First-in-Human, Phase I Study of Sigvotatug Vedotin, an Integrin Beta-6–Directed Antibody-Drug Conjugate: Results From Dose Expansion in Advanced Non–Small Cell Lung Cancer

Abstract

PURPOSE

Integrin beta-6 (IB6) is highly expressed in non–small cell lung cancer (NSCLC) and other solid tumors and potentially associated with poor outcomes. Sigvotatug vedotin (SV), a novel IB6-directed antibody-drug conjugate, demonstrated acceptable safety and encouraging antitumor activity in dose escalation. We report updated results for dose-expansion regimens in advanced NSCLC (aNSCLC).

METHODS

SGNB6A-001 is an open-label, multicenter, dose-escalation/dose-expansion phase I study evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of SV in patients with select advanced solid tumors. After dose escalation, dose expansion further explored three regimens: 1.25 mg/kg total body weight (TBW) on Days 1 and 8 of a 21-day cycle, 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks), and 1.8 mg/kg adjusted ideal body weight (AiBW) once every 2 weeks. Eligible patients had prior chemotherapy and immunotherapy or targeted therapy if indicated. Primary end points were safety and determination of an optimal dosing schedule. Secondary end points were antitumor activity, PK, and immunogenicity.

RESULTS

As of November 26, 2024, 117 patients with aNSCLC were treated in the above cohorts. Any-grade and grade ≥3 treatment-emergent adverse events occurred in 98% and 48% of all patients, respectively, and in 94% and 35% of patients receiving SV 1.8 mg/kg AiBW once every 2 weeks. Modeling revealed that the AiBW regimen resulted in lower PK variability than TBW regimens. The objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC.

CONCLUSION

SV demonstrated a manageable safety profile and promising antitumor activity with durable responses in aNSCLC. PK and clinical data support further investigation with the recommended 1.8-mg/kg AiBW once every 2 weeks dosing regimen.

INTRODUCTION

In 2022, approximately 2.5 million new lung cancer cases were diagnosed globally¹; non–small cell lung cancer (NSCLC) accounts for nearly 90% of lung cancers.² Despite significant improvements in frontline treatment options for advanced NSCLC (aNSCLC), an unmet need remains for novel more effective second-line or later treatments.^3,4

CONTEXT

• Key Objective

• This analysis of the phase I SGNB6A-001 study reports safety and activity of sigvotatug vedotin (SV) in patients with advanced non–small cell lung cancer (NSCLC) that received one of the dose-expansion regimens.

• Knowledge Generated

• Any-grade and grade ≥3 treatment-emergent adverse events were reported by 98% and 48% of patients overall, respectively. Objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC. Based on pharmacokinetics and clinical data, 1.8 mg/kg adjusted ideal body weight once every 2 weeks is the recommended dosing regimen to be further investigated.

• Relevance (T.E. Stinchcombe)

• This early phase study defined the optimal dosing and the patient population for future trials. The activity observed in non-squamous, taxane-naïve NSCLC is promising.*

• *Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.

Integrins are transmembrane heterodimers with roles in cellular adhesion, motility, and proliferation.^5,6 Integrin beta-6 (IB6), which exclusively forms the alpha-v/beta-6 adhesion receptor, contributes to cancer progression by promoting tissue remodeling and wound repair, processes that malignant cells may exploit to invade surrounding healthy tissue.^5-7 While IB6 is constitutively expressed at low levels in various epithelial tissues, it is highly expressed in numerous solid tumors, including NSCLC.^5-8 Several studies have suggested that IB6 expression may be associated with poor prognosis; however, these studies have several limitations.^9-13 This relationship should be further explored in prospective trials.

Because of its restricted expression in normal tissues and high expression in various tumors, IB6 is a promising target for antibody-drug conjugate (ADC) therapies.^5,10,14,15 Sigvotatug vedotin (SV), a novel IB6-directed vedotin-based ADC, consists of a humanized IB6-specific monoclonal antibody linked to the cytotoxic agent monomethyl auristatin E (MMAE) via a protease-cleavable linker.⁵ After rapid SV internalization, MMAE is released in cells and disrupts microtubule dynamics, leading to cell cycle arrest and apoptosis.^5,16

Preclinical SV studies have shown significant antitumor activity across various cancer models, including NSCLC.⁵ In preclinical NSCLC models, SV demonstrated activity in squamous cell and adenocarcinoma histologies and across a range of IB6 expression levels. In these models, a positive association was suggested between the IB6 expression level and SV activity.

