Phase I Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, Monotherapy in Patients with Advanced Non–Small Cell Lung Carcinoma

c-Met is a tyrosine kinase receptor expressed on the surface of epithelial and endothelial cells. Activation of c-Met by hepatocyte growth factor, its only known ligand, has been shown to control cell proliferation, angiogenesis, survival, and cellular motility (1, 2). Dysregulation of c-Met signaling via receptor overexpression has been implicated in the development of non–small cell lung cancer (NSCLC; refs. 3–5) and has been reported in other epithelial solid tumors, including breast (6), colorectal (7, 8), ovarian (9), and prostate cancers (10).

NSCLC represents 85% of all lung cancers and is the leading cause of cancer-related death worldwide (11, 12). Patients with NSCLC typically present with locally advanced or metastatic disease and have poor 5-year survival (13). Although chemotherapy generally provides a modest benefit in survival (14), the development of targeted agents in recent years has significantly improved prognosis for oncogene-related biomarker-selected subgroups (15–17). Aberrant c-Met signaling is common in NSCLC and believed to occur via multiple mechanisms, some of which introduce MET oncogene-addicted phenotypes, such as MET exon 14 skip mutations and high-level MET gene amplification. However, in many others, despite c-Met expression, oncogene addiction does not manifest. Deregulated c-Met signaling in general has been associated with poor prognosis (18–20), tumorigenesis, resistance to chemotherapy/radiotherapy (21), and acquired resistance to EGFR tyrosine kinase inhibitors (TKI; ref. 22). The presence of surface expression of c-Met protein in both MET oncogene-addicted and nonaddicted forms may introduce a therapeutic sensitivity for a c-Met–directed antibody–drug conjugate (ADC) that utilizes c-Met as the means to preferentially deliver a cytotoxic payload to the cancer cells.

The first-in-class ADC telisotuzumab vedotin (Teliso-V) was created by linking the anti–c-Met humanized mAb ABT-700 to the potent antimicrotubule pharmacophore monomethyl auristatin E (MMAE) via a valine-citrulline linker. ABT-700 has been shown to specifically direct Teliso-V to c-Met–expressing tumor cells with high affinity (23–24). Binding of Teliso-V to c-Met results in the internalization of the ADC, cleavage of the linker, followed by the intracellular release of the MMAE payload (24). MMAE then inhibits cell division and other tumor cell functions by blocking tubulin polymerization, which results in cancer cell death. In a first-in-human phase I trial of unconjugated ABT-700, antitumor activity was observed in patients with MET-amplified advanced solid tumors but not in patients with c-Met–overexpressing tumors without MET amplification, consistent with c-Met expression alone not defining an oncogene-addicted state (25, 26). In contrast, Teliso-V, which in addition to disrupting c-Met signaling also delivers a toxic payload, has demonstrated promising antitumor activity in preclinical studies in cells overexpressing c-Met, independent of MET amplification status, potentially expanding the target population for this drug to patients whose tumors express c-Met, regardless of their addiction to the MET oncogene (24). This led to the design of a phase I/Ib dose-escalation and -expansion study in patients with solid tumors not initially preselected by c-Met protein expression. We previously reported the initial results from the dose-finding study of 48 patients with solid tumors receiving a range of 0.15 to 3.3 mg/kg doses of Teliso-V monotherapy once every 3 weeks (27). The initial recommended phase II dose (RP2D) of Teliso-V monotherapy (2.7 mg/kg once every 3 weeks) showed activity with a treatment-emergent adverse event (AE) profile that included fatigue, nausea, constipation, decreased appetite, vomiting, dyspnea, diarrhea, peripheral edema, and neuropathy. With regard to activity, Teliso-V monotherapy at doses ≥2.4 mg/kg once every 3 weeks showed promising efficacy in patients with c-Met–overexpressing NSCLC, with 3 (19%) patients achieving partial response (PR) and a median duration of response (DOR) of 4.8 months.

Herein, we report additional clinical results from this ongoing phase I/Ib study where Teliso-V monotherapy has been evaluated in both once every 2 weeks and once every 3 weeks administration schedules in a larger cohort of patients with NSCLC. The primary endpoints were the safety and pharmacokinetics (PK) of Teliso-V monotherapy once every 2 weeks and once every 3 weeks and the RP2D for the Teliso-V once every 2 weeks schedule. The secondary endpoint was evidence of antitumor activity of the once every 2 weeks and once every 3 weeks schedules in patients with c-Met–positive NSCLC. Exploratory analyses included evaluation of PK and pharmacodynamic modeling of the effects of dose and administration schedules on NSCLC tumor response and safety in patients who progressed after at least two prior lines of therapy.

