2577 - Intracranial and extracranial efficacy of lorlatinib in the post second-generation ALK tyrosine kinase inhibitor (TKI) setting

Background

The selective, potent, brain-penetrant 3^rd-generation (gen) ALK TKI lorlatinib is approved for the treatment of patients (pts) with ALK+ metastatic non-small cell lung cancer (NSCLC) whose disease has progressed following 2^nd-gen ALK TKIs.

Methods

In this ongoing ph 2 study (NCT01970865), 139 pts with ALK+ advanced NSCLC with ≥1 prior 2^nd-gen ALK TKI, ± chemotherapy (CT), were enrolled in expansion cohorts—EXP3B, EXP4 and EXP5—based on treatment history. Overall, intracranial (IC) and extracranial (EC) antitumor activity were assessed by independent central review, per modified RECIST v1.1. Recurrent event analysis on within-patient time to progression (TTP) was conducted comparing TTP on lorlatinib with TTP on the last prior 2^nd-gen ALK TKI.

Results

Of the 139 pts with ≥1 prior 2^nd-gen ALK TKI (EXP3B–5), 28 had 1 prior 2^nd-gen ALK TKI as their only ALK TKI (EXP3B), 65 had 2 prior ALK TKIs (EXP4) and 46 had 3 prior ALK TKIs (EXP5). As of data cutoff (02 Feb 2018), the ORR in EXP3B–5 was 40% (95% CI 32–49), median duration of response (DOR) was 7.1 mo (95% CI 5.6–24.4) and median PFS was 6.9 mo (95% CI 5.4–8.2). Responses were observed in pts who had also received prior CT (n/N=40/93; ORR 43% [95% CI 33–54]) as well as in CT-naïve pts (n/N=16/46; ORR 35% [95% CI 21–50]). IC- and EC-ORR in EXP3B–5 and individual cohorts are shown in the table. In EXP3B–5, median IC DOR was 12.4 mo (95% CI 5.8–NR) and median EC DOR was 9.7 mo (95% CI 6.1–NR). Based on 121 evaluable pts, no significant differences were observed in terms of TTP between lorlatinib and last prior 2^nd-gen ALK TKI (HR 0.86, 95% CI 0.64–1.16).Table:

1487PD

Patients with ≥1 measurable CNS metastases at baseline

EC, extracranial; IC, intracranial; ORR, objective response rate

Conclusions

In the post 2^nd-gen ALK TKI setting, lorlatinib showed clinically meaningful antitumor activity in both IC and EC compartments, with a trend towards elevated IC vs EC ORR particularly in pts with fewer lines of therapy. Despite pts having a worse prognosis at a later line, lorlatinib showed a similar TTP compared with the last 2^nd-gen ALK TKI.

Clinical trial identification

NCT01970865.

Editorial acknowledgement

Jade Drummond of inScience Communications, Springer Healthcare, Chester, UK; funded by Pfizer Inc.

Legal entity responsible for the study

Pfizer Inc.

Funding

Pfizer Inc.

Disclosure

D.R. Camidge: Honoraria (self): Roche; Honoraria (self): G1 Therapeutics; Honoraria (self): Mersana; Honoraria (self), Research grant / Funding (self): Takeda; Honoraria (self): AstraZeneca; Honoraria (self): Genoptix; Honoraria (self): Ignyta; Honoraria (self): Daiichi Sankyo; Honoraria (self): Hansoh; Honoraria (self): Lycera; Honoraria (self): Biothera; Honoraria (self): Revolution Medicines. B.J. Solomon: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Eisai; Licensing / Royalties: Veristrat (Biodesix); Licensing / Royalties: UpToDate; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Institution: Merck Sharp & Dohme; Advisory / Consultancy, Research grant / Funding (institution), Institution: Pfizer; Advisory / Consultancy, Institution: Genentech. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: Guardant Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Research grant / Funding (institution): Fundación Merck Salud; Research grant / Funding (institution): EMD Serono. B. Besse: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Onxeo; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Inivata; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Biogen; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): MSD Oncology; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tiziana Therapeutics. A. Bearz: Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. S. Peters: Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca. F. Toffalorio: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. A. Abbattista: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. H. Thurm: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. G. Peltz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. R. Wiltshire: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): ARIAD Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo Pharmaceuticals; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharma; Research grant / Funding (institution): TP Therapeutics.