Clinical safety, pharmacokinetics (PK), and antitumor activity of SV are being evaluated with advanced solid tumors in the phase I SGNB6A-001 study (ClinicalTrials.gov identifier: NCT04389632).^17-19 Safety, tolerability, and encouraging antitumor activity were demonstrated in the dose-escalation portion of this study, including in patients with aNSCLC. Based on initial results, select SV regimens were chosen for the dose-expansion portion to determine the recommended dose regimen and to further evaluate safety and efficacy. Here, we report results for patients with aNSCLC who received these expansion regimens during either the dose-escalation or dose-expansion portion.

METHODS

Study Design

SGNB6A-001 is an open-label, multicenter, dose-escalation, dose-expansion phase I study evaluating safety, tolerability, PK, and antitumor activity of SV in adults with advanced solid tumors. The study includes multiple parts, with parts A (dose escalation) and B (dose expansion) evaluating the safety and tolerability of SV monotherapy.

The trial adhered to Good Clinical Practice guidelines, the Declaration of Helsinki, and applicable regulatory requirements. Written informed consent was obtained before any study-related procedures were conducted. The study protocol, including amendments, was reviewed and approved by an institutional review board or ethics committee.

Patients and Treatment

Dose escalation enrolled patients with metastatic or unresectable solid tumors that were relapsed, refractory, or intolerant of standard-of-care therapies (see the study protocol for full eligibility criteria). Dose expansion enrolled patients into disease-specific cohorts; cohorts with ongoing enrollment at data cutoff are not included in this report. For cohorts with locally advanced or metastatic NSCLC, patients must have received platinum-based chemotherapy and a PD-1/PD-L1 inhibitor either in combination or sequentially, if indicated. If an actionable genetic alteration was documented, previous exposure to targeted therapies following local guidelines was required. During the study, the protocol was updated to exclude patients with increased risk for interstitial lung disease (ILD) or pneumonitis, including patients with a history of ILD or pneumonitis requiring steroids, current or suspected ILD or pneumonitis, known diffusing capacity of the lung for carbon monoxide <50%, or grade ≥3 pulmonary disease unrelated to underlying malignancy. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 and no active central nervous system metastases. Patients with previously treated brain metastases were eligible if clinically stable ≥4 weeks before study treatment after brain metastasis treatment with no new or enlarging brain metastases and corticosteroids for symptoms discontinued for ≥7 days before first dose of SV.

Dose-expansion regimens were chosen based on initial results from dose escalation, including safety, preliminary antitumor activity, and PK (Data Supplement, Figs S1 and S2, online only).^17-19 The dose-expansion portion first evaluated 1.25 mg/kg of total body weight (TBW) on Days 1 and 8 of a 21-day cycle (twice every 3 weeks) and 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks). While these regimens demonstrated antitumor activity with acceptable safety, variation in SV exposure by body weight was noted. Patients with high body weight received larger SV doses, resulting in high systemic exposure and subsequently increased toxicity risk; patients with low body weight received smaller SV doses, resulting in low systemic exposure and subsequently lower antitumor activity. Population PK modeling and simulation suggested that a regimen of 1.8 mg/kg of adjusted ideal body weight (AiBW) once every 2 weeks would result in similar average SV exposure as the initial TBW-based regimens while mitigating the SV exposure variation by body weight. The 1.8-mg/kg once every 2 weeks regimen was evaluated in part A and chosen as the third dose-expansion regimen.

This analysis of the dose-expansion regimens includes patients from part A who received one of the expansion regimens or 1.2 mg/kg TBW twice every 3 weeks, which was only evaluated in a few patients and grouped with 1.25 mg/kg TBW twice every 3 weeks in this analysis. Weight-based dosing was determined by the patient's baseline TBW and adjusted if TBW changed ≥10% from baseline or the previous cycle. Based on exposure-safety analysis, a weight cap of 100 kg was implemented in the 1.25-mg/kg twice every 3 weeks cohorts during part B.

