Tumor mutation burden and circulating tumor DNA in combined CTLA-4 and PD-1 antibody therapy in metastatic melanoma – results of a prospective biomarker study

Table 3 Impact of patients’ and disease characteristics (combined variables) on treatment response and overall survival since the beginning of combined immunotherapy

	Total n = 35	Responder n = 15	Non-Responder n = 20	Response P value	Overall survival P value
Combination of TMB [Mut/Mb] and ctDNA [copies/ml] detection³
TMB > 23 Mut/Mb + ctDNA not detectable	3	3	0	< 0.0001 ^1*	0.005 ^2*
TMB > 23 Mut/Mb + ctDNA detectable	3	3	0
TMB ≤ 23 Mut/Mb + ctDNA not detectable	8	5	3
TMB ≤ 23 Mut/Mb + ctDNA detectable	13	0	13
Combination of TMB [Mut/Mb] and ctDNA [copies/ml] increase³
TMB > 23 Mut/Mb + ctDNA not increasing	4	4	0	< 0.0001 ^1*	0.032 ^2*
TMB > 23 Mut/Mb + ctDNA increasing	1	1	0
TMB ≤ 23 Mut/Mb + ctDNA not increasing	12	5	7
TMB ≤ 23 Mut/Mb + ctDNA increasing	9	0	9
Combination of TMB [Mut/Mb] and cell-free DNA [ng/ml]⁴
TMB > 23 Mut/Mb + cfDNA decrease > 50%	3	3	0	0.001 ^1*	0.016 ^2*
TMB > 23 Mut/Mb + cfDNA stable	1	1	0
TMB > 23 Mut/Mb + cfDNA increase > 50%	1	1	0
TMB ≤ 23 Mut/Mb + cfDNA decrease > 50%	3	1	2
TMB ≤ 23 Mut/Mb + cfDNA stable	11	4	7
TMB ≤ 23 Mut/Mb + cfDNA increase > 50%	7	0	7
Combination of TMB [Mut/Mb] and liver metastases
TMB > 23 Mut/Mb + no liver metastases	6	6	0	< 0.0001 ^1*	0.018 ^2*
TMB ≤ 23 Mut/Mb + no liver metastases	14	5	9
TMB ≤ 23 Mut/Mb + liver metastases	10	1	9
Combination of TMB [Mut/Mb] and sex
TMB > 23 Mut/Mb + male	6	6	0	0.002 ^1*	0.010 ^2*
TMB ≤ 23 Mut/Mb + female	9	2	7
TMB ≤ 23 Mut/Mb + female	15	4	11

* significant (in bold).
¹Exact Chi-Square Test for Trend (Monte Carlo Simulation)
²Log rank test for Trend
³ctDNA measured by tumor-specific variant [copies/ml plasma] at first follow-up after start of combined immunotherapy
⁴Cell-free DNA [ng/ml plasma] at first follow-up after start of combined immunotherapy