Exposure-response analyses for the MET inhibitor tepotinib including patients in the pivotal VISION trial: support for dosage recommendations

Abstract

Purpose: Tepotinib is a highly selective MET inhibitor approved for treatment of non-small cell lung cancer (NSCLC) harboring METex14 skipping alterations. Analyses presented herein evaluated the relationship between tepotinib exposure, and efficacy and safety outcomes.

Methods: Exposure-efficacy analyses included data from an ongoing phase 2 study (VISION) investigating 500 mg/day tepotinib in NSCLC harboring METex14 skipping alterations. Efficacy endpoints included objective response, duration of response, and progression-free survival. Exposure-safety analyses included data from VISION, plus four completed studies in advanced solid tumors/hepatocellular carcinoma (30-1400 mg). Safety endpoints included edema, serum albumin, creatinine, amylase, lipase, alanine aminotransferase, aspartate aminotransferase, and QT interval corrected using Fridericia's method (QTcF).

Results: Tepotinib exhibited flat exposure-efficacy relationships for all endpoints within the exposure range observed with 500 mg/day. Tepotinib also exhibited flat exposure-safety relationships for all endpoints within the exposure range observed with 30-1400 mg doses. Edema is the most frequently reported adverse event and the most frequent cause of tepotinib dose reductions and interruptions; however, the effect plateaued at low exposures. Concentration-QTc analyses using data from 30 to 1400 mg tepotinib resulted in the upper bounds of the 90% confidence interval being less than 10 ms for the mean exposures at the therapeutic (500 mg) and supratherapeutic (1000 mg) doses.

Conclusions: These analyses provide important quantitative pharmacologic support for benefit/risk assessment of the 500 mg/day dosage of tepotinib as being appropriate for the treatment of NSCLC harboring METex14 skipping alterations.

Registration numbers: NCT01014936, NCT01832506, NCT01988493, NCT02115373, NCT02864992.

Keywords: Dose selection; METex14 skipping alteration; NSCLC; Targeted therapies; Tyrosine kinase inhibitor.

Conflict of interest statement

Wenyuan Xiong was employed by Merck Healthcare KGaA, Darmstadt, Germany for the duration of the study. Sofia Friberg Hietala and Joachim Nyberg are employees of Pharmetheus AB, Sweden. Orestis Papasouliotis, Andreas Johne, Karin Berghoff, Kosalaram Goteti, Jennifer Dong, Pascal Girard, Karthik Venkatakrishnan, and Rainer Strotmann are employees of Merck Healthcare KGaA, Darmstadt, Germany.

© 2022. The Author(s).

Figures

Fig. 1

Association between tepotinib exposure and independently assessed (panels a–c) or investigator-assessed (panel a) efficacy outcomes in patients with NSCLC and MET exon 14 skipping alterations. Objective response rate (a), duration of response (b), and progression-free survival (c) by tepotinib AUCτ,ss quartile. OR and PFS analyses include all 146 patients; duration of response is based on 66 patients who attained an objective response. The lines represent the Clopper–Pearson 95% CI and points are observed OR per AUC quartile (dark gray represents OR assessed by independent evaluation, and light gray represents OR assessed by investigator review). In panels b and c, shaded areas represent 95% confidence intervals. AUCτ,ss, area under the curve at steady state; CI, confidence interval; NSCLC, non-small cell lung cancer; OR, objective response; ORR, objective response rate; PFS, progression-free survival

Fig. 2

Relationship between tepotinib AUC24h quartile and edema events and change in serum albumin levels. Panel a presents time-to-first edema event stratified by tepotinib AUC24h quartile on the day of the edema event or day of censoring. Panel b presents the distribution of mean tepotinib AUC24h during 1 week prior to an edema event according to edema severity (maximum severity per participant). Panel c presents impact of age on the predicted risk of edema based on the final TTE model with model-estimated hazard ratios for edema relative to a typical participant of median age of 66 years (the closed symbols represent the median hazard ratio for the applicable age category. The whiskers represent the 90% CI of the median values, based on 100 bootstrap datasets. The vertical black line represents the hazard ratio for a typical patient in the analysis data set, aged 66 years). Panel d presents the visual predictive check of the indirect response model of serum albumin with an inhibitory effect of tepotinib exposure on albumin formation. In panels a and d, shaded areas represent 95% CI. In panel e, solid and dashed red lines represent the observed median, 5th and 95th percentiles; the shaded red area represents the 95% CI of the model predicted median, and the shaded blue areas represent the 95% CI of the model predicted 5th and 95th percentiles. Dots are observed values. Panel e presents a Kaplan–Meier analysis of time-to-first edema event stratified by quartiles of baseline serum albumin. Panel f presents mean change from baseline serum albumin according to edema severity. AUC24h, 24-h area under the curve; CI, confidence interval; TTE, time-to-event