Eligibility criteria for enrollment have been described previously (27). Briefly, patients with solid tumors and with measurable disease according to RECIST version 1.1 (28) that progressed on standard therapy, or for which no standard therapy was available, were enrolled in the dose-escalation phase. For the expansion phase, patients with NSCLC having c-Met membrane H-score ≥150 (c-Met+) via central lab assessment or local lab-reported MET amplification/MET exon 14 skipping mutation were enrolled. During the study, inclusion criteria were updated in response to a requirement from the FDA to require eligible patients to have received and progressed on or experienced failure of an immune checkpoint inhibitor prior to receiving Teliso-V monotherapy. Patients with grade ≥2 neuropathy were excluded. All patients provided written informed consent, and the study was approved by the local ethics committee or institutional review board. The study was conducted in accordance with International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki. This study is registered with ClinicalTrials.gov (NCT02099058).

This was an open-label, multicenter, phase I/Ib study of Teliso-V monotherapy administered as an intravenous infusion once every 2 weeks in 4-week cycles or once every 3 weeks in 3-week cycles. The study was conducted in two parts, dose escalation and expansion. Part 1 enrolled patients with advanced solid tumors of multiple types, and dose escalation was performed following a standard 3+3 design to define the safety, MTD, and PK profile of Teliso-V once every 3 weeks and once every 2 weeks regimens. In once every 3 weeks cohorts, patients received Teliso-V at doses ranging from 0.15 to 3.3 mg/kg. In once every 2 weeks cohorts, initiated once the once every 3 weeks dose of 2.7 mg/kg was selected as potential RP2D, patients received Teliso-V at fixed doses of 1.6, 1.9, and 2.2 mg/kg; the starting dose was selected to approximate the dose intensity of 2.4 mg/kg once every 3 weeks. Dose-limiting toxicities (DLT) with the once every 2 weeks schedule were determined during the first 28-day cycle and are defined in the Supplementary Data. In the second phase of this study (dose expansion), the RP2Ds of Teliso-V once every 2 weeks and once every 3 weeks were further evaluated for safety, tolerability, and antitumor efficacy in biomarker-selected patients with c-Met+ NSCLC. Teliso-V was administered until disease progression or unacceptable toxicity.

During the study, the manufacturing process of Teliso-V was modified to specifically enrich conjugates with a stoichiometry of two to four MMAE molecules per antibody molecule to eliminate unconjugated antibody. Teliso-V produced through the new process was evaluated during dose escalation and expansion in up to 50 patients dosed once every 2 weeks and once every 3 weeks. The newly processed Teliso-V conjugate showed comparable safety and tolerability to that of the antecedent ADC, and the protocol was amended to transition all ongoing patients to treatment with the newly processed Teliso-V at the same dose level and dosing schedule.

Safety was evaluated on the basis of reported treatment-emergent AEs, electrocardiograms, physical examination, vital signs, and laboratory test examinations. AEs were collected from the time of first dose of Teliso-V until 60 days after discontinuation or the start of a new anticancer treatment. The Medical Dictionary for Regulatory Activities was used to classify AEs by preferred term, and toxicity was graded using the NCI Common Terminology Criteria for Adverse Events version 4.03.

For both Teliso-V once every 2 weeks and once every 3 weeks schedules, blood samples for PK evaluations were collected on: cycle 1 day 1 (predose and 30 minutes after infusion); during study visits on cycle 1 days 2, 4, 8, and 15; on cycle 2 day 1 and on day 1 of every subsequent cycle (predose and 30 minutes after infusion); and at the final visit. Serum concentrations of Teliso-V conjugate, total ABT-700 antibody, and plasma concentrations of MMAE molecule were examined using validated methods. PK parameters were estimated by noncompartmental analysis.

Tumor response was evaluated using contrast-enhanced CT (or MRI or noncontrast CT if contrast was not tolerated). Radiographic tumor assessments of the head, chest, abdomen, and pelvis were performed at baseline (within 28 days before cycle 1 day 1) and every 6 weeks after the start of Teliso-V treatment for patients in the once every 3 weeks dosing schedule, or every 8 weeks for patients in the once every 2 weeks dosing schedule, until disease progression or study termination, and at the final visit for patients without documented radiographic progression if clinically warranted. Changes in the size of target lesions were evaluated using RECIST version 1.1 (28) and the objective response rate (ORR), progression-free survival (PFS), and DOR were determined.

