The prognostic impact of immune-related adverse events during anti-PD1 treatment in melanoma and non–small-cell lung cancer: a real-life retrospective study

Figures & data

Table 1. Characteristics of melanoma patients

Patients
N	120
Age (y), m (iqr)	66 (55–74)
Sex, n (%)
Men	73 (60.8)
Women	47 (39.2)
ECOG-PS, n (%)
0	66 (55.0)
1	37 (30.8)
2	14 (11.7)
3	3 (2.5)
Steroids, n (%)
≤10mg/d	102 (85.0)
>10mg/d	18 (15.0)
Histological subtype, n (%)
SSM	30 (25.0)
Nodular	26 (21.7)
Other	64 (53.3)
Stage, n (%)
M0	12 (10.0)
M1a-M1b	26 (21.7)
M1c	82 (68.3)
Brain metastases, n (%)	36 (30.0)
Number of metastatic sites, m (iqr)	2 (1–3)
BRAF mutation, n (%)	38 (31.9)
Time since cancer diagnosis (y), m (iqr)	2 (1–5)
Treatment
Previous systemic therapy
At least one, n (%)	65 (54.2)
Number of prior lines, m (iqr)	1 (0–1)
Anti-PD1, n (%)
Nivolumab	50 (41.7)
Pembrolizumab	70 (58.3)
Time on anti-PD1 (mo), m (iqr)	4 (2–10)

m (iqr): median (interquartile range). d: day, ECOG-PS: Eastern Cooperative Oncology Group – Performance Status, mo: month, NSCLC: non-small cell lung cancer, PD1: programmed cell death-1, SSM: superficial spreading melanoma, y: year.

Table 2. Characteristics of NSCLC patients

Patients
N	191
Age (y), m (iqr)	63 (56–68)
Sex, n (%)
Men	121 (63.4)
Women	70 (36.6)
Smoker, n (%)
Present or past	168 (89.8)
Never	19 (10.2)
ECOG-PS, n (%)
0	37 (19.4)
1	132 (69.1)
2	16 (8.4)
3	5 (2.6)
4	1 (0.5)
Steroids, n (%)
≤10mg/d	163 (86.7)
>10mg/d	25 (13.3)
Histological subtype, n (%)
Squamous	44 (23.0)
Others	147 (77.0)
adenocarcinoma	135 (70.7)
Stage, n (%)
IIIB	17 (8.9)
IV	174 (91.1)
Brain metastases, n (%)	44 (23.0)
Number of metastatic sites, m (iqr)	2 (1–2)
EGFR mutation, n (%)	9 (5.0)
Time since cancer diagnosis (y), m (iqr)	1 (0.6–2)
Treatment
Line of anti-PD1, n (%)
Second	92 (48.2)
Third	72 (37.7)
Fourth or more	27 (14.1)
Anti-PD1, n (%)
Nivolumab	191 (100)
Length of time on anti-PD1 (mo), m (iqr)	2 (1–8)

m (iqr): median (interquartile range). d: day, ECOG-PS: Eastern Cooperative Oncology Group – Performance Status, mo: month, NSCLC: non-small cell lung cancer, PD1: programmed cell death-1, y: year.

Table 3. Summary of irAEs in melanoma patients

	Melanoma patients (n = 120)
	All grades, n (%)	Grade 3–5, n (%)	Time to irAE (mo), m (iqr)	Steroids, n (%)	Discontinuation, n (%)
Any	58 (48.3)	13 (10.8)	2.8 (1.0–5.7)	21 (17.5)	16 (13.3)
Skin	31 (25.8)	1 (0.8)	2.8 (1.4–8.5)	2 (1.7)	1 (0.8)
Vitiligo	7 (5.8)	0 (0.0)	6.4 (5.4–12.1)	0 (0.0)	0 (0.0)
Rash	17 (14.2)	0 (0.0)	2.6 (1.3–3.9)	1 (0.8)	0 (0.0)
Endocrine	10 (8.3)	2 (1.7)	2.4 (1.1–3.0)	0 (0.0)	2 (1.7)
Thyroid	7 (5.8)	0 (0.0)	2.7 (1.6–3.0)	0 (0.0)	0 (0.0)
Diarrhea or colitis	19 (15.8)	3 (2.5)	0.7 (0.5–3.0)	7 (5.8)	3 (2.5)
Hepatitis	2 (1.7)	2 (1.7)	17.8 (11.4–24.1)	2 (1.7)	2 (1.7)
Pneumonitis	4 (3.3)	1 (0.8)	4.5 (3.3–8.0)	4 (3.3)	3 (2.5)
Interstitial nephritis	4 (3.3)	1 (0.8)	4.4 (3.4–8.9)	4 (3.3)	4 (3.3)
Arthralgia	5 (4.2)	1 (0.8)	5.8 (2.7–7.3)	3 (2.5)	1 (0.8)
Myocarditis	1 (0.8)	1 (0.8)	3.5	1 (0.8)	1 (0.8)

m (r): median (range), mo: (month).

