A Phase I Study of DLYE5953A, an Anti-LY6E Antibody Covalently Linked to Monomethyl Auristatin E, in Patients with Refractory Solid Tumors

Sara M. Tolaney; Khanh T. Do; Joseph P. Eder; Patricia M. LoRusso; Colin D. Weekes; Sarat Chandarlapaty; Ching-Wei Chang; Shang-Chiung Chen; Denise Nazzal; Eva Schuth; Flavia Brunstein; Montserrat Carrasco-Triguero; Walter C. Darbonne; Jennifer M. Giltnane; William M. Flanagan; S. Renee Commerford; Alexander Ungewickell; Geoffrey I. Shapiro; Shanu Modi

doi:10.1158/1078-0432.CCR-20-1067

DOI: 10.1158/1078-0432.CCR-20-1067 Published November 2020

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Figure 1.
Time on DLYE5953A treatment at RP2D of 2.4 mg/kg Q3W for patients with NSCLC (nonsquamous histology, unless noted otherwise) and patients with MBC (HER2-negative/HR+, unless noted otherwise). Patients with MBC (n = 6) dosed at 2.4 mg/kg DLYE5953A during dose escalation are also included as the six lanes at the bottom of the MBC plot. All patients have discontinued DLYE5953A treatment.
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Figure 2.
Best response to DLYE5953A treatment at the RP2D of 2.4 mg/kg Q3W for patients with NSCLC and MBC. Patients who did not undergo a posttreatment CT scan (n = 5) were nonevaluable for best response. Patients with MBC (n = 6) dosed at 2.4 mg/kg DLYE5953A during dose escalation are also included.
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Figure 3.
Patient vignettes. A, A 64-year-old female diagnosed with NSCLC in 2013 with LY6E IHC score of 3+ had received prior cisplatin/pemetrexed (neoadjuvant), carboplatin/pemetrexed, and nivolumab. This patient received DLYE5953A at the R2PD and demonstrated a PR after cycle 2 that was confirmed with subsequent imaging (∼46% best response). This patient was discontinued from study due to growth of a new lesion following cycle 6. B, A 38-year-old female diagnosed with TNBC in 2014 with a LY6E IHC score of 3+ had received cyclophosphamide/doxorubicin/paclitaxel (adjuvant), cisplatin, and eribulin/pembrolizumab. This patient received five cycles of DLYE5953A at the RP2D and achieved a best response of SD at −14% at cycle 2. Her C4 scans indicated regrowth of target lesions (increase of 13% from nadir at C2). She withdrew from study following cycle 5 to undergo a mastectomy.

Table 1.

Baseline and disease characteristics of patients with MBC and NSCLC treated at the RP2D of 2.4 mg/kg and all patients on treatment (0.2–2.4 mg/kg).

	2.4 mg/kg	2.4 mg/kg	All patients
Variable	MBC (n = 29)	NSCLC (n = 25)	(N = 68)
Age (years) median	54	63	58
(range)	(33–71)	(45–82)	(33–82)
Gender, n (%)
Male	1 (3)	12 (48)	13 (19)
Female	28 (97)	13 (52)	55 (81)
ECOG status, n (%)
0	17 (59)	4 (16)	23 (34)
1	12 (41)	21 (84)	45 (66)
Median time (months) between initial diagnosis and metastatic disease^a	31.5	0.2	8
(range)	(0–256.3)	(0–35.2)	(0–256.3)
NSCLC histology
Squamous	-	8 (32)	8 (32)
Nonsquamous	-	17 (68)	17 (68)
Breast cancer histology
HR+, HER2−	21 (72)	-	24 (69)
TNBC	8 (28)	-	11 (31)
Median prior lines of hormone therapy in HR+, HER2− MBC (adv/met)^b	3	-	-
(range)	(0–4)	-	-
Cytotoxic regimen (adv/met)
Prior platinum (≥1)	9 (31)	25 (100)	43 (63)
Prior taxane (≥1)	26 (90)	16 (64)	53 (78)
Prior immunotherapy (≥1)	2 (7)	22 (88)	24 (35)

↵^aOne patient in the MBC group had no metastatic date available, and one patient in the dose-escalation group had no initial diagnosis date available.
↵^bRepresents the median number of lines of hormonal therapy in the advanced/metastatic setting for the 21 patients with HR+, HER2− patients treated at 2.4 mg/kg. See Supplementary Table S1 for demographic data for remaining patients who participated in the dose-escalation group.

Table 2.

AEs related to DLYE5953A in patients with MBC (2.4 mg/kg), NSCLC (2.4 mg/kg), and all patients (0.2–2.4 mg/kg), and with an occurrence of ≥10% in patients overall.

