1281P - Impact of common germline variants on the toxicity profile and pharmacokinetics of alectinib

Background

Alectinib is a small-molecule kinase inhibitor, that is used as a first-line treatment for anaplastic lymphoma kinase–positive (ALK+) non-small cell lung cancer (NSCLC). Albeit generally well-tolerated, a considerable subset of patients require dose adjustments or treatment interruptions due to drug related toxicity. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of alectinib may upfront identify patients at risk for toxicity.

Methods

In this multicentre observational cohort study in patients with advanced ALK+ NSCLC receiving alectinib treatment, we studied the association between toxicity, pharmacokinetics and genetic variants in ABCB1, CYP3A4, PPAR-α, POR and CYP3A5. Demographic data and adverse events were retrospectively collected from five tertiary hospitals. Dose-normalised alectinib trough levels were calculated from plasma samples obtained in various prospective trials. SNPs were considered significant at p < 0.05.

Results

Among 215 patients, 47% experienced severe toxicity (i.e. grade ≥ 3 toxicity (14% of all patients), or any toxicity resulting in dose reduction (43% of all patients) or treatment termination (6% of all patients)). Patients who experienced severe toxicity had +18·5% (95%CI: 2·9 - 36·6%) higher alectinib trough levels (673 versus 568 ng/mL; p = 0·019). Among homozygous carriers of the PPAR-α 209G>A variant a significant absolute increase in incidence of severe toxicity of 31% (p = 0·018) was present, with similar increases observed for grade ≥ 3 toxicities in patients carrying one or two risk alleles (+11% and +26%; p = 0·024 and 0·004, respectively). In terms of pharmacokinetics, patients who carried at least one CYP3A4*22 allele or were homozygous for PPAR-α 209G>A demonstrated higher trough levels of +30·4% (95%CI: 4·0 - 63·6%; p = 0·022) and +29·9% (95%CI: 1·1 - 66·8%; p = 0·041), respectively.

Conclusions

The presence of PPAR-α 209G>A and CYP3A4*22 variants significantly increases alectinib-induced toxicity and exposure. Implementing pre-emptive genotyping for these variants with subsequent dose adjustments could provide a practical approach to reduce adverse effects in patients treated with alectinib.

Clinical trial identification

Erasmus University Medical Centre Ethics Committee Registration Number: MEC 2022-158.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Erasmus MC Personalized Medicine Fund.

Disclosure

B. Muntinghe: Other, AACR-Bristol Myers Squibb Scholar-in-Training award 2022 travel support to attend the AACR Annual Meeting 2022: AACR - Bristol Myers Squibb. M.S. Paats: Financial Interests, Institutional, Advisory Board: Amgen, Eli Lily, Janssen, Merck, Pfizer; Financial Interests, Institutional, Invited Speaker: Chiesi, Eli Lilly, Roche. I. Bahce: Financial Interests, Institutional, Advisory Board: BMS, Boehringer Ingelheim, AstraZeneca, Roche, Pfizer, Takeda, MSD; Financial Interests, Institutional, Research Grant: BMS, Boehringer Ingelheim, AstraZeneca. L.E. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, AnHeart; Financial Interests, Institutional, Invited Speaker, for educational webinar: AstraZeneca, Lilly; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: Benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, Sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: Medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: Gilead; Financial Interests, Institutional, Local PI: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, AbbVie, MSD, Gilead; Non-Financial Interests, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Other, vice chair scientific committee: Dutch Thoracic Group. A.J. Van Der Wekken: Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Janssen, Lilly, Merck KGaA, Novartis, Roche, Pfizer, Takeda; Financial Interests, Institutional, Speaker, Consultant, Advisor, Invited Speaker: Pfizer, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Boehringer Ingelheim, Roche, Pfizer, Takeda. A.C. Dingemans: Financial Interests, Institutional, Advisory Board: Roche, Amgen, Bayer, AstraZeneca, Boehringer Ingelheim, Jansen, Mirati; Financial Interests, Institutional, Invited Speaker: Lilly, Jansen; Financial Interests, Institutional, Other, IDMC: Roche; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Local PI: Lilly, Amgen, Daiichi Sankyo, JNJ, Mirati; Financial Interests, Institutional, Coordinating PI: Roche; Financial Interests, Institutional, Steering Committee Member: Roche; Non-Financial Interests, Other, Chair EORTC lung cancer group: EORTC; Non-Financial Interests, Member: IASCL, ASCO, AACR. R.H. Mathijssen: Financial Interests, Institutional, Invited Speaker: Bayer, Novartis; Financial Interests, Institutional, Advisory Board: Servier, NaDeNo Nanoscience; Financial Interests, Institutional, Research Grant, Investigator-initiated research: Astellas, Bayer, Cristal Therapeutics, Pfizer, Roche, Sanofi, Servier, Boehringer-Ingelheim, Novartis, Nordic Pharma; Financial Interests, Institutional, Coordinating PI: Pamgene; Financial Interests, Institutional, Funding: Echo Pharmaceuticals, Deuter Oncology. All other authors have declared no conflicts of interest.