Patients continued treatment until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, start of a subsequent anticancer therapy, pregnancy, or study termination by the sponsor.

Trial End Points and Assessments

Primary end points focused on safety and tolerability of SV and identification of the recommended dose regimen as determined by a Safety Monitoring Committee. Safety was monitored and adverse events (AEs) and laboratory test result abnormalities were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 from the study beginning through the end of treatment or 30 days after the last study treatment, whichever was later. Secondary end points were confirmed objective response rate (ORR), duration of objective response (DOR), and progression-free survival (PFS), all per RECIST version 1.1 by the investigator; overall survival (OS); estimates of PK parameters; and immunogenicity. Details about the schedule of assessments, including tumor response imaging, blood tests, and IB6 expression, are given in the Supplemental Methods (Data Supplement).

Statistical Analysis Plan

The all-treated patient analysis set included all patients treated with any amount of SV and was used for safety and primary efficacy analyses. The PK analysis set included all patients who received any amount of SV and had at least one reportable value for SV ac-MMAE, total antibody, or MMAE concentration.

For ORR, a complete response (CR) or partial response (PR) was considered confirmed if the disease assessment ≥4 weeks after initial response continued to show the corresponding response. A best response of stable disease indicated the patient achieved ≥1 stable disease assessment or better ≥5 weeks after the start of treatment, but the patient did not qualify for CR or PR. Patients whose disease response could not be evaluated per the response criteria were scored as not evaluable. Those patients, along with those without a postbaseline response assessment, were counted as nonresponders in ORR calculations.

The Kaplan-Meier method was used to estimate PFS and OS for the all-treated patient analysis set and DOR for patients who achieved a confirmed response. PFS was defined as the time from the start of SV to first documentation of progressive disease or death because of any cause. Details about censoring for PFS and OS are provided in the Supplemental Statistics (Data Supplement).

Other Assessments

A fit-for-purpose population PK model was developed to evaluate ac-MMAE PK. The model incorporated data from all patients with NSCLC from the dose-escalation and dose-expansion portions. Individual empirical Bayes estimates were used to predict SV ac-MMAE average concentrations (Cavg) following the SV expansion cohort dosing regimens of 1.25 mg/kg TBW twice every 3 weeks, 1.5 mg/kg TBW once every 2 weeks, and 1.8 mg/kg AiBW once every 2 weeks. A Cavg over the first 6 weeks of treatment was selected as the exposure metric to account for the different dosing schedules.

RESULTS

Patient Demographics and Disease Characteristics

At data cutoff (November 26, 2024), 117 patients with aNSCLC received ≥1 dose of an SV expansion regimen (1.25 mg/kg TBW twice every 3 weeks [n = 47], 1.5 mg/kg TBW once every 2 weeks [n = 39], and 1.8 mg/kg AiBW once every 2 weeks [n = 31]). Overall, the median age was 65 years, 69% had an ECOG PS of 1, 52% were male, 79% had nonsquamous histology, and 16% had a history of brain metastasis. Patients were heavily pretreated, with a median of 3.0 prior systemic therapies in any setting, and most patients received platinum therapy (96%), a PD-1 or PD-L1 inhibitor (91%), and taxane-containing therapy (67%; Table 1). In the overall population, 92% of patients with immunohistochemistry-evaluable biopsies (67 of 73) had IB6 expression on ≥1% of tumor cells, including 90% with nonsquamous histology (53 of 59) and 100% with squamous histology (14 of 14; Data Supplement, Fig S3).

TABLE 1.

