Evaluating the role of FAMIly history of cancer and diagnosis of multiple neoplasms in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: the multicenter FAMI-L1 study

Figures & data

Table 1. Patient features

	N° (%)
	822
Age (years)
Median Range Elderly (≥ 70)	68 21–92 359 (43.7)
Sex
Male Female	552 (67.1) 270 (32.9)
ECOG PS
0 – 1 ≥2	689 (83.8) 133 (16.2)
Primary tumor
NSCLC Melanoma Renal cell carcinoma Others	475 (57.8) 190 (23.1) 133 (16.2) 24 (2.9)
Number of metastatic sites
≤2 > 2	407 (49.5) 415 (50.5)
Type of anti-PD-1/PD-L1 agent
Pembrolizumab Nivolumab Atezolizumab	239 (29.1) 559 (68) 24 (2.9)
Treatment line of immunotherapy
First Nonfirst	214 (26) 608 (74)
FHC
Negative FHC-low FHC-high	458 (55.7) 289 (35.2) 75 (9.1)
FHC-straight line	270 (32.8)
FHC-collateral line	167 (20.3)
MN
Negative MN-low MN-high	699 (85.1) 108 (13.1) 15 (1.8)
MN-synchronous	29 (3.5)
MN-methacronous	94 (11.4)

Table 2. Activity data for overall population and subgroups

ORR analysis
Variable (comparator)	Response ratio	ORR (%) (95% CI)	p-value
Overall	270/775	34.8 (30.8–39.2)	-
FHC Positive Negative	130/347 140/428	37.5 (31.3–44.5) 32.7 (27.5–38.6)	0.1675
FHC-Straight line Positive Negative	101/256 169/519	39.5 (32.1–47.9) 32.6 (27.8–37.8)	0.0584
FHC-Collateral line Positive Negative	56/161 214/614	34.8 (35.3–56.3) 34.9 (26.3–45.2)	0.9866
FHC (FHC-negative) FHC-low FHC-high	101/275 29/72	36.7 (29.9–44.6) 40.3 (26.9–57.8)	0.3288
Multiple neoplasm Yes No	46/116 224/659	39.7 (29.0–52.8) 34.0 (29.6–38.7)	0.2380
MN (no MN) MN-low MN-high	41/104 5/12	39.4 (28.2–53.4) 41.7 (13.5–97.2)	0.4922
MN (no MN) MN-synchronous MN-metachronous	7/27 39/89	25.9 (10.4–53.4) 43.8 (31.2–59.9)	0.1156

Table 3. Univariate and multivariate analyses for PFS

	Progression-free survival
	Univariate analysis	Multivariate analysis
Variable (comparator)	HR (95% CI); p-value	HR (95% CI); p-value
FHC Positive vs negative	0.92 (0.76–1.10); p = .3705	-
FHC-Straight line Positive vs negative	0.87 (0.72–1.06); p = .1790	-
FHC-Collateral line Positive vs negative	0.91 (0.73–1.15); p = .4722	-
FHC (FHC-negative) FHC-low FHC-high	0.98 (0.81–1.19); p = .9116 0.69 (0.48–0.97); p = .0379	0.94 (0.78–1.14); p = .5845 0.64 (0.45–0.91); p = .0148
Multiple neoplasm Yes vs no	0.78 (0.61–1.02); p = .0771	-
MN (MN-negative) MN-low MN-high	0.79 (0.60–1.04); p = .1060 0.73 (0.34–1.55); p = .4170	-
MN (MN-negative) MN-synchronous MN-metachronous	0.84 (0.51–1.38); p = .4939 0.77 (0.58–1.04); p = .0912	-
Primary tumor (NSCLC) Melanoma Kidney Others	0.60 (0.47–0.76); p < .0001 0.79 (0.62–1.02); p = .0716 1.34 (0.81–2.22); p = .2516	0.70 (0.54–0.90); p = .0053 0.65 (0.51–0.84); p = .0012 1.11 (0.66–1.84); p = .6911
Sex Male vs female	1.15 (0.95–1.40); p = .1309	-
Age Elderly vs nonelderly	1.02 (0.85–1.22); p = .7982	-
Treatment lineNonfirst vs first	1.46 (1.16–1.84); p = .0011	1.33 (1.03–1.71); p = .0261
N° of metastatic sites >2 vs ≤2	1.71 (1.43–2.06); p < .0001	1.62 (1.35–1.95); p < .0001
ECOG PS ≥2 vs 0–1	2.14 (1.72–2.67); p < .0001	2.14 (1.72–2.69); p < .0001

Table 4. Univariate and multivariate analyses for OS

	Overall survival
	Univariate analysis	Multivariate analysis
Variable (comparator)	HR (95% CI); p-value	HR (95% CI); p-value
FHC Positive vs negative	0.81 (0.65–1.01); p = .0612	-
FHC-Straight line Positive vs negative	0.79 (0.63–1.01); p = .0572	-
FHC-Collateral line Positive vs negative	0.82 (0.62–1.08); p = .8207	-
FHC (FHC-negative) FHC-low FHC-high	0.87 (0.69–1.10); p = .2652 0.61 (0.39–0.93); p = .0210	0.84 (0.67–1.06); p = .1600 0.57 (0.37–0.88); p = .0114
MN Yes vs no	0.86 (0.63–1.17); p = .3403	-
MN (MN-negative) MN-low MN-high	0.83 (0.62–1.15); p = .2837 1.05 (0.49–2.23); p = .8909	-
MN (MN-negative) MN-synchronous MN-metachronous	1.01 (0.57–1.75); p = .9753 0.82 (0.58–1.16); p = .2624	-
Primary tumor (NSCLC) Melanoma Kidney Others	0.46 (0.35–0.62); p < .0001 0.56 (0.44–0.82); p = .0014 1.34 (0.75–2.39); p = .3239	0.54 (0.40–0.74); p = .0001 0.49 (0.36–0.68); p < .0001 1.03 (0.57–1.85); p = .9233
Sex Male vs female	1.51 (1.19–1.92); p = .0006	1.30 (1.02–1.65); p = .0317
Age Elderly vs nonelderly	1.15 (0.93–1.42); p = .1972	-
Treatment line Nonfirst vs first	1.41 (1.07–1.84); p = .0129	1.19 (0.88–1.61); p = .2361
N° of metastatic sites >2 vs ≤2	1.66 (1.34–2.06); p < .0001	1.52 (1.22–1.89); p = .0001
ECOG PS ≥2 vs 0–1	3.09 (2.43–3.92); p < .0001	3.05 (2.39–3.89); p < .0001