Membrane c-Met expression was analyzed prospectively for the preselection of patients for dose expansion. c-Met expression was determined centrally by Flagship Biosciences via IHC using CONFIRM anti-Total c-Met SP44 antibody (Ventana Medical Systems) and ultraView Universal DAB Detection Kit (Ventana Medical Systems). Semiquantitative evaluation of the IHC staining was performed to determine the final H-score, ranging from 0 to 300. c-Met+ was defined by an H-score ≥150, the same H-score cutoff used previously (27). MET exon 14 skipping and EGFR mutations were reported on the basis of data provided by study sites. MET amplification status was determined by either site reporting of local FISH assay results, or central (Personal Genome Diagnostics) sequencing of plasma or tumor DNA from available samples. Additional details and biomarker methods can be found in the Supplementary Data.

The safety population included all patients who received one or more dose of Teliso-V. The efficacy-evaluable population included patients with NSCLC having c-Met H-score ≥150 who received one or more dose of Teliso-V with at least one postdose tumor assessment, or discontinued treatment before the first postdose assessment due to AEs, radiographic progressive disease (PD), clinical PD, or death. All safety and efficacy analyses were descriptive with no statistical inference drawn from the data. Definitions of efficacy variables can be found in the Supplementary Data. Efficacy data were analyzed by histology (squamous and nonsquamous NSCLC) and, for nonsquamous NSCLC patients, by dosing schedule. Because of the low numbers, data of patients with squamous NSCLC from once every 2 weeks and once every 3 weeks dosing cohorts were pooled for efficacy analyses.

From January 2015 to July 2018, 672 patients were screened for the full study (including several study arms) and 52 patients with NSCLC were enrolled in the Teliso-V monotherapy arms; 28 received Teliso-V monotherapy at ≥1.6 mg/kg doses once every 2 weeks and 24 received ≥2.4 mg/kg doses once every 3 weeks, constituting the safety population. The median age of the total population was 66 years (range, 30–86), and the majority of patients were male (n = 27, 52%). Patient demographic and baseline characteristics of the safety and efficacy-evaluable populations are summarized in Table 1. The median number of prior therapies was 3 (range, 0 to ≥7); 65% of patients received prior antimicrotubule agents. Further details on prior anticancer therapies are provided in Supplementary Table S1.

In total, 47 of 52 enrolled patients had c-Met expression tested by IHC; 12 (26%) patients had no intervening anticancer regimen between biopsy and Teliso-V (time range between biopsy and Teliso-V initiation 0.03–4.6 months), 33 (70%) had at least one intervening regimen (time range between biopsy and Teliso-V initiation 2.6–63.4 months), and for 2 (4%) patients biopsy dates were not known. In total, 44 enrolled patients had available c-Met expression results and 40 of these had a c-Met H-score ≥150 and were efficacy evaluable (c-Met+, 7 squamous, 33 nonsquamous; Table 2). In the efficacy-evaluable population, 18 patients received Teliso-V once every 2 weeks and 22 received Teliso-V once every 3 weeks; 2 patients had MET amplification, 1 had MET exon 14 skipping mutation, and 2 had canonical EGFR sensitizing mutations per site reporting. Among the 12 safety population patients who were not part of the efficacy population, 2 patients were MET amplified, 1 had MET exon 14 skipping mutation, and 1 had EGFR exon 20 insertion per site reporting.

At the time of data cutoff, all 52 safety-evaluable patients had discontinued treatment. In Teliso-V once every 2 weeks cohorts, no DLTs were reported at any tested dose level, and the MTD was not formally identified. The 1.9 mg/kg dose was selected for the expansion phase on the basis of overall safety and PK data. In cohorts receiving Teliso-V once every 3 weeks, the 2.7 mg/kg dose level was chosen for further evaluation on the basis of overall safety and tolerability (27). Patients received Teliso-V monotherapy for a median of 10.1 weeks (range, 0.1–60.1); median treatment duration was 19.6 weeks (range, 0.1–60.1) in once every 2 weeks cohorts and 6.1 weeks (0.1–57.1) in once every 3 weeks cohorts.

Fifty-one patients (98%) experienced at least one treatment-emergent AE, including all 28 (100%) patients in the Teliso-V once every 2 weeks cohorts and 23 of 24 (96%) in the once every 3 weeks cohorts, most of grade 1 or 2 severity. Treatment-emergent AEs of all grades experienced by ≥10% of patients with c-Met+ NSCLC are summarized in Table 3. The most common (≥30% of patients) treatment-emergent AEs were peripheral neuropathy (57%; all types), fatigue (50%), nausea (39%), and dizziness (32%) in Teliso-V once every 2 weeks cohorts, and fatigue (58%), nausea (38%), and dyspnea (33%) in once every 3 weeks cohorts. Overall, 34 (65%) patients reported grade ≥3 treatment-emergent AEs, including 19 (68%) and 15 (63%) patients receiving Teliso-V once every 2 weeks and once every 3 weeks, respectively. Other than malignant neoplasm progression [progression of the disease under study during the treatment-emergent AE reporting period; 6 (21%) patients], grade ≥3 treatment-emergent AEs in 2 or more patients were fatigue, peripheral neuropathy, anemia, hypokalemia, increased gamma-glutamyltransferase, gait disturbance, and musculoskeletal chest pain [2 (7%) patients each] in once every 2 weeks cohorts, and anemia [3 (13%) patients], fatigue, dyspnea, chronic obstructive pulmonary disease exacerbation, pneumonia, and hyponatremia [2 (8%) patients each] in once every 3 weeks cohorts.