Baseline Characteristics

Characteristic	NSCLC—All Dose-Expansion Groups (N = 117)
Age, years, median (range)	65 (30-79)
Sex, No. (%)
Male	61 (52)
Female	56 (48)
Race, No. (%)
White	73 (62)
Asian	4 (3)
Black or African American	4 (3)
Unknown	3 (3)
Not reportable	33 (28)
ECOG PS, No. (%)
0	36 (31)
1	81 (69)
Disease stage, No. (%)
Metastatic	112 (96)
Locally advanced or recurrent	5 (4)
Histology, No. (%)
Nonsquamous	93 (79)
Squamous	24 (21)
Molecular characteristics, No. (%)
EGFR mutation	9 (8)
ALK mutation	1 (1)
ROS1 mutation	2 (2)
History of brain metastasis, No. (%)
Yes	19 (16)
No	98 (84)
PD-L1 status, No. (%)
TPS <1	49 (42)
TPS ≥1 and <50	34 (29)
TPS ≥50	25 (21)
Missing	9 (8)
Prior lines of systemic treatment received in any setting, No., median (range)	3.0 (1-10)
Previous systemic treatment received in any setting, No. (%)
Platinum therapy	112 (96)
PD-1/PD-L1 inhibitor	106 (91)
Taxane-containing therapy	78 (67)

Abbreviations: ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; NSCLC, non–small cell lung cancer; TPS, tumor proportion score.

Pharmacokinetic Analysis and Dose Recommendation

SV ac-MMAE and unconjugated MMAE demonstrated dose-dependent increases in exposure, with minimal accumulation with repeat dosing across all escalation and expansion dosing regimens (Data Supplement, Fig S2).

A population PK model was used to characterize ac-MMAE PK. The model incorporated data from 127 patients with NSCLC across all dosing regimens from dose escalation and dose expansion. SV ac-MMAE Cavg was compared across body weight groups of <60 kg (n = 32), ≥60 to <80 kg (n = 53), and ≥80 kg (n = 42) for each of the simulated SV dose-expansion regimens (Fig 1). While the median SV ac-MMAE Cavg increased with higher body weight across all dosing regimens, the 1.8-mg/kg AiBW regimen had lower PK variability across body weight groups relative to the TBW regimens.

FIG 1.

PopPK model‒predicted SV ac-MMAE Cavg for the expansion dosing regimens across body weight groups. All patients with NSCLC who received any SV dose from the escalation and expansion portions and provided at least one postdose PK sample as of the March 2024 cutoff (N = 127) were included. The three expansion dosing regimens were simulated for each individual patient and grouped by body weight category. The AiBW regimen increased SV ac-MMAE exposure in low-body-weight patients and reduced SV ac-MMAE exposure in high-body-weight patients. The dashed lines indicate the interquartile range across the body weight groups for the AiBW regimen. ^aDays 1 and 8 of a 21-day cycle. ^bDays 1 and 15 of a 28-day cycle. ac-MMAE, antibody-conjugated MMAE; AiBW, adjusted ideal body weight; Cavg, average concentration; MMAE, monomethyl auristatin E; NSCLC, non–small cell lung cancer; PK, pharmacokinetic; PopPK, population pharmacokinetic; SV, sigvotatug vedotin; TBW, total body weight.

Of 268 patients who provided both a baseline and ≥1 postbaseline antidrug antibody (ADA) sample, 53 had treatment-emergent ADA, with 52 having treatment-induced ADA and one having treatment-boosted ADA (Data Supplement, Table S1).

Safety

All Patients With NSCLC—Across SV Dose-Expansion Groups

In the overall population, nearly all patients (n = 115 [98%]) reported any-grade treatment-emergent AEs (TEAEs), with almost half (n = 56 [48%]) reporting at least one grade ≥3 event (Table 2; Data Supplement, Table S2). More than a quarter of patients reported the most common all-causality TEAEs of fatigue, peripheral sensory neuropathy, nausea, diarrhea, decreased appetite, and dyspnea (Data Supplement, Table S2). Any-grade and grade ≥3 TRAEs were reported by 94 (80%) and 19 (16%) patients, respectively (Data Supplement, Tables S2 and S3). In addition to individual TEAEs, AEs of interest by composite term were determined using pooled search terms (Table 2; Data Supplement, Table S4). The composite term of peripheral neuropathy was reported in 52 patients (44%), with no grade ≥3 events, and ILD or pneumonitis was reported in six patients (5%), with two grade ≥3 events (2%).

TABLE 2.

