Impact of pseudoprogression and treatment beyond progression on outcome in patients with non-small cell lung cancer treated with immune checkpoint inhibitors

Figures & data

Figure 1. Flow diagram of patient recruitment process.

Table 1. Baseline characteristics of patients.

	All patients (n = 189)	Patients according to response
		Durable response (n = 34)	RECIST 1.1-PD (n = 134)	Early termination (n = 21)
Age*	64.6 ± 10.4	66.1 ± 8.5	63.4 ± 10.8	69.8 ± 9.0
Sex
Male Female	140 (74.1) 49 (25.9)	27 (79.4) 7 (20.6)	101 (75.4) 33 (24.6)	12 (57.1) 9 (42.9)
ECOG PS at baseline
0 1 2 3 4	8 (4.2) 135 (71.4) 23 (12.2) 12 (6.3) 11 (5.8)	2 (5.9) 28 (82.4) 3 (8.8) 1 (2.9) 0 (0.0)	6 (4.5) 101 (75.4) 17 (12.7) 7 (5.2) 3 (2.2)	0 (0.0) 6 (28.6) 3 (14.3) 4 (19.0) 8 (38.1)
Smoking history
Never	52 (27.5)	5 (14.7)	37 (27.6)	10 (47.6)
Ex-smoker	123 (65.1)	26 (76.5)	88 (65.7)	9 (42.9)
Current smoker	14 (7.4)	3 (8.8)	9 (6.7)	2 (9.5)
Drug/Regimen
Nivolumab Pembrolizumab Atezolizumab Durvalumab Avelumab Clinical trial	82 (43.4) 82 (43.4) 10 (5.3) 4 (2.1) 1 (0.5) 10 (5.3)	13 (38.2) 16 (47.1) 2 (5.9) 1 (2.9) 0 (0.0) 2 (5.9)	63 (47.0) 51 (38.1) 8 (6.0) 3 (2.2) 1 (0.7) 8 (6.0)	6 (28.6) 15 (71.4) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Histology
Adenocarcinoma Squamous cell carcinoma Small cell carcinoma Others^†	110 (58.2) 60 (31.7) 2 (1.1) 17 (9.0)	19 (55.9) 10 (29.4) 1 (2.9) 4 (11.8)	79 (59.0) 44 (32.8) 0 (0.0) 11 (8.2)	12 (57.1) 6 (28.6) 1 (4.8) 2 (9.5)
Actionable mutation^‡
None	92 (69.7)	18 (75.0)	67 (72.0)	7 (46.7)
EGFR	31 (23.5)	4 (16.7)	20 (21.5)	7 (46.7)
ALK	2 (1.5)	0 (0.0)	2 (2.2)	0 (0.0)
ROS-1	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
BRAF	1 (0.8)	0 (0.0)	1 (1.1)	0 (0.0)
Others^§	6 (4.5)	2 (8.3)	3 (3.2)	1 (6.7)

Data are the number of patients, with the percentage in parentheses, unless otherwise indicated.

*Data are the mean ± standard deviation.

^†Undifferentiated carcinoma (n = 6), mucinous adenocarcinoma (n = 4), sarcomatoid carcinoma (n = 2), mixed adenocarcinoma and squamous cell carcinoma (n = 2), mixed adenocarcinoma and small cell carcinoma (n = 1), neuroendocrine carcinoma (n = 1), and giant cell carcinoma (n = 1).

^‡Actionable mutation, which is a target of anti-cancer therapy, was available from tissue data in 132 patients.

^§RET fusion (n = 3), MET amplification (n = 2), and MET exon 14 skipping (n = 1).

PD, progressive disease; ECOG PS, Eastern Cooperative Oncology Group performance status.

Table 2. Patterns and outcomes of patients with pseudoprogression.

Patients	Pattern	Time to RECIST 1.1–1st PD (months)	Change in tumor burden at RECIST 1.1–1st PD	Time to reset (months)	Time to RECIST 1.1–2nd PD (months)	Overall survival (months)	Survival status at the time of evaluation
PsP1 (Figure S1)	PD: Appearance of NL Reset to PR: Decrease of TL, NTL, and NL	29.3	−85.4%*	30.9	-	30.9	Alive
PsP2	PD: Increase of NTL Reset to PR: Decrease of TL, NTL	2.1	14.1%^†	3.4	-	2.3	Alive
PsP3 (Figure S2)	PD: Increase of TL and NTL Reset to SD: Decrease of TL, NTL	4.9	28.3%	7.7	-	10.8	Alive
PsP4	PD: Increase of NTL Reset to SD: Decrease of TL, NTL	3.1	−14.5%^†	4.3	6.8	7.2	Alive
PsP5 (Figure S3)	PD: Increase of TL Reset to PR: Decrease of TL	1.9	23.3%	3.2	-	12.7	Alive
PsP6	PD: Increase pf NTL Reset to SD: Decrease of TL, NTL	2.2	−20.7%^†	8.0	9.6	17.0	Died
PsP7 (Figure S4)	PD: Increase of TL and NTL Reset to PR: Decrease of TL, NTL	5.0	37.0%	7.4	-	11.2	Alive

TL, target lesion; NTL, non-target lesion; NL, new lesion; PD, progressive disease; PR, partial response; SD, stable disease.