A total of 42 patients had at least one treatment-related AE of any grade, including 23 (82%) and 19 (79%) patients in once every 2 weeks and once every 3 weeks dosing cohorts, respectively. Most frequent treatment-related AEs (≥20% of patients) were fatigue (32%), nausea (29%), hypoalbuminemia (25%), peripheral neuropathy (25%), and peripheral sensory neuropathy (21%) in the once every 2 weeks schedule, and fatigue (38%) and nausea (33%) in once every 3 weeks cohorts. Grade ≥3 treatment-related AEs occurring in 2 or more patients included fatigue (2 patients in once every 2 weeks and once every 3 weeks cohorts, each), anemia (2 patients in once every 3 weeks cohorts), and peripheral sensory neuropathy (2 patients in once every 2 weeks cohorts and 1 patient in once every 3 weeks cohorts). Serious AEs were reported in 12 and 10 patients in once every 2 weeks and once every 3 weeks cohorts, respectively. No Teliso-V–related deaths were reported.

In Teliso-V once every 2 weeks cohorts, dose reduction or interruption due to an AE occurred in 7 (25%) and 15 (54%) patients, respectively. Six (21%) patients discontinued treatment due to AEs, 4 of whom (14%) discontinued due to Teliso-V–related AEs. Five (18%) patients discontinued Teliso-V due to peripheral neuropathy (1 patient each for grades 1 and 3 and 3 patients for grade 2), and 1 patient due to grade 3 gait disturbance.

In once every 3 weeks cohorts, Teliso-V dose reduction or interruption due to an AE was required in 3 (13%) and 9 (38%) patients, respectively. Of the 18 (35%) patients who discontinued treatment due to AEs, discontinuation due to Teliso-V–related AEs occurred in 8 (15%) patients: grade 2 pneumonitis (n = 1), grade 2 (n = 3) and grade 3 (n = 2) peripheral sensory neuropathy, grade 3 gait disturbance (n = 1), grade 1 peripheral neuropathy (n = 1), and grade 1 dizziness (n = 1). One event each of peripheral sensory neuropathy (grade 3) and gait disturbance was reported in the same patient.

In once every 2 weeks cohorts, any-grade peripheral neuropathy was observed in 16 (57%) patients, whereas in once every 3 weeks cohorts peripheral neuropathy was seen in 6 (25%) patients. The median time to onset of peripheral neuropathy was 3.3 months (range, 0.2–9.2) in once every 2 weeks cohorts and 3.5 months (range, 0.3–6.2) in once every 3 weeks cohorts (Supplementary Table S2). The median duration of peripheral neuropathy was slightly shorter in once every 2 weeks cohorts (2.8 months; range, 0.03–11.3) than in once every 3 weeks cohorts (5.4 months; range, 2.8–13.7). Grade ≥2 peripheral neuropathy was observed in 11 (39%) patients in once every 2 weeks cohorts and 6 (25%) patients in once every 3 weeks cohorts. The median time to onset of grade ≥2 peripheral neuropathy was 5.6 months (range, 0.7–9.2) and 4.2 months (range, 3.0–6.2) in once every 2 weeks and once every 3 weeks cohorts, respectively. The median duration of grade ≥2 peripheral neuropathy was 9.5 months (range, 0.2–25.2) in once every 2 weeks cohorts and 5.4 months (range, 2.8–54.8) in once every 3 weeks cohorts. In 4 patients in once every 2 weeks cohorts (14%) and 4 patients in once every 3 weeks cohorts (17%), Teliso-V dosing was interrupted due to peripheral neuropathy. Teliso-V dose was reduced as a response to peripheral neuropathy in 5 (18%) patients in once every 2 weeks cohorts and 1 (4%) patient in once every 3 weeks cohorts. The cumulative dose of Teliso-V correlated with neuropathy grade (P < 0.001).