Fig. 2

Relationship between tepotinib AUC24h quartile and edema events and change in serum albumin levels. Panel a presents time-to-first edema event stratified by tepotinib AUC24h quartile on the day of the edema event or day of censoring. Panel b presents the distribution of mean tepotinib AUC24h during 1 week prior to an edema event according to edema severity (maximum severity per participant). Panel c presents impact of age on the predicted risk of edema based on the final TTE model with model-estimated hazard ratios for edema relative to a typical participant of median age of 66 years (the closed symbols represent the median hazard ratio for the applicable age category. The whiskers represent the 90% CI of the median values, based on 100 bootstrap datasets. The vertical black line represents the hazard ratio for a typical patient in the analysis data set, aged 66 years). Panel d presents the visual predictive check of the indirect response model of serum albumin with an inhibitory effect of tepotinib exposure on albumin formation. In panels a and d, shaded areas represent 95% CI. In panel e, solid and dashed red lines represent the observed median, 5th and 95th percentiles; the shaded red area represents the 95% CI of the model predicted median, and the shaded blue areas represent the 95% CI of the model predicted 5th and 95th percentiles. Dots are observed values. Panel e presents a Kaplan–Meier analysis of time-to-first edema event stratified by quartiles of baseline serum albumin. Panel f presents mean change from baseline serum albumin according to edema severity. AUC24h, 24-h area under the curve; CI, confidence interval; TTE, time-to-event

Fig. 2

Relationship between tepotinib AUC24h quartile and edema events and change in serum albumin levels. Panel a presents time-to-first edema event stratified by tepotinib AUC24h quartile on the day of the edema event or day of censoring. Panel b presents the distribution of mean tepotinib AUC24h during 1 week prior to an edema event according to edema severity (maximum severity per participant). Panel c presents impact of age on the predicted risk of edema based on the final TTE model with model-estimated hazard ratios for edema relative to a typical participant of median age of 66 years (the closed symbols represent the median hazard ratio for the applicable age category. The whiskers represent the 90% CI of the median values, based on 100 bootstrap datasets. The vertical black line represents the hazard ratio for a typical patient in the analysis data set, aged 66 years). Panel d presents the visual predictive check of the indirect response model of serum albumin with an inhibitory effect of tepotinib exposure on albumin formation. In panels a and d, shaded areas represent 95% CI. In panel e, solid and dashed red lines represent the observed median, 5th and 95th percentiles; the shaded red area represents the 95% CI of the model predicted median, and the shaded blue areas represent the 95% CI of the model predicted 5th and 95th percentiles. Dots are observed values. Panel e presents a Kaplan–Meier analysis of time-to-first edema event stratified by quartiles of baseline serum albumin. Panel f presents mean change from baseline serum albumin according to edema severity. AUC24h, 24-h area under the curve; CI, confidence interval; TTE, time-to-event

Fig. 3

Change in serum creatinine following tepotinib administration. Panel a presents the change from baseline in serum creatinine concentrations following first dose of study medication for all individual patients. Each line represents the data for one participant. The solid blue line is a LOESS smooth. The y-axis is truncated at -50 and 200 μmol/L and the x-axis at 365 days. Panel b presents the individual maximum change from baseline in serum creatinine concentration versus tepotinib AUC24h. Dots represent observations. The solid black line is a LOESS smooth. The vertical blue lines indicate the PK model simulated median (solid line), 5th and 95th percentiles (dashed lines) of AUCτ,ss at a dose of 500 mg. Panel c presents individual serum creatinine concentrations taken from 56 observations from 11 patients over time following a single administration of tepotinib (500 mg) in healthy volunteers in study 007. The black lines represent individual patient data and the blue line is a LOESS smooth. AUC24h, 24-h area under the curve; AUCτ,ss, area under the curve at steady state; LOESS, locally estimated scatterplot smoothing; PK, pharmacokinetics

Fig. 4

Relationship of ΔQTcF interval versus tepotinib plasma concentration. The model derived predicted population ΔQTcF from baseline is shown as the continuous blue line and the two-sided 90% bootstrapped confidence limits of predicted mean ΔQTcF are shown as broken lines for pooled study patients. The vertical red lines correspond to geometric mean Cmax at steady state in the 500 mg and 1400 mg dose levels. The brown horizontal lines represent the regulatory threshold of potential concern of 10 ms, and an additional 20 ms reference line as a threshold of potential clinical relevance applicable for oncology drugs. Open symbols represent observed data. CI, confidence interval; QTcF, QT interval corrected using Fredericia’s formula

Fig. 5

Relationship between tepotinib exposure and grade ≥ 3 adverse event, and dose reduction due to an adverse event. Panel a presents Kaplan–Meier analysis of time-to-first grade ≥ 3 AE stratified according to tepotinib exposure quartile. Panel b presents Kaplan–Meier analysis of time-to-first dose reduction due to an AE stratified according to tepotinib exposure quartile. Shaded areas represent 95% confidence intervals. AE, adverse event; AUCτ,ss, area under the curve at steady state