Table 4. Summary of irAEs in NSCLC patients

	NSCLC patients (n = 191)
	All grades, n (%)	Grade 3–5, n (%)	Time to irAE (mo), m (iqr)	Steroids, n (%)	Discontinuation, n (%)
Any	58 (30.4)	9 (4.7)	1.9 (1.0–3.8)	22 (11.5)	20 (10.5)
Skin	25 (13.1)	1 (0.5)	2.3 (1.1–6.8)	1 (0.5)	1 (0.5)
Vitiligo	1 (0.5)	0 (0.0)	3.9	0 (0.0)	0 (0.0)
Rash	11 (5.8)	1 (0.5)	4.2 (1.0–9.0)	1 (0.5)	1 (0.5)
Endocrine	12 (6.3)	1 (0.5)	1.5 (1.0–2.4)	3 (1.6)	1 (0.5)
Thyroid	11 (5.8)	0 (0.0)	1.1 (0.9–2.2)	3 (1.6)	1 (0.5)
Diarrhea or colitis	19 (9.9)	3 (1.6)	2.8 (1.1–10.0)	5 (2.6)	6 (3.1)
Hepatitis	3 (1.6)	2 (1.0)	3.8 (0.5–15.9)	3 (1.6)	3 (1.6)
Pneumonitis	5 (2.6)	1 (0.5)	4.0 (3.0–5.7)	5 (2.6)	5 (2.6)
Interstitial nephritis	1 (0.5)	1 (0.5)	1.1	1 (0.5)	1 (0.5)
Arthralgia	7 (3.7)	0 (0.0)	8.5 (1.0–13.1)	2 (1.0)	1 (0.5)
Myocarditis	1 (0.5)	1 (0.5)	0.5	1 (0.5)	1 (0.5)

m (r): median (range), mo: (month).

Figure 1.: Overall survival with or without irAEs

NSCLC: non-small cell lung cancer.

Table 5. Multivariate analysis of overall and progression-free survival

	Overall Survival		Progression-Free Survival
	HR (95%CI)	P	HR (95%CI)	p
Steroids > 10mg/d at baseline	1.80 [1.26–2.57]	0.001	1.90 [1.34–2.68]	<0.001
Time since cancer diagnosis ≥ 1.3 y	0.70 [0.53–0.93]	0.012	-	-
Two or more prior treatment lines	-	-	1.46 [1.14–1.88]	0.003
Early irAE*	0.58 [0.41–0.84]	0.003	0.36 [0.26–0.50]	<0.001
Late irAE*	0.28 [0.16–0.50]	<0.001	0.24 [0.16–0.37]	<0.001
Time on anti-PD1 ≥ median time** on anti-PD1	0.21 [0.15–0.29]	<0.001	0.10 [0.07–0.13]	<0.001

*The reference (HR = 1.00) is the group of patients without irAE. Early and late irAEs are defined respectively as occurring before or after 12 weeks for patients with melanoma and 8 weeks for patients with NSCLC. **Median time on anti-PD1 was 2 months for patients with melanoma and 4 months for patients with NSCLC. d: day, HR (IC95): Hazard Ratio (95% confidence interval), irAE: immune-related adverse event, PD1: programmed cell death protein 1, y: year.

Table 6. Association of overall response rate with irAEs

	Overall response rate n/N (%)
	irAE present	irAE absent	p
Any	62/115 (53.9)	23/178 (12.9)	<0.001
Cutaneous	37/56 (66.1)	48/237 (20.3)	<0.001
Rash	16/28 (57.1)	69/265 (26.0)	<0.001
Endocrine	11/22 (50.0)	74/271 (27.3)	0.024
Digestive	18/41 (43.9)	67/252 (26.6)	0.023

Digestive irAEs include immune-related diarrhea/colitis and hepatitis; irAE: immune-related adverse event