Exposure-safety and exposure-efficacy analyses of polatuzumab vedotin in patients with relapsed or refractory diffuse large B-cell lymphoma

Figures & data

Table 1. Study details, treatment arms, exposure metrics and endpoints included in the exposure-response analyses.

Exposure-response analysis	Studies	Analyte/exposure metrics	Arm included (dose)	N total (n by arm)	Endpoints
Exposure-safety analyses in R/R DLBCL	Supportive studies DCS4968g GO27834	acMMAE AUC, Cmax	Pola monotherapy (0.1–2.4 mg/kg Q3W until PD or unacceptable toxicity) Pola + R (2.4 mg/kg Q3W for up to 1 year or until PD or unacceptable toxicity) Pola + G (1.8 mg/kg Q3W × eight cycles)	119 (36/40/43)	AESI: grade ≥3 neutropenia, grade ≥2 PN, grade ≥3 infection and infestation, grade ≥3 anemia, grade ≥3 thrombocytopenia, grade ≥3 diarrhea, grade ≥3 AST increase (by lab), grade ≥3 ALT increase (by lab), and grade ≥3 total bilirubin increase (by lab) Dose intensity related measurements: pola dose modification due to AE, time to first dose modification (reduction, delay or early discontinuation) due to AE, pola dose intensity, R dose intensity, and B dose intensity (pivotal study only)
		Unconjugated MMAE AUC, Cmax
	Pivotal study GO29365	acMMAE AUC, Cmax Unconjugated MMAE AUC, Cmax	Pola + BR (1.8 mg/kg Q3W × six cycles) Pola + BG (1.8 mg/kg Q3W × six cycles)	69 (44/25)
Exposure-efficacy analyses in R/R DLBCL	Supportive studies DCS4968g GO27834	acMMAE AUC	Pola monotherapy (0.1–2.4 mg/kg Q3W until PD or unacceptable toxicity) Pola + R (2.4 mg/kg Q3W for up to 1 year or until PD or unacceptable toxicity)	76 (36/40)	INV-BOR up to cycle 8 landmark by PET-CT or CT; INV-OR at cycle 8 landmark by PET-CT or CT
	Pivotal study GO29365	acMMAE AUC	Pola + BR (1.8 mg/kg Q3W × six cycles) BR Q3W × six cycles	84 (44/40)	IRC-CR at PRA by PET-CT; IRC-OR at PRA by PET-CT (IRC-OR); IRC-BOR by PET-CT or CT; IRC-DOR up to clinical cutoff date; IRC-PFS; OS The BR control arm was included in the Kaplan-Meier time-to-event efficacy analyses (IRC-DOR; IRC-PFS; OS)

ac: antibody conjugate; AE: adverse event; AESI: adverse event of special interest; ALT: alanine aminotransferase; AST: aspartate aminotransferase;

AUC: area under the concentration − time curve; B: bendamustine; BOR: best overall response; C_max: maximum concentration; CR: complete response; CT: computed tomography; DLBCL: diffuse large B-cell lymphoma; DOR: duration of response; G: obinutuzumab; INV: investigator; IRC: independent review committee; MMAE: mono-methyl auristatin E; OR: objective response; OS: overall survival; PET: positron emission tomography; PD, progressive disease; PFS: progression-free survival; PK: pharmacokinetics; PN: peripheral neuropathy; pola: polatuzumab vedotin; PRA: primary response assessment; Q3W: every 3 weeks; R: rituximab; R/R: relapsed/refractory.

Table 2. Number (%) of patients with AEs in the exposure-safety analyses.

	N (%) patients with AE
	Supportive studies (N = 119)			Pivotal study
	All doses (N = 119) (pola; pola + R, pola + G)	Pola 1.8 mg/kg (N = 46) (pola; pola + G)	Pola 2.4 mg/kg (N = 67) (pola; pola + R)	Pola 1.8 mg/kg (N = 69) (pola + BR; Pola + BG)
Grade ≥3 neutropenia	39 (32.8)	12 (26.1)	26 (38.8)	35 (50.7)
Grade ≥2 PN	30 (25.2)	10 (21.7)	20 (29.9)	10 (14.5)
Grade ≥3 infections and infestations	12 (10.1)	6 (13.0)	6 (9.0)	20 (29.0)
Grade ≥3 anemia	9 (7.6)	3 (6.5)	6 (9.0)	13 (18.8)
Grade ≥3 thrombocytopenia	6 (5.0)	5 (10.9)	1 (1.5)	24 (34.8)
Grade ≥3 diarrhea	5 (4.2)	0	5 (7.5)	4 (5.8)
Grade ≥3 AST increase	2 (1.7)	0	2 (3.0)	1 (1.4)
Grade ≥3 ALT increase	3 (2.5)	1 (2.2)	2 (3.0)	1 (1.4)
Grade ≥3 bilirubin increase	1 (0.8)	1 (2.2)	0	2 (2.9)
Pola dose modification due to AE	32 (26.9)	11 (23.9)	21 (31.3)	40 (58.0)

AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; PN: peripheral neuropathy; pola: polatuzumab vedotin.

Shading indicates AEs of low frequency (<5% or <5 events) in the supportive studies (N = 119) and pivotal study (n = 69) population that were not included in the exposure-safety analyses.