Overall Safety Summary

Safety Population	NSCLC—All Dose-Expansion Groups (N = 117), No. (%)				NSCLC—1.8 mg/kg AiBW Once Every 2 Weeksa (n = 31), No. (%)
	All Causality		Treatment-Related		All Causality		Treatment-Related
Any-grade TEAE	115 (98)		94 (80)		29 (94)		27 (87)
Grade ≥3 TEAEs	56 (48)		19 (16)		11 (35)		5 (16)
SAEs	43 (37)		9 (8)		8 (26)		3 (10)
TEAEs leading to death	3 (3)		1 (1)		1 (3)		0
TEAEs leading to discontinuation	18 (15)		13 (11)		6 (19)		4 (13)
TEAEs leading to dose interruption	38 (32)		18 (15)		9 (29)		3 (10)
TEAEs leading to dose reduction	25 (21)		20 (17)		9 (29)		8 (26)

AE of Interest by Composite Term	All Causality, No. (%)		Treatment-Related, No. (%)		All Causality, No. (%)		Treatment-Related, No. (%)
AE Composite Term	Any Grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3	Any grade	Grade ≥3
GI	76 (65)	4 (3)	45 (38)	2 (2)	18 (58)	1 (3)	15 (48)	1 (3)
Peripheral neuropathy	52 (44)	0	43 (37)	0	17 (55)	0	14 (45)	0
Oral or pharyngeal mucositis	26 (22)	0	15 (13)	0	5 (16)	0	5 (16)	0
Neutropenia	19 (16)	9 (8)	17 (15)	9 (8)	8 (26)	3 (10)	7 (23)	3 (10)
Hepatoxicity	15 (13)	2 (2)	8 (7)	0	2 (6)	0	2 (6)	0
Anemia	13 (11)	5 (4)	7 (6)	1 (1)	2 (6)	1 (3)	1 (3)	0
Infusion-related reaction	8 (7)	2 (2)	8 (7)	2 (2)	2 (6)	1 (3)	2 (6)	1 (3)
Interstitial lung disease or pneumonitis	6 (5)	2 (2)	4 (3)	2 (2)	0	0	0	0
Hyperglycemia	6 (5)	0	5 (4)	0	2 (6)	0	2 (6)	0
Injection site reactions	4 (3)	0	1 (1)	0	3 (10)	0	1 (3)	0

NOTE. Composite terms include a pool of common TEAEs grouped based on search criteria. See the Data Supplement (Table S4) for further details.

Abbreviations: AE, adverse event; AiBW, adjusted ideal body weight; NSCLC, non–small cell lung cancer; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

^aDays 1 and 15 of a 28-day cycle.

Serious TEAEs occurred in 43 patients (37%), with dyspnea (n = 7 [6%]) and pneumonia (n = 6 [5%]) being the most common. Nine patients (8%) had serious TRAEs, with pneumonitis (n = 2 [2%]) and diarrhea (n = 2 [2%]) being the most common. Three TEAEs led to death, including cardiac arrest, failure to thrive, and pneumonitis. Only pneumonitis was considered treatment-related.

The median duration of treatment was 3.3 months (range, 0.7-31.8), with a median relative dose intensity of 99% (range, 39-106). TEAEs led to 18 (15%) permanent dose discontinuations, with peripheral sensory neuropathy being the most common cause (n = 7 [6%]). Among those 18 patients, the median time to discontinuation was 5.9 months (range, 0.8-15.9). TRAEs led to 13 (11%) permanent dose discontinuations, with peripheral sensory neuropathy being the most common cause (n = 7 [6%]).

