Abstract
Background: Increased tumor mutational burden (TMB) and inflammation are associated with improved clinical outcomes to immuno-oncology (I-O) therapy in many tumor types. Genomic correlates of response to nivolumab (N) vs dacarbazine (D) (CheckMate [CM] 066; NCT01721772) and N+ipilimumab (I) combination therapy or N vs I (CM 067; NCT01844505) were evaluated for association of TMB and an inflammatory gene signature with clinical outcomes.
Methods: In pretreatment tumor samples from eligible patients (pts), TMB was analyzed by whole-exome sequencing using median number of total missense mutations to define high vs low TMB (TMB-H/TMB-L). Associations of TMB with progression-free survival (PFS) and overall survival (OS) were evaluated per protocol-defined exploratory analyses using 4-year follow-up data for both trials. PFS and OS associations with an inflammatory signature were assessed by RNAseq in CM 067 samples only and grouped into tertiles for analysis. HR and 95% CI were calculated using Cox modeling and P values were calculated using the Wald test.
Results: In CM 066, TMB was evaluable in 122 of 411 pts. PFS and OS were significantly longer in pts treated with N, but not with D, for TMB-H vs TMB-L tumors. The benefit of PFS and OS for N vs D was greater in pts with TMB-H than TMB-L (Table). In CM 067, 583 of 937 pts were evaluable for TMB and 299 were evaluable using an inflammatory signature. PFS and OS were longer in each treatment (tx) arm in pts with TMB-H vs TMB-L (Table). Across tx arms, a numerical benefit was observed for PFS and OS in pts with high vs low inflammatory signature (Table). TMB-H and a high inflammatory signature score were independently associated with clinical outcomes to I-O.
Conclusions: High TMB or high inflammatory signature was associated with benefit to I-O. TMB status did not differentiate between N+I and N, and higher inflammatory status increased the likelihood of benefit for N+I and N, suggesting further evaluation of these biomarkers to characterize the response to I-O regimens in melanoma.
Association of TMB (CM 066) or TMB and inflammatory signature (CM 067) with PFS and OS
| Categorical comparison | Clinical measure HR (95% CI; P value) | CM 066 | ||
| N | D | |||
| Patients with evaluable TMB, n (high, low) | 53 (23, 30) | 69 (38, 31) | ||
| TMB-H vs TMB-L | PFS OS | 0.33 (0.16-0.69; 0.0031) 0.43 (0.2-0.91; 0.027) | 0.67 (0.39-1.10; 0.13) 0.66 (0.39-1.10; 0.13) | |
| N vs D in TMB-H | PFS OS | 0.28 (0.14-0.59; 0.00083) 0.35 (0.17-0.73; 0.0046) | ||
| N vs D in TMB-L | PFS OS | 0.57 (0.33-0.99; 0.047) 0.55 (0.31-0.98; 0.044) | ||
| Categorical comparison | Clinical measure HR (95% CI; P value) | CM 067 | ||
| N+I | N | I | ||
| Patients with evaluable TMB, n (high, low) | 197 (94, 103) | 192 (95, 97) | 194 (101, 93) | |
| TMB-H vs TMB-L | PFS OS | 0.56 (0.39-0.81; 0.002) 0.53 (0.34-0.81; 0.0032) | 0.45 (0.31-0.65; 0.00002) 0.48 (0.31-0.72; 0.00046) | 0.64 (0.47-0.87; 0.005) 0.59 (0.42-0.83; 0.0022) |
| N+I vs N in TMB-H | PFS OS | 0.95 (0.63-1.40; 0.81) 0.97 (0.60-1.60; 0.88) | - | |
| N+I vs N in TMB-L | PFS OS | 0.77 (0.56-1.10; 0.12) 0.87 (0.61-1.30; 0.46) | - | |
| Patients with evaluable inflammatory signature, n (low, med, high) | 93 (33, 32, 28) | 106 (39, 31, 36) | 100 (28, 36, 36) | |
| Inflammatory signature, high vs low | PFS OS | 0.38 (0.18-0.80; 0.01) 0.53 (0.24-1.18; 0.12) | 0.60 (0.34-1.00; 0.069) 0.35 (0.18-0.69; 0.0025) | 0.48 (0.27-0.85; 0.012) 0.52 (0.27-1.00; 0.049) |
| Categorical comparison | Clinical measure HR (95% CI; P value) | CM 066 | ||
| N | D | |||
| Patients with evaluable TMB, n (high, low) | 53 (23, 30) | 69 (38, 31) | ||
| TMB-H vs TMB-L | PFS OS | 0.33 (0.16-0.69; 0.0031) 0.43 (0.2-0.91; 0.027) | 0.67 (0.39-1.10; 0.13) 0.66 (0.39-1.10; 0.13) | |
| N vs D in TMB-H | PFS OS | 0.28 (0.14-0.59; 0.00083) 0.35 (0.17-0.73; 0.0046) | ||
| N vs D in TMB-L | PFS OS | 0.57 (0.33-0.99; 0.047) 0.55 (0.31-0.98; 0.044) | ||
| Categorical comparison | Clinical measure HR (95% CI; P value) | CM 067 | ||
| N+I | N | I | ||
| Patients with evaluable TMB, n (high, low) | 197 (94, 103) | 192 (95, 97) | 194 (101, 93) | |
| TMB-H vs TMB-L | PFS OS | 0.56 (0.39-0.81; 0.002) 0.53 (0.34-0.81; 0.0032) | 0.45 (0.31-0.65; 0.00002) 0.48 (0.31-0.72; 0.00046) | 0.64 (0.47-0.87; 0.005) 0.59 (0.42-0.83; 0.0022) |
| N+I vs N in TMB-H | PFS OS | 0.95 (0.63-1.40; 0.81) 0.97 (0.60-1.60; 0.88) | - | |
| N+I vs N in TMB-L | PFS OS | 0.77 (0.56-1.10; 0.12) 0.87 (0.61-1.30; 0.46) | - | |
| Patients with evaluable inflammatory signature, n (low, med, high) | 93 (33, 32, 28) | 106 (39, 31, 36) | 100 (28, 36, 36) | |
| Inflammatory signature, high vs low | PFS OS | 0.38 (0.18-0.80; 0.01) 0.53 (0.24-1.18; 0.12) | 0.60 (0.34-1.00; 0.069) 0.35 (0.18-0.69; 0.0025) | 0.48 (0.27-0.85; 0.012) 0.52 (0.27-1.00; 0.049) |
Citation Format: F. Stephen Hodi, Jedd D. Wolchok, Dirk Schadendorf, James Larkin, Max Qian, Abdel Saci, Tina C. Young, Sujaya Srinivasan, Han Chang, Megan Wind-Rotolo, Jasmine I. Rizzo, Donald G. Jackson, Paolo A. Ascierto. Genomic analyses and immunotherapy in advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT037.
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