Figure 1. Kaplan–Meier survival curves according to FHC. (a) Progression-free survival. FHC-negative: 9.3 months (95% CI: 7.5–10.6; 277 events); FHC-low: 8.4 months (95% CI: 7–11.4; 166 events); FHC-high: 20.5 months (95% CI: 8.7–26.4; 36 events). (b) Overall survival. FHC-negative: 18.2 months (95% CI: 14.9–23.9; 250 censored patients); FHC-low: 20.8 months (95% CI: 15.4–20.9; 176 censored patients); FHC-high: 31.6 months (95% CI: 26.2–31.6; 51 censored patients)

Figure 2. Kaplan–Meier survival curves according to MN. (a) Progression-free survival. MN-negative: 8.7 months (95% CI: 7.6–10.2; 414 events); MN-low: 12.3 months (95% CI: 8.3–28.9; 58 events); MN-high: 14.4 months (95% CI: 3.6–14.5; 7 events). (b) Overall survival. MN-negative: 20.5 months (95% CI: 15.7–27.1; 43 censored patients); MN-low: 26.2 months (95% CI: 18.7–48.9; 66 censored patients); MN-high: 15.9 months (95% CI: 10.5–15.9; 8 censored patients)

Table 5. Univariate and multivariate analysis for incidence of irAEs of any grade

Variable (comparator)	Events ratio	Incidence (95% CI)	p-value
irAEs of any grade – Univariate analysis
Overall	329/822	40.0 (35.8–44.6)
FHC Positive Negative	163/364 166/458	44.8 (38.1–52.2) 36.2 (30.9–42.2)	0.0132
FHC-Straight line Positive Negative	129/270 200/552	47.8 (39.8–56.7) 36.2 (31.3–41.6)	0.0015
FHC-Collateral line Positive Negative	75/167 254/655	44.9 (35.3–56.3) 38.8 (34.1–43.8)	0.1491
FHC (FHC-negative) FHC-low FHC-high	121/289 42/75	41.9 (34.7–50.0) 56.0 (40.3–75.7)	0.1240 0.0012
Multiple neoplasm Yes No	49/123 280/699	39.8 (46.8–86.0) 40.1 (46.8–86.0)	0.9634
MN (MN-negative) MN-low MN-high	43/108 6/15	39.8 (28.8–53.6) 40 (14.7–87.1)	0.9619 0.9964
MN (MN-negative) MN-synchronous MN-metachronous	15/29 34/94	51.7 (28.9–85.3) 36.2 (25.1–50.5)	0.2101 0.4697
Primary tumor (NSCLC) Melanoma Kidney Others	170/475 95/190 62/133 2/24	35.8 (30.6–41.6) 50.0 (40.4–61.1) 46.6 (35.7–59.7) 8.3 (1.0–30.1)	0.0007 0.0232 0.0050
Sex Male Female	196/552 133/270	35.5 (30.7–40.8) 49.3 (41.2–58.3)	0.0002
Age Elderly Non-elderly	186/463 143/359	40.2 (34.6–46.3) 39.8 (33.6–46.9)	0.9215
Treatment line First Nonfirst	92/214 237/608	43.0 (34.6–52.7) 39.0 (34.1–44.2)	0.3034
N° of metastatic sites >2 ≤2	150/415 179/407	36.1 (30.6–42.4) 43.9 (37.7–50.9)	0.0203
ECOG PS ≥2  0–1	34/133 295/689	25.6 (17.7–35.7) 42.8 (38.1–47.9)	0.0002
irAEs of any grade – Multivariate analysis
Variable (comparator)	Coefficient	Std. Error	p-value
FHC (yes vs no)	0.3870	0.1498	0.0098
Primary tumor (NSCLC) Melanoma Kidney Others	-0.5456 0.6012 –1.7464	-0.1798 0.2050 0.7519	-0.0024 0.0034 0.0202
Sex	−0.4783	0.1563	0.0022
N° of metastatic sites	−0.2747	0.1497	0.0666
ECOG-PS	−0.6687	0.2213	0.0025
Nagelkerke R^2: 0.0945
irAEs of any grade – Multivariate analysis
Variable (comparator)	Coefficient	Std. Error	p-value
FHC (FHC-negative) FHC-low FHC-high	0.2795 0.7989	0.1602 0.2624	0.0810 0.0023
Primary tumor (NSCLC) Melanoma Kidney Others	-0.5614 0.6176 –1.6780	-0.1803 0.2058 0.7520	0.0019 0.0027 0.0257
Sex	−0.4594	0.1571	0.0034
N° of metastatic sites	−0.2526	0.1505	0.0932
ECOG-PS	−0.6865	0.2222	0.0020
Nagelkerke R^2: 0.1003