The systemic exposure of Teliso-V conjugate after single-dose infusion was approximately dose proportional across 0.6 to 3.3 mg/kg doses once every 3 weeks (27) and 1.6 to 2.2 mg/kg doses once every 2 weeks. The mean concentration–time curves for Teliso-V conjugate, total antibody, and MMAE after single infusion of Teliso-V 2.7 mg/kg dose in the once every 3 weeks schedule, and of 1.9 mg/kg dose in the once every 2 weeks schedule are represented in Fig. 1. The mean harmonic half-life was 2 to 4 days for Teliso-V conjugate and total antibody, and approximately 5 days for free MMAE.

The median predicted trough plasma concentration (C_min) using population PK modeling (29) was higher for the 1.9 mg/kg once every 2 weeks (0.96 μg/mL) than the 2.7 mg/kg once every 3 weeks (0.25 μg/mL) dosing schedule (Supplementary Table S3). Exposure-response analyses predicted a higher probability of achieving objective responses (31% vs. 20%) and of grade ≥2 peripheral neuropathy occurrence (33% vs. 17%) for the 1.9 mg/kg once every 2 weeks regimen compared with the 2.7 mg/kg once every 3 weeks regimen.

The 1.9 mg/kg once every 2 weeks schedule resulted in approximately 3.8-fold higher predicted C_min, as compared with the 2.7 mg/kg once every 3 weeks RP2D schedule, with an overall similar total weekly dose. Although no DLTs were observed with either the 1.9 mg/kg or the highest tested 2.2 mg/kg once every 2 weeks doses, the clinical efficacy and safety data, the rate of late-onset peripheral neuropathy (which may be associated with cumulative dose), similarity of total weekly dose to once every 3 weeks RP2D, and considerations related to the balance between achievable duration of dosing and dose intensity led to the nomination of 1.9 mg/kg as RP2D for the once every 2 weeks schedule.

Among the 40 patients included in the efficacy-evaluable population, efficacy data were analyzed by dosing schedule cohorts and by NSCLC histology.

Overall, 9 of 40 [23%; 95% confidence interval (CI), 10.8–38.5] patients achieved confirmed objective response (Table 4), including 1 (3%) patient with CR (once every 2 weeks cohort) and 8 (20%) patients with PR; ORR was 28% (95% CI, 9.7–53.5; 5 of 18 patients) in once every 2 weeks and 18% (95% CI, 5.2–40.3; 4 of 22 patients) in once every 3 weeks cohorts. Median DOR was 8.7 months (95% CI, 5.5–10.6) and the disease control rate was 70% (95% CI, 53.5–83.4). Two (5%) patients (1 each in once every 2 weeks and once every 3 weeks cohorts) had unconfirmed PRs, 19 (48%) patients (9 in once every 2 weeks and 10 in once every 3 weeks cohorts) had stable disease (SD), and 10 (25%) patients (3 in once every 2 weeks and 7 in once every 3 weeks cohorts) had PD as best response. Percentage change to nadir in the sum of diameters of target lesions in the 38 patients with one or more postdose tumor assessment are represented in Fig. 2A. The PFS curves are shown in Fig. 2B.

Among 33 patients with nonsquamous NSCLC, 6 (18%) had confirmed objective responses (Table 4). In once every 2 weeks cohorts, the ORR was 31% (95% CI, 11.0–58.7; 5 of 16 patients) and in once every 3 weeks cohorts, the ORR was 6% (95% CI, 0.1–28.7; 1 of 17 patients). For patients with squamous NSCLC (n = 7) the ORR was 43% (95% CI, 9.9–81.6; 3 of 7 patients); all responses were in the once every 3 weeks cohort.

Fifteen (37.5%) patients in the efficacy-evaluable population had high c-Met H-scores of 225 or above, and this population was included in an exploratory efficacy analysis. All these patients had nonsquamous NSCLC (45.5% of all evaluable nonsquamous NSCLC), 7 in once every 2 weeks and 8 in once every 3 weeks Teliso-V cohorts. Four objective responses (ORR = 26.7%; 95% CI, 7.8–55.1) were observed in this subgroup, 3 in once every 2 weeks (ORR = 43%; 95% CI, 9.9–81.6), and 1 in once every 3 weeks (ORR = 13%; 95% CI, 0.3–52.7) Teliso-V cohorts. Five of 25 patients with an H-score of 150 to 224 had an objective response (ORR = 20%; 95% CI, 6.8–40.7). The median PFS in once every 2 weeks cohorts was 8.0 months (range, 1.2–9.1) and the median treatment duration was 19.6 weeks (range, 0.1–60.1). For patients in once every 3 weeks cohorts, the median PFS was not reached (1.2–not estimable) and median treatment duration was 6.1 weeks (range, 0.1–57.1).

