermediate Numerous + Confirmed CR/PR ORR, n/n (%) Investigator BICR Tumor PD-L1 expression 1% < 1% 6/21 (28.6) 13/45 (28.9) 7/2 (35.) 11/45 (24.4) ORR, n/n (%) Investigator BICR Abundance of PD-L1 expressing immune cells Rare Intermediate Numerous 5/23 (21.7) 5/2 (25.) 9/23 (39.1) 4/22 (18.2) 4/2 (2.) 1/23 (43.5) Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

14 Reduction in Target Lesions Regardless of BRAF Mutation Status and Lynch Syndrome Investigator-Assessed Best Change in Target Lesion Size, % BRAF Mutation Status Mutant Wildtype + Confirmed CR/PR Investigator-Assessed Best Change in Target Lesion Size, % Clinical History of Lynch Syndrome Yes No + Confirmed CR/PR ORR, n/n (%) Investigator BICR BRAF mutation status Mutant Wild type 3/12 (25.) 12/28 (42.9) 2/12 (16.7) 9/27 (33.3) KRAS mutation status Mutant Wild type 7/26 (26.9) 12/28 (42.9) 6/26 (23.1) 9/27 (33.3) ORR, n/n (%) Investigator BICR Clinical history of Lynch syndrome Yes No 8/23 (34.8) 8/26 (3.8) 8/23 (34.8) 6/26 (23.1) Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

15 Safety Five patients b (6.8%) experienced 1 AE leading to discontinuation, including abdominal pain, increased ALT, colitis, acute kidney injury, stomatitis, and vomiting (1 of each event) No deaths were reported due to study drug toxicity All Patients [n = 74] Patients, n (%) Any grade Grade 3 4 Any TRAE 51 (68.9) a 15 (2.3) TRAEs reported in 1% of patients Fatigue Diarrhea Pruritus Lipase increased Rash 17 (23.) 16 (21.6) 1 (13.5) 9 (12.2) 8 (1.8) 1 (1.4) 1 (1.4) 6 (8.1) a One grade 5 event of sudden death was reported; this death was not attributed to study drug toxicity on autopsy b One of these patients discontinued due to disease progression Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

16 Patient-Reported Outcomes: EORTC QLQ-C3 Mean Change From Baseline Better Worse Global Health Status/ QOL Mean Change From Baseline Better Worse Role Functioning Clinically meaningful ( 1-point change) 1 improvements were reported in QOL, functioning, and symptoms as early as week Weeks Weeks Mean Change From Baseline Worse Better 13 Fatigue Weeks Patients Mean Change From Baseline Worse Better 13 Appetite Loss Weeks Patients Mean Change From Baseline Better Worse 13 Pain Weeks Patients QOL, quality of life 1. Osoba D, et al. J Clin Oncol. 1998;16(1): Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

17 Patient-Reported Outcomes: EQ-5D Population Norm Patients Patients who continued treatment for 19 weeks achieved a level of health per the EQ-5D VAS that would be regarded as equal to or exceeding the general health of many populations 1 VAS, Visual Analog Scale 1. Janssen B, et al. In: Szende A, et al (Eds). Self-Reported Population Health: An International Perspective based on EQ-5D. Springer Netherlands, 214:19-3. Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

18 Conclusions Nivolumab monotherapy provided durable responses, disease control, and long-term survival (12-month OS rate, 73.8%) in patients with dmmr/msi-h metastatic CRC Responses were observed regardless of tumor or immune cell PD-L1 expression, BRAF or KRAS mutation status, or clinical history of Lynch syndrome Nivolumab was well tolerated, with a safety profile consistent with that reported in other solid tumors; no new safety signals were observed Patient-reported outcome analyses showed clinically meaningful improvements in functioning, symptoms, and quality of life These results suggest that nivolumab should be considered a new standard of care for patients with previously treated dmmr/msi-h advanced CRC Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.

Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA

Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA 3531 Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch repair (dmmr)/high microsatellite instability (MSI-H) metastatic colorectal cancer