Figure 1. Logistic regression for grade ≥2 PN with acMMAE exposure [(A) AUC; (B) C_max], grade ≥3 anemia with unconjugated MMAE exposure [(C) AUC; (D) C_max], INV-BOR with acMMAE exposure [(E) AUC], and INV-OR with acMMAE exposure [(F) AUC], for R/R DLBCL patients in the supportive studies. Red solid line = logistic regression model prediction; green shaded area = 90% confidence intervals; points show exposure of individual patients with events (p = 1) and without events (p = 0); black squares and vertical green lines = observed fraction of patients with events in each exposure group and 90% confidence intervals for these fractions; dashed vertical lines = bounds of exposure groups. Note: the exposure-safety analyses of the supportive studies in A–D were based on 119 R/R DLBCL patients receiving single-agent pola (0.1–2.4 mg/kg), pola + R (2.4 mg/kg), and pola + G (1.8 mg/kg) up to the eight-cycle landmark. The exposure-efficacy analyses of the supportive studies in E–F were based on 76 R/R DLBCL patients receiving single-agent pola (0.1–2.4 mg/kg) or pola + R (2.4 mg/kg) up to the eight-cycle landmark. ac: antibody conjugate; AUC: area under the concentration − time curve; BOR: best overall response; C_max: maximum concentration; DLBCL: diffuse large B-cell lymphoma; G: obinutuzumab; INV: investigator; MMAE: mono-methyl auristatin E; OR: objective response; PN: peripheral neuropathy; pola: polatuzumab vedotin; R: rituximab.

Figure 2. Kaplan-Meier plot for time to first pola dose modification due to AE with unconjugated MMAE exposure in the supportive studies [(A) AUC; (B) C_max], time to first pola dose modification due to AE with acMMAE exposure in the pivotal study [(C) C_max], and time to death (OS) by acMMAE exposure in the pivotal study [(D) AUC]. Note: Low and high exposure were stratified by median exposure; p-value in the figure legends: p-value of the log-rank test comparing patients with low and high exposure; the BR control arm was included in the Kaplan-Meier plots of OS (D), but not the Cox PH analysis of OS. ac: antibody conjugate; AE: adverse event; AUC: area under the concentration − time curve; C_max: maximum concentration; MMAE: mono-methyl auristatin E; OS: overall survival; PH: proportional hazards.

Table 3. Summary of the exposure-safety analyses based on the supportive and pivotal studies.

Adverse event	Analysis type	N	N (%) with event	p value
				acMMAE		Unconjugated MMAE
				AUC	Cmax	AUC	Cmax
Supportive studies
Grade ≥3 neutropenia	Linear logistic regression	119	39 (32.8)	.091	.157	.338	.339
Grade ≥2 PN		119	30 (25.2)	.003 (+)	.011 (+)	.571	.755
Grade ≥3 infections and infestations		119	12 (10.1)	.615	.631	.066	.101
Grade ≥3 anemia		119	9 (7.6)	.866	.964	.010 (+)	.015 (+)
Grade ≥3 thrombocytopenia		119	6 (5.0)	.638	.928	.327	.221
Pola dose modification due to AE		119	32 (26.9)	.340	.256	.455	.325
Time to the first pola dose  modification due to AE	Cox PH model	119	32 (26.9)	.359	.601	.004 (−)	.002 (−)
Pola dose intensity	LOWESS regression	119	–	–	–	–	–
R dose intensity		40	–	–	–	–	–
Pivotal study
Grade ≥3 neutropenia	Linear logistic regression	69	35 (50.7)	.649	.269	.810	.993
Grade ≥2 PN		69	10 (14.5)	.586	.965	.309	.226
Grade ≥3 infections and infestations		69	20 (29.0)	.376	.879	.765	.930
Grade ≥3 anemia		69	13 (18.8)	.888	.390	.117	.119
Grade ≥3 thrombocytopenia		69	24 (34.8)	.781	.780	.253	.253
Pola dose modification due to AE		69	40 (58.0)	.100	.062	.448	.465
Time to the first pola dose modification due to AE	Cox PH model	69	40 (58.0)	.145	.009 (−)	.639	.541
Pola dose intensity	LOWESS regression	69	–	–	–	–	–
B dose intensity		69	–	–	–	–	–
R dose intensity		44	_	–	–	–	–

ac: antibody-conjugated; AE: adverse event; AUC: area under the concentration − time curve; B: bendamustine; C_max: maximum concentration; Cox PH: Cox proportional hazards; LOWESS, Locally Weighted Scatterplot Smoothing; MMAE: mono-methyl auristatin E; PN, peripheral neuropathy; pola: polatuzumab vedotin; R: rituximab.

Gray shaded cells indicate p value <.05; when p-value <.05, (+) indicates the endpoint of interest increases with increasing exposure; (−) sign indicates the endpoint of interest decreases with increasing exposure.

Table 4. Summary of the exposure-efficacy analyses based on acMMAE AUC in the supportive and pivotal studies.

Endpoint	Analysis type	N evaluable	N (%) with event	p value
Supportive studies
INV-BOR up to cycle 8	Linear logistic regression	76	31 (40.8)	.037 (+)
INV-OR at cycle 8		76	23 (30.3)	.014 (+)
Pivotal study
IRC-CR at PRA	Linear logistic regression	44	19 (43.2)	.521
IRC-OR at PRA		44	21 (47.7)	.956
IRC-BOR		44	26 (59.1)	.852
IRC-DOR at clinical cutoff date	Cox PH model	26	11 (42.3)	.057
IRC-PFS		44	26 (59.1)	.102
OS		44	24 (54.5)	.048 (+)

ac: antibody-conjugated; AUC: area under the concentration − time curve; BOR: best overall response; DOR: duration of response; Cox PH: Cox proportional hazards; CR: complete response; INV: investigator; IRC: independent review committee; MMAE: mono-methyl auristatin E; OR: objective response; OS: overall survival; PFS: progression-free survival; PRA: primary response assessment.

Shaded cells indicate p value <.05; when p value <.05, (+) indicates the endpoint of interest increases with increasing exposure; (−) indicates the endpoint of interest decreases with increasing exposure.

Data availability statement

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