Patients Who Received SV 1.8 mg/kg AiBW Once Every 2 Weeks

Based on the PK results showing less variability with the 1.8-mg/kg AiBW dosing regimen across body weight groups compared with the TBW dosing regimens, safety was further assessed in the subgroup of patients who received the SV dose of 1.8 mg/kg AiBW once every 2 weeks. The safety profile of this subgroup was relatively comparable with that observed in the overall population across all dose-expansion groups (Table 2; Data Supplement, Tables S2 and S3). Among patients who received 1.8 mg/kg AiBW once every 2 weeks SV, 29 (94%) experienced any-grade all-causality TEAEs, with 11 (35%) experiencing grade ≥3 events. Any-grade and grade ≥3 TRAEs were reported by 27 (87%) and five (16%) patients, respectively. For AEs of interest by composite term, the incidence of any-grade peripheral neuropathy was slightly higher (n = 17 [55%]) than in the overall population. However, no cases of ILD or pneumonitis were reported. Serious TEAEs occurred in eight patients (26%), with pneumonia (n = 3 [10%]) being the only event occurring in >1 patient. One patient in this subpopulation had a TEAE (cardiac arrest) that led to death but was not treatment-related.

The median duration of treatment with the 1.8 mg/kg AiBW once every 2 weeks dose was 3.7 months (range, 0.9-19.6), with a median relative dose intensity of 91% (range, 70-103). TEAEs led to six (19%) permanent dose discontinuations, with peripheral sensory neuropathy being the only cause reported by >1 patient (n = 3 [10%]). In those six patients, the median time to discontinuation was 6.3 months (range, 5.1-15.9). A lower incidence of TRAEs leading to permanent dose discontinuations (n = 4 [13%]) was observed with this dosing regimen, with peripheral sensory neuropathy being the most common cause (n = 3 [10%]).

Efficacy

In the overall population, the confirmed ORR was 19% (95% CI, 12 to 27), with three CRs and 19 PRs (Table 3; Fig 2). The median DOR in the 22 responders was 11.3 months (95% CI, 5.1 to 14.5). The median duration of follow-up was 21.0 months (95% CI, 18.7 to 25.3). The median PFS was 3.6 months (95% CI, 2.7 to 5.3), and the median OS was 10.8 months (95% CI, 8.1 to 12.9; Figs 3A and 3B). Efficacy was generally similar across dosing regimens (Data Supplement, Table S5).

TABLE 3.

Efficacy End Points

End Point	NSCLC—All Dose-Expansion Groups (N = 117)	Nonsquamous, Taxane-Naïve NSCLC—All Dose-Expansion Groups (n = 42)
ORR, % (95% CI)	19 (12 to 27)	29 (16 to 45)
Best overall response, No. (%)
CR	3 (3)	2 (5)
PR	19 (16)	10 (24)
Stable disease	58 (50)	22 (52)
Progressive disease	30 (26)	6 (14)
Not evaluable	1 (1)	0
No assessment	6 (5)	2 (5)
DOR, months, median (95% CI)a	11.3 (5.1 to 14.5)	12.8 (5.0 to NE)
Time to response, months, median (range)a	1.6 (0.7-7.3)	1.6 (0.7-7.3)
DCR, % (95% CI)	68 (59 to 77)	81 (66 to 91)
PFS, months, median (95% CI)	3.6 (2.7 to 5.3)	6.4 (4.5 to 9.2)
OS, months, median (95% CI)	10.8 (8.1 to 12.9)	14.8 (11.5 to 16.9)

Abbreviations: CR, complete response; DCR, disease control rate; DOR, duration of response; NE, not estimable; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.

^a Calculated for responders: 22 patients in the overall population and 12 patients in the nonsquamous, taxane-naïve population.

FIG 2.

Antitumor activity of sigvotatug vedotin. (A) Maximum percent change from baseline in sums of diameters of target lesions and (B) percent change from baseline in tumor size over time in patients across all dose-expansion groups. (C) Maximum percent change from baseline in sums of diameters of target lesions and (D) percent change from baseline in tumor size over time in patients with nonsquamous taxane-naïve NSCLC across all dose-expansion groups. ^aDays 1 and 8 of a 21-day cycle. ^bThis group includes patients who received 1.2 mg/kg TBW twice every 3 weeks in part A. ^cPatients without a postbaseline assessment eligible for efficacy analysis are not included here. ^dDays 1 and 15 of 28-day cycle. AiBW, adjusted ideal body weight; NSCLC, non–small cell lung cancer; TBW, total body weight.

FIG 3.

(A) PFS and (B) OS of all patients across all dose-expansion groups. (C) PFS and (D) OS of patients with nonsquamous taxane-naïve NSCLC across all dose-expansion groups. NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival.