Five patients (3 in once every 2 weeks, 2 in once every 3 weeks cohorts) had MET amplification identified based either on site reporting or on centrally performed circulating tumor DNA analysis. Two patients with MET amplification were included in the efficacy-evaluable cohort: 1 had an objective response and 1 had SD. The patient with a MET exon 14 skipping mutation was a nonresponder whose best response was PD (c-Met H-score 190). In addition, 2 patients with sensitizing EGFR mutations (L858R or del19) were included in the efficacy-evaluable population, and these were both nonresponders (PD; c-Met H-scores 245 and 170).

The c-Met pathway is commonly dysregulated in solid tumors, at times as a major oncogenic driver event and at times as a passenger or paraneoplastic event. Several new agents that block this pathway have been developed over the past years, including small molecules that inhibit c-Met tyrosine kinase activity and downstream signaling, as well as antibodies against c-Met or hepatocyte growth factor. c-Met TKIs have shown meaningful antitumor activity in patients with MET oncogene-addicted tumors harboring MET exon 14 skip mutations, and, to a lesser extent, MET amplification (17, 30–32). The c-Met TKIs tepotinib and capmatinib have recently received regulatory approvals in NSCLC with MET exon 14 skip mutations (33, 34). However, efficacy of agents targeting c-Met signaling in patients with c-Met–overexpressing tumors that lack MET exon 14 skipping mutations or amplification has been disappointing (26, 35–38). Although MET genomic alterations compatible with MET oncogene addiction are only present in approximately 4% of patients with NSCLC, as many as 30% to 50% of patients with NSCLC have tumors that overexpress c-Met (19, 20, 39).

Teliso-V is an ADC targeted to c-Met that is tolerated with a manageable safety profile when administered as monotherapy at the defined RP2D of 2.7 mg/kg once every 3 weeks dosing schedule (27). In addition, ≥2.4 mg/kg doses of Teliso-V once every 3 weeks showed preliminary antitumor activity in patients with c-Met–overexpressing NSCLC, including those who had tumors lacking MET amplification or MET exon 14 mutations (27). However, 2.7 mg/kg doses of Teliso-V once every 3 weeks failed to meet prespecified response criteria in patients with c-Met–positive squamous cell NSCLC in the Lung-MAP S1400K clinical trial (40). During this trial, there were also three grade 5 events: two cases of pneumonitis in patients who were immune checkpoint inhibitor refractory, and one case of bronchopulmonary hemorrhage in an immune checkpoint inhibitor–naive patient. Although the Lung-MAP S1400K trial was terminated, Teliso-V 1.9 mg/kg once every 2 weeks is being investigated in both squamous and nonsquamous NSCLC in an ongoing phase II study (NCT03539536).

In this study, the 2.7 mg/kg Teliso-V once every 3 weeks dosing regimen was further evaluated and the manageable safety profile was confirmed in a larger cohort of patients with c-Met+ NSCLC. In addition, an alternative Teliso-V monotherapy once every 2 weeks schedule was assessed at 1.6, 1.9, and 2.2 mg/kg doses in patients with c-Met+ NSCLC, and the Teliso-V 1.9 mg/kg dose was selected for the once every 2 weeks dose-expansion phase on the basis of its safety and PK profile. Teliso-V 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks yielded approximately dose-proportional systemic exposures, with total antibody and conjugate exposures being highly correlated after single-dose infusion (Fig. 1). The most frequent AEs (in >30% of patients) were peripheral neuropathy (57%; all types), fatigue (50%), nausea (39%), and dizziness (32%) in once every 2 weeks dosing cohorts, and fatigue (58%), nausea (38%), and dyspnea (33%) in once every 3 weeks cohorts.

Peripheral neuropathy is an expected class toxicity of antimicrotubule agents, frequently observed following treatment with MMAE-based ADCs in patients with hematologic and solid tumors (41). Moreover, in this study, a large proportion of patients either presented with baseline neuropathy (31%) or had received previous treatment with antimicrotubule agents (65%) and/or other neurotoxic chemotherapy (73%; Table 1), which are well-known risk factors for neuropathy. Despite this, exposure-safety analyses did not identify prior history of peripheral neuropathy or prior therapy with neurotoxic agents as significant covariates; the small patient sample size may impact the results. However, a trend to higher rate of peripheral neuropathy was observed in patients who had received a prior therapy with microtubule inhibitors (Supplementary Table S2). Peripheral neuropathy associated with Teliso-V was mostly sensory and generally mild or moderate in severity. Grade 3 peripheral neuropathy occurred in only 3 patients, 2 in the once every 2 weeks cohort and 1 in the once every 3 weeks cohort.