*PD by the occurrence of NL despite the extent of TL was decreased.

^†PD by increase of NTL despite the change in the extent of TL was < +20%.

Figure 2. Spider plot of tumor burden changes during ICI treatment in seven patients with PsP. Asterisks indicate the increase of non-target lesions (PsP2, PsP4, PsP6) or the occurrence of new lesion (PsP1) at the time of 1st PD per RECIST 1.1. Except one patient who experienced PsP at 29.3 months (PsP1), the time from baseline to PsP was approximately 3 months (average, 3.2 months; range, 1.9–5.0 months). The time from PsP to reset of all seven pseudoprogressors was approximately 3 months (average, 2.4 months; range, 1.2–5.8 months).

Figure 3. Impact of PsP on progression-free survival in patients treated with immune checkpoint inhibitors. (a) Kaplan–Meier curves of PFS in patients with PsP (n = 7) and without PsP (n = 182). PFS was significantly longer in the seven patients with PsP (median, not reached) than in the 182 patients without PsP (median, 3.8 months; 95% CI, 3.9–4.6 months, P = .02) (b) Kaplan–Meier curves of PFS according to RECIST 1.1 and iRECIST. There was no significant difference between PFS according to RECIST 1.1 (median, 3.8 months; 95% CI, 3.1–4.8 months) and that according to iRECIST (median, 4.1 months; 95% CI, 3.1–5.4 months) (P = .58).

Figure 4. Kaplan–Meier curves of OS in three groups of patients according to response to ICI. There were significant differences in OS among the durable response group (median, not reached), RECIST 1.1-PD group (median, 11.1 months; 95% CI, 9.3 months–not reached) and early termination group (median, 1.3 months; 95% CI, 0.8–1.7 months) (P < .001).

Figure 5. Kaplan–Meier curves of OS in patients with TBP and without TBP. The median OS was significantly longer in the TBP group (17.2 months; 95% CI, 10.2 months–not reached) than in the non-TBP group (7.4 months; 95% CI, 4.4–12.1 months) (P < .001).

Table 3. Characteristics between TBP and non-TBP patients.

	TBP (n = 67)	Non-TBP (n = 67)	P value
Age*	64.1 ± 9.1	62.6 ± 12.2	0.42
Sex ratio			0.01
Male Female	57 (85.1) 10 (14.9)	44 (65.7) 23 (34.3)
ECOG PS at baseline			0.15
0 1 2 3 4	3 (4.5) 55 (82.1) 4 (6.0) 5 (7.5) 0 (0.0)	3 (4.5) 46 (68.7) 13 (19.4) 2 (3.0) 3 (4.5)
ECOG PS at the time of RECIST 1.1-PD			0.02
0 1 2 3 4	1 (1.5) 42 (62.7) 15 (22.4) 8 (11.9) 1 (1.5)	0 (0.0) 29 (43.3) 15 (22.4) 13 (19.4) 10 (14.9)
Change in tumor burden			0.01
1 (20–50% increase) 2 (50–100% increase) 3 (100–200% increase) 4 (>200% increase)	25 (37.3) 17 (25.4) 18 (26.9) 7 (10.4)	19 (28.4) 10 (14.9) 16 (23.9) 22 (32.8)

Data are the number of patients, with the percentage in parentheses, unless otherwise indicated.

*Data are the mean ± standard deviation.

TBP, treatment beyond progression; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, progressive disease.

Table 4. Univariate and multivariate Cox proportional hazard analysis of OS in patients with RECIST 1.1-PD.

	Univariate analysis			Multivariate analysis
Covariate	Hazard ratio	95% CI	P value	Hazard ratio	95% CI	P value
TBP	0.33	0.19, 0.59	<0.001	0.37	0.20, 0.70	0.002
ECOG PS at baseline
1 2 3 4	0.70 1.58 3.23 15.70	0.22, 2.29 0.45, 5.61 0.87, 11.94 4.09, 60.23	0.56 0.48 0.08 <0.001	0.97 1.36 2.01 4.82	0.23, 4.09 0.28, 6.60 0.35, 11.54 0.64, 36.54	0.96 0.70 0.44 0.13
Tumor burden increase at PD on RECIST 1.1
2 (50–100% increase) 3 (100–200% increase) 4 (>200% increase)	2.09 2.94 4.77	0.91, 4.77 1.39, 6.20 2.22, 10.26	0.08 0.01 <0.001	2.62 2.50 3.28	1.12, 6.16 1.17, 5.37 1.47, 7.34	0.03 0.02 0.004
Age	1.01	0.99, 1.03	0.31	-	-	-
Sex ratio (M:F)	1.05	0.62, 1.77	0.85	-	-	-

OS, overall survival; PD, progressive disease; TBP, treatment beyond progression; ECOG PS, Eastern Cooperative Oncology Group performance status; CI, confidence interval.

Figure 6. Kaplan–Meier curves of OS and PFS based on iRECIST to compare outcomes between patients with PsP (n = 7) and non-pseudoprogressors treated with TBP (n = 60). (a) The median OS did not significantly differ (not reached vs. 17.2 months, respectively, P = .2). (b) The median PFS based on iRECIST was significantly different between the two groups (not reached vs. 3.4 months [95% CI, 2.6–4.2 months]) for patients with PsP and non-pseudoprogressor with TBP (P < .001).