Efficacy was assessed in key subpopulations defined by histology and prior taxane exposure. In a nonsquamous, taxane-naïve subpopulation (n = 42), confirmed ORR was higher (29%; 95% CI, 16 to 45) than that in the overall population, with two CRs and 10 PRs (Table 3; Fig 2). The median DOR in those 12 responders was 12.8 months (95% CI, 5.0 to not estimable [NE]). The median duration of follow-up was 25.3 months (95% CI, 20.2 to NE). In addition, median PFS (6.4 months [95% CI, 4.5 to 9.2]) and median OS (14.8 months [95% CI, 11.5 to 16.9]; Figs 3C and 3D) were numerically higher in this subpopulation. In the nonsquamous, taxane-naïve subpopulation, efficacy was generally similar across dosing regimens (Data Supplement, Table S5). Efficacy was also assessed in patients with nonsquamous (n = 93) and squamous histology (n = 24) regardless of prior taxane exposure (Data Supplement, Table S6). Confirmed ORR (19% v 17%), median DOR (11.3 v 5.1 months), median PFS (4.2 v 2.5 months), and median OS (11.0 v 10.7 months) were all numerically higher in patients with nonsquamous versus squamous histology.

DISCUSSION

In this phase I study of SV in patients with heavily pretreated aNSCLC, manageable safety and initial antitumor activity from the dose-escalation portion of the study were confirmed.¹⁹ SV's PK profile was further explored and defined along with a more comprehensive understanding of SV's clinical activity and safety profile; based on those results, the study's primary objective was met with identification of the recommended regimen of 1.8 mg/kg AiBW once every 2 weeks. The study also identified a population of interest, namely, patients with nonsquamous, taxane-naïve, previously treated NSCLC, for further evaluation in phase III studies.

In the PK modeling, SV ac-MMAE Cavg increased with the body weight groups (<60 kg, ≥60 to <80 kg, ≥80 kg) for all regimens, with lower variability across body weight groups with AiBW versus TBW dosing regimens. Originally used for weight-based dosing of aminoglycoside antibiotics in individuals with obesity, AiBW dosing reduces the slope of the linear relationship between TBW and total dose to reduce the risk of overdosing patients with higher body weight and higher adiposity.^20-22 AiBW dosing, when applied to patients of all body weights, also results in higher total doses for patients with low body weight compared with TBW dosing,^21,22 but ac-MMAE exposure is comparable with the TBW dosing regimens. When applied to SV, AiBW dosing significantly reduced PK variability, and this is expected to improve efficacy in patients with body weight <60 kg while reducing the risk of exposure-related toxicity in patients with body weight ≥80 kg.

The safety profile of SV was similar to that seen in this study's dose-escalation portion and in studies with other vedotin-based ADCs, with constitutional symptoms, gastrointestinal effects, and peripheral neuropathy being the most common AEs.^19,23-26 In prior trials evaluating vedotin-based ADCs in patients with previously treated solid tumors, almost all patients reported any-grade TEAEs (94%-98%) and 29%-54% of patients reported grade ≥3 TRAEs.^23-26 In the overall population, any-grade TEAEs were reported by 98% of patients, with grade ≥3 TEAEs reported by 48% of patients. However, only 16% of patients experienced grade ≥3 TRAEs. Incidences of treatment-emergent ILD or pneumonitis (5%) and stomatitis (11%) were relatively low. The treatment-related pneumonitis death occurred before the protocol amendment excluding patients with a high risk of pneumonitis and providing pneumonitis management guidance. Incidences of any-grade (94%) and grade ≥3 TEAEs (35%) were moderately improved in the subpopulation of patients who received the recommended dose of 1.8 mg/kg AiBW once every 2 weeks. TEAEs were manageable, with treatment-related discontinuation rates of 11% in the overall population and 13% in the 1.8-mg/kg AiBW once every 2 weeks subgroup. The safety profile of 1.8 mg/kg AiBW once every 2 weeks was relatively consistent with that in the overall population, which, in addition to the PK modeling, supports its selection as the recommended phase III dosing regimen.