The main difference in the toxicity profile between the two schedules was the higher incidence of peripheral neuropathy (all types) observed in the ≥1.6 mg/kg Teliso-V once every 2 weeks cohorts compared with ≥2.4 mg/kg once every 3 weeks (57% vs. 25%). Significantly, median Teliso-V treatment duration was approximately three-fold longer in once every 2 weeks (19.6 weeks) than in once every 3 weeks (6.1 weeks) cohorts, which may have contributed to the higher incidence of peripheral neuropathy observed in patients following the Teliso-V once every 2 weeks regimen. Peripheral neuropathy was considered related to Teliso-V in 13 of 16 cases in once every 2 weeks cohorts and 5 of 6 cases in once every 3 weeks cohorts. The median time to onset of neuropathy was similar in both dosing regimens, whereas its median duration appeared to be slightly longer for patients in once every 3 weeks cohorts (3 vs. 5 months; Supplementary Table S2). A greater incidence of peripheral neuropathy has also been observed with other MMAE-containing ADCs when they are administered at a higher frequency, such as brentuximab vedotin, an FDA-approved ADC that uses MMAE payload (42, 43), or glembatumumab vedotin (44). In line with this observation, the higher minimum trough concentration reached with the 1.9 mg/kg once every 2 weeks dosing regimen compared with 2.7 mg/kg once every 3 weeks was identified in exposure-safety analyses as a potential reason for the greater probability for grade ≥2 peripheral neuropathy with Teliso-V 1.9 mg/kg once every 2 weeks (Supplementary Table S3).

Overall antitumor objective responses were observed in 9 of 40 patients (23%), which is notable in this highly pretreated (median three prior therapies) population with advanced disease characterized by a large baseline size of target lesions (>100 mm in 32% of patients). Responses were achieved in 3 of 7 (43%) patients with squamous and in 6 of 33 (18%) with nonsquamous NSCLC. Responses were of significant duration (median DOR 4.8 and 10.6 months, respectively). Neither NSCLC histology nor c-Met H-scores were found to be significant covariates in exposure-efficacy analyses. Although response rates appeared to be higher for patients who had c-Met H-scores of 225 or above than for patients with c-Met H-scores of 150 to 224, no clear conclusions can be drawn from this observation due to the limited number of patients analyzed. All 3 responders (3 PR) with squamous NSCLC were enrolled in once every 3 weeks cohorts, and among the 6 responders with nonsquamous NSCLC, 5 received Teliso-V once every 2 weeks (1 CR and 4 PR) and 1 Teliso-V once every 3 weeks (PR). Predictions from the exposure-efficacy analyses are in line with the higher efficacy of Teliso-V 1.9 mg/kg once every 2 weeks dosing regimen in patients with nonsquamous NSCLC (Supplementary Table S3). Notably, the majority of responses (8 of 9) occurred in patients without known MET amplification or MET exon 14 skip mutations. Other studies are further evaluating c-Met protein expression as a potential predictive marker.

Study limitations include predefining c-Met+ as an H-score of ≥150 on the basis of results from preclinical studies and incomplete data on MET amplification and MET exon 14 skip mutation status (not all patients were tested due to tissue availability limitations). The use of c-Met expression levels as a biomarker has been hampered, in part, by the heterogeneous c-Met expression levels within tumors and the availability in most cases of only archival tissue obtained at the time of diagnosis for analyses. Consequently, a standardized method to quantify c-Met levels is still lacking and the c-Met expression threshold required for anticancer activity has not been validated. The semiquantitative method used here to define c-Met+ shows correlation between membrane c-Met receptor intensity by IHC and MET mRNA levels (27). The ORR of 22% observed in the population of patients with a c-Met H-score ≥150 combined with lack of correlation between the level of c-Met expression and antitumor activity within this preselected population suggests that although the ≥150 H-score cutoff could represent a valid c-Met expression threshold for Teliso-V efficacy, additional resistance mechanisms independent of c-Met expression may limit antitumor responses.

In conclusion, Teliso-V monotherapy was tolerated at both the 1.9 mg/kg once every 2 weeks and 2.7 mg/kg once every 3 weeks dosing schedules in patients with NSCLC. In addition, Teliso-V monotherapy demonstrated encouraging preliminary efficacy in heavily pretreated patients with advanced c-Met–expressing NSCLC. On the basis of the higher ORR in patients with nonsquamous NSCLC in Teliso-V once every 2 weeks cohorts, the higher C_min reached with the once every 2 weeks schedule, and the similar tolerability of both schedules, the 1.9 mg/kg once every 2 weeks dosing regimen was selected as the Teliso-V monotherapy RP2D for further clinical development. Additional studies with Teliso-V as monotherapy and in combination therapy in patients with lung cancer are ongoing.