	2.4 mg/kg MBC	2.4 mg/kg NSCLC	0.2–2.4 mg/kg All patients
MedDRA term	(n = 29)^a	(n = 25)	(N = 68)
Patients with ≥1 AE	29 (100)	23 (92)	63 (93)
Alopecia	20 (69)	13 (52)	36 (53)
Fatigue	15 (52)	10 (40)	31 (46)
Nausea	12 (41)	8 (32)	26 (38)
Peripheral neuropathy^b	13 (45)	6 (24)	22 (32)
Peripheral sensory neuropathy	12 (48)	3 (12)	16 (24)
Peripheral motor neuropathy	8 (28)	0	8 (12)
Paresthesia	1 (3)	2 (8)	4 (6)
Chills	8 (28)	5 (20)	19 (28)
Decreased appetite	8 (28)	7 (28)	19 (28)
Diarrhea	8 (28)	4 (16)	14 (21)
Constipation	9 (31)	1 (4)	12 (18)
Aspartate aminotransferase increased	6 (21)	5 (20)	11 (16)
Back pain	6 (21)	2 (8)	10 (15)
Alanine aminotransferase increased	6 (21)	3 (12)	9 (13)
Anemia	7 (24)	1 (4)	8 (12)
Dry mouth	4 (14)	1 (4)	8 (12)
Mucosal inflammation	6 (21)	1 (4)	9 (13)
Myalgia	5 (18)	2 (8)	9 (13)
Neutropenia	4 (14)	5 (20)	9 (13)
Pruritus	8 (28)	1 (4)	9 (13)
Vomiting	4 (14)	3 (12)	8 (12)
Arthralgia	5 (17)	0	7 (10)
Dry eye	4 (14)	3 (12)	7 (10)
Headache	5 (17)	0	7 (10)
Pyrexia	4 (14)	2 (8)	7 (10)

↵^aSix of the patients with MBC were studied in the 2.4 mg/kg dose-escalation cohort, and 23 were studied in the dose-expansion cohort at the RP2D of 2.4 mg/kg. See Supplementary Table S3 for all common AEs occurring in patients with MBC and NSCLC treated at the RP2D of 2.4 mg/kg. Supplementary Table S4 provides a summary of AEs in patients who participated in the dose-escalation cohort, including one patient with ovarian cancer treated at 2.4 mg/kg.
↵^bPeripheral neuropathy includes the following terms: peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, neuralgia, hypoesthesia, paresthesia, and muscular weakness. Terms with incidence n = 1 in the total patient population are not included in Table 2. Some patients experienced more than one peripheral neuropathy event.

Table 3.

Selected mean (SD) pharmacokinetic parameters for total antibody and unconjugated MMAE after DLYE5953A treatment at cycle 1.

Total antibody	Number of patients^a	C_max (μg/mL)	AUC_0-inf (day*μg/mL)	t_1/2 (day)	V_ss (mL/kg)	CL (mL/day/kg)
Cohorts:
0.2 mg/kg	3	3.45	13.6	7.05	126	16.6
		(1.14)	(6.2)	(1.61)	(39)	(6.1)
0.4 mg/kg	3	7.74	29.8	8.38	109	13.6
		(0.62)	(3.6)	(1.89)	(13.9)	(1.8)
0.8 mg/kg	3	16.1	89.7	13.3	129	10.1
		(4.6)	(37.1)	(1.2)	(41)	(4.0)
1.6 mg/kg	4	36.9	141	4.97	71.6	12.0
		(8.9)	(37)	(1.94)	(27.3)	(2.5)
2.4 mg/kg	7	44.1	219	7.60	90.5	11.9
		(11.5)	(69)	(2.709)	(20.4)	(3.3)
2.4 mg/kg	22	47.0	258	7.02	88.0	10.0
MBC		(9.7)	(77)	(2.31)	(24.4)	(2.7)
2.4 mg/kg	24	46.4	253	7.27	87.4	10.9
NSCLC		(7.6)	(101)	(2.38)	(20.9)	(4.4)

Unconjugated MMAE	Number of patients^a	C_max (ng/mL)	AUC_0-inf (day*ng/mL)	t_max (day)
Cohorts:
0.2 mg/kg	3	0.461	3.18	1.64
		(0.057)	(0.61)	(0.57)
0.4 mg/kg	3	0.728	7.13	1.65
		(0.161)	(NA)	(0.57)
0.8 mg/kg	3	1.69	13.4	2.01
		(1.05)	(11.7)	(0.05)
1.6 mg/kg	4	6.17	66.6	5.43
		(3.85)	(35.6)	(6.95)
2.4 mg/kg	7	6.07	53.1	3.01
		(2.26)	(27)	(2.62)
2.4 mg/kg	14	4.08	34.9	3.10
MBC		(2.08)	(18.2)	(3.46)
2.4 mg/kg	10	4.85	36.5	2.71
NSCLC		(2.44)	(16.8)	(2.23)

Abbreviations: AUC_0-inf, area under the concentration−time curve from time zero extrapolated to infinite time; CL, clearance; C_max, maximum observed plasma concentration; V_ss, volume of distribution at steady state; t_1/2, terminal half-life; t_max, time to reach maximum concentration.
↵^aNumber of patients with at least one pharmacokinetic parameter estimated.