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
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 212. http://globocan.iarc.fr/pages/fact_sheets_population.aspx. Accessed January 24, 216. 2. Goldstein J, et al. Ann Oncol. 214;25(5):132-138. 3. Venderbosch S, et al. Clin Cancer Res. 214;2(2):5322-533. 4. Giannakis M, et al. Cell Reports. 216;15(4):857-865. 5. Llosa NJ, et al. Cancer Discov. 215;5(1):43-51. Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.
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.
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.
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 1 2 3 65 (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.
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 = 66 21 (28.4) 45 (6.8) n = 66 23 (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.
Exposure and Disposition Patients, n (%) dmmr/msi-h per Local Laboratory [n = 74] Median follow-up (range), months 7.4 (.3 25.3) 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.
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, 42.9 2 (27.) 17.4, 38.6 19 (35.8) 23.1, 5.2 17 (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.
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.
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 6 12 18 24 3 36 42 48 54 6 66 72 78 84 9 96 12 18 Weeks Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.
Progression-Free Survival Probability of PFS, % a 1 9 8 7 6 5 4 3 2 1 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 3 6 9 12 15 18 21 24 Months 74 48 22 14 12 1 7 3 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.
Overall Survival Probability of Survival, % a No. at risk 1 9 8 7 6 5 4 3 2 1 Median OS [95% CI], months 12-month OS rate [95% CI], % 3 6 9 12 15 18 21 24 27 Months 74 64 54 24 21 21 14 1 3 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.
Reduction in Target Lesions Regardless of PD-L1 Expression Investigator-Assessed Best Change in Target Lesion Size, % 1 5-5 -1 Tumor PD-L1 Expression 1% <1% + Confirmed CR/PR Investigator-Assessed Best Change in Target Lesion Size, % 1 5-5 -1 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.
Reduction in Target Lesions Regardless of BRAF Mutation Status and Lynch Syndrome Investigator-Assessed Best Change in Target Lesion Size, % 1 5-5 -1 BRAF Mutation Status Mutant Wildtype + Confirmed CR/PR Investigator-Assessed Best Change in Target Lesion Size, % 1 5-5 -1 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.
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.
Patient-Reported Outcomes: EORTC QLQ-C3 Mean Change From Baseline 3 2 1-1 -2 Better Worse Global Health Status/ QOL Mean Change From Baseline 3 2 1-1 -2 Better Worse Role Functioning Clinically meaningful ( 1-point change) 1 improvements were reported in QOL, functioning, and symptoms as early as week 13-3 13 19 25 31 37 43 49 55 61 67 73 79 Weeks -3 13 19 25 31 37 43 49 55 61 67 73 79 Weeks Mean Change From Baseline 3 2 1-1 -2-3 Worse Better 13 Fatigue 19 25 31 37 43 49 55 61 67 73 79 Weeks Patients 7 49 42 39 26 16 11 15 13 12 14 13 11 Mean Change From Baseline 3 2 1-1 -2-3 Worse Better 13 Appetite Loss 19 25 31 37 43 49 55 61 67 73 79 Weeks Patients 7 49 42 39 26 16 11 15 13 12 14 13 11 Mean Change From Baseline 3 2 1-1 -2-3 Better Worse 13 Pain 19 25 31 37 43 49 55 61 67 73 79 Weeks Patients 7 49 42 39 26 16 11 15 13 12 14 13 11 QOL, quality of life 1. Osoba D, et al. J Clin Oncol. 1998;16(1):139-144. Overman MJ, et al. J Clin Oncol. 217;35(Suppl 4): Abstract 519.
Patient-Reported Outcomes: EQ-5D Population Norm Patients 65 59 48 41 39 25 17 11 14 12 12 13 13 11 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.
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.