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D.R. Camidge reports personal fees from AbbVie outside the submitted work. D. Morgensztern reports other support from AbbVie, Gilead, Bristol Myers Squibb, G1 Therapeutics, PharmaMar, Lilly, and Takeda outside the submitted work. R.S. Heist reports other support from Novartis, Daiichi Sankyo, and EMD Serono, as well as grants from Novartis, Daiichi Sankyo, AbbVie, Roche, Corvus, Turning Point, Lilly, Exelixis, and Mirati outside the submitted work. E. Vokes reports personal fees from AbbVie, AstraZeneca, BeiGene, BioNTech, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Merck, and Novartis outside the submitted work. J.W. Goldman reports grants and personal fees from AbbVie during the conduct of the study; J.W. Goldman also reports grants, personal fees, and other support from AstraZeneca, as well as grants and personal fees from Janssen and Genentech outside the submitted work. D.S. Hong reports grants from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, Medimmune, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, Seagen, Takeda, Turning Point Therapeutics, Verstatem, and VM Oncology during the conduct of the study, as well as other support from Adaptimmune, Alpha Insights, Acuta, Alkermes, Amgen, Aumbiosciences, Atheneum, Axiom, Barclays, Boxer Capital, BridgeBio, CDR-life AG, COR2ed, COG, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, Ziopharm, Bayer, Genmab, AACR, ASCO, SITC, OncoResponse, and Telperian Inc. outside the submitted work. T.M. Bauer reports grants from Sponsor during the conduct of the study, as well as personal fees from Pfizer, Lilly, BMS, AstraZeneca, Guardant Health, and Foundation Medicine outside the submitted work. J.H. Strickler reports grants and personal fees from AbbVie during the conduct of the study. J.H. Strickler also reports grants and personal fees from Amgen, Genentech, Bayer, Seagen, Silverback Therapeutics, and AstraZeneca; personal fees from Mereo, Natera, Pfizer, Viatris, and Inivata; and grants from AStar D3, Curegenix, Daiichi Sankyo, Exelixis, Leap Therapeutics, Nektar, Sanofi Genzyme, and Gossamer Bio outside the submitted work. E. Angevin reports grants from AbbVie during the conduct of the study, as well as personal fees from Roche, MSD, GSK, Medimmune, and Celgene outside the submitted work. M. Motwani reports other support from AbbVie outside the submitted work. A. Parikh reports employment and ownership of stock with AbbVie Inc. B.A. Bach reports employment and ownership of stock with AbbVie Inc. J. Wu reports employment and ownership of stock with AbbVie Inc. P.B. Komarnitsky reports other support from AbbVie outside the submitted work. K. Kelly reports grants from AbbVie during the conduct of the study, as well as grants and personal fees from AbbVie outside the submitted work. No disclosures were reported by the other authors.

D.R. Camidge: Conceptualization, investigation, writing–original draft, writing–review and editing. D. Morgensztern: Investigation, writing–original draft, writing–review and editing. R.S. Heist: Investigation, writing–original draft, writing–review and editing. M. Barve: Investigation, writing–original draft, writing–review and editing. E. Vokes: Investigation, writing–original draft, writing–review and editing. J.W. Goldman: Investigation, writing–original draft, writing–review and editing. D.S. Hong: Investigation, writing–original draft, writing–review and editing. T.M. Bauer: Investigation, writing–original draft, writing–review and editing. J.H. Strickler: Investigation, writing–original draft, writing–review and editing. E. Angevin: Investigation, writing–original draft, writing–review and editing. M. Motwani: Conceptualization, investigation, writing–original draft, writing–review and editing. A. Parikh: Conceptualization, investigation, writing–original draft, writing–review and editing. Z. Sun: Conceptualization, investigation, writing–original draft, writing–review and editing. B.A. Bach: Conceptualization, investigation, writing–original draft, writing–review and editing. J. Wu: Conceptualization, investigation, writing–original draft, writing–review and editing. P.B. Komarnitsky: Conceptualization, investigation, writing–original draft, writing–review and editing. K. Kelly: Investigation, writing–original draft, writing–review and editing.

AbbVie Inc. and the authors thank the patients who participated in this clinical trial, the study coordinators, and support staff. The authors would like to thank Louie Naumovski from AbbVie for his contributions to the study and publication. Medical writing support was provided by Iratxe Abarrategui, PhD, CMPP, from Aptitude Health, The Hague, The Netherlands, and funded by AbbVie Inc. AbbVie Inc. provided financial support for the study (NCT02099058) and participated in the design, study conduct, analysis, and interpretation of data, as well as the writing, review, and approval of the manuscript. ABBV-399 utilizes ABT-700, an antibody licensed from Pierre Fabre, and ADC technology licensed from Seattle Genetics.

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