In the overall population, patients whose disease responded to SV demonstrated durable responses, with an ORR of 19% and a median DOR of 11.3 months. Median PFS (3.6 months) and median OS (10.8 months) were promising in the overall heavily pretreated population. Moreover, SV's antitumor activity was higher in the subpopulation of patients with nonsquamous, taxane-naïve NSCLC, with an ORR of 29%, a median DOR of 12.8 months, a median PFS of 6.4 months, and a median OS of 14.8 months. A comparison based on histology regardless of prior taxane exposure demonstrated that SV's antitumor activity was higher in the nonsquamous versus squamous subpopulation. However, because of the potential impact of prior taxane therapy on the activity of vedotin-based ADCs,²⁷ as well as the limited sample size, it is difficult to conclude whether this activity difference is solely based on histology or if it is influenced by the higher rate of prior taxane exposure in squamous NSCLC. Given the increased antitumor activity, patients with nonsquamous, taxane-naïve NSCLC have been identified as a population of interest in future SV studies.

Based on these results, a randomized, phase III trial (SigVie-002; Be6A Lung-01; ClinicalTrials.gov identifier: NCT06012435) is evaluating SV versus docetaxel for nonsquamous taxane-naïve aNSCLC which received prior therapy per standard of care.^8,28 Additional work from this phase I study is ongoing, namely, investigating SV plus pembrolizumab with or without platinum-based chemotherapy. Initial data on SV plus pembrolizumab were previously reported,²⁸ and the combination is being investigated in an additional phase III trial (SigVie-003; Be6A Lung-02; ClinicalTrials.gov identifier: NCT06758401) actively enrolling patients with treatment-naïve aNSCLC with a PD-L1 tumor proportion score of ≥50.³⁰

In conclusion, SV is a novel, investigational, first-in-human IB6-directed vedotin-based ADC that has demonstrated manageable safety and encouraging efficacy as monotherapy in >100 patients with aNSCLC in this phase I study. The clinical activity and safety profile of SV monotherapy and in combination with pembrolizumab are being further assessed in ongoing phase III studies (ClinicalTrials.gov identifier: NCT06012435 and  NCT06758401).^8,28,30 The SigVie-002 study will also evaluate the association between IB6 expression and SV antitumor activity. Based on these further assessments, SV has the potential to become the first IB6-directed therapy for patients with aNSCLC.

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-02016.

Upon request and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

AUTHOR CONTRIBUTIONS

Conception and design: Kartik Sehgal, Emiliano Calvo, Vladimir Galvao, Afshin Dowlati, Fernando Rivera Herrero, Juanita S. Lopez, Cesar Augusto Perez, Scott Knowles

Administrative support: Afshin Dowlati

Provision of study materials or patients: Kartik Sehgal, Emiliano Calvo, Bruno Bockorny, Afshin Dowlati, Tatiana Hernandez-Guerrero, Fernando Rivera Herrero, Juanita S. Lopez, Amita Patnaik

Collection and assembly of data: Solange Peters, Sarina A. Piha-Paul, Kartik Sehgal, Emiliano Calvo, Bruno Bockorny, Vladimir Galvao, Afshin Dowlati, Tatiana Hernandez-Guerrero, Fernando Rivera Herrero, Edwin Kingsley, Juanita S. Lopez, Amita Patnaik, Cesar Augusto Perez, Rachel E. Sanborn, Scott Knowles, Yimo Wang, Antoine Hollebecque

Data analysis and interpretation: Kartik Sehgal, Emiliano Calvo, Bruno Bockorny, Vladimir Galvao, Afshin Dowlati, Elisa Fontana, Fernando Rivera Herrero, Edwin Kingsley, Juanita S. Lopez, Amita Patnaik, Cesar Augusto Perez, Rachel E. Sanborn, Scott Knowles, Gabriela Patilea-Vrana, Jerry Li, Tianhua Wang, Antoine Hollebecque

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

First-in-Human, Phase I Study of Sigvotatug Vedotin, an Integrin Beta-6–Directed Antibody-Drug Conjugate: Results From Dose Expansion in Advanced Non–Small Cell Lung Cancer

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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