Abstract CT223: Updated efficacy and safety from the phase 3 CROWN study of first-line lorlatinib vs crizotinib in advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC)

Abstract

Background: Lorlatinib improved progression-free survival (PFS) and demonstrated intracranial (IC) activity in patients (pts) with untreated advanced ALK+ NSCLC in the interim analysis of the randomized, Phase 3, CROWN study of lorlatinib vs crizotinib. We report updated 36-month follow-up data. Methods: 296 pts with previously untreated advanced ALK+ NSCLC were randomized 1:1 to oral lorlatinib (100 mg QD; n=149) or crizotinib (250 mg BID; n=147), stratified by presence of CNS metastases (mets) and ethnicity. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints included overall survival, PFS by investigator, and objective response (OR), IC-OR, IC time to progression (IC-TTP), duration of response (DR), IC-DR (all by BICR), and safety. Results: At data cutoff (Sep 20, 2021), median duration of follow-up for PFS was 36.7 months for lorlatinib and 29.3 months for crizotinib. Median PFS by BICR was NR (95% CI, NR-NR) for lorlatinib and 9.3 months (95% CI, 7.6-11.1) for crizotinib (HR, 0.27; 95% CI, 0.18-0.39). PFS by investigator results were similar (Table). For pts with brain mets at baseline (n=37 lorlatinib/n=39 crizotinib), the HR for IC-TTP for lorlatinib vs crizotinib was 0.10 (95% CI, 0.04-0.27), and for pts without brain mets (n=112/n=108) was 0.02 (95% CI, 0.002-0.14). OR, IC-OR, DR, and IC-DR were all improved with lorlatinib vs crizotinib (Table). All-cause grade 3-4 adverse events (AEs) and AEs leading to treatment discontinuation were reported in 76% and 7% of pts with lorlatinib and 57% and 10% of pts with crizotinib, respectively. No new safety signals emerged. Conclusions: These updated long-term data from CROWN confirm the efficacy of lorlatinib over crizotinib in pts with treatment-naïve ALK+ NSCLC, with no new safety signals detected, and support the use of lorlatinib in pts with untreated ALK+ NSCLC with and without brain mets. Summary of other efficacy resultsa Clinical trial information: NCT03052608 Funding: Pfizer Inc. ITT population Lorlatinib(n=149) Crizotinib(n=147) % alive without progression at:12 mo (95% CI) 78 (70–84) 38 (29–47) 24 68 (60–75) 22 (14–30) 36 64 (55–71) 19 (12–27) Median PFS by investigator, mo (95% CI) NR (NR–NR) 9.1 (7.4–10.9) HR (95% CI) 0.19 (0.13–0.27) Confirmed OR, n (%) [95% CI] 115 (77) [70–84] 86 (59) [50–67] Median DR,b mo (95% CI) NR (NR–NR) 9.6 (9.0–12.9) Patients with measurable or nonmeasurable brain metastases at baseline (n=37) (n=39) Median PFS, mo (95% CI) NR (18.2–NR) 7.2 (3.7–9.2) HR (95% CI) 0.21 (0.10–0.44) Confirmed IC-OR, n (%) [95% CI] 24 (65) [48–80] 7 (18) [8–34] Complete response, n (%) 22 (60) 5 (13) Median IC-DR,b mo (95% CI) NR (NR–NR) 9.4 (6.0–11.1) Patients without brain metastases at baseline (n=112) (n=108) Median PFS, mo (95% CI) NR (NR–NR) 11.0 (9.0–14.6) HR (95% CI) 0.29 (0.19–0.44) aBy blinded independent central review unless stated otherwise. bIn patients with a confirmed complete or partial response. CI, confidence interval; DR, duration of response; HR, hazard ratio; ITT, intention- to-treat; NR, not reached; IC, intracranial; OR, objective response; PFS, progression-free survival. Citation Format: Benjamin Solomon, Todd Bauer, Tony Mok, Geoffrey Liu, Julien Mazieres, Filippo de Marinis, Yasushi Goto, Dong-Wan Kim, Yi-Long Wu, Mikhail Dvorkin, Jacek Jassem, Froylán López-López, Ross Soo, Anna Polli, Elisa Dall'O, Laura Iadeluca, Francesca Toffalorio, Enriqueta Felip. Updated efficacy and safety from the phase 3 CROWN study of first-line lorlatinib vs crizotinib in advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT223.

Lorlatinib and compound mutations in ALK+ large-cell neuroendocrine lung carcinoma: a case report

“…#3 in Table 2), while newer, next-generation ALK inhibitors appear to elicit stronger responses: for example, our patient showed a durable, 10-month-long PR to second-line alectinib after early progression within 3 months under first-line crizotinib, and also achieved an 8 monthlong disease stabilization under lorlatinib in the 6 th therapy line (Figure 1, Table 2). Of note, the PFS of 3 months and treatment duration of 5 months observed under crizotinib in our patient were considerably shorter that the median PFS of 10-12 months for upfront use of this drug in phase 3 studies (Solomon et al 2022;Mok et al 2020), while the PFS of 10 and 8 months observed in our patient under subsequent alectinib and lorlatinib, respectively, were not shorter (actually slightly longer) than the 7.1 and 6.6 months reported for these drugs by phase 2 trials in the pretreated setting (Novello et al 2018;Felip et al 2021). It is also noteworthy that resistance to lorlatinib was caused by compound ALK mutations, whose development was facilitated by alectinib, under which the ALK:p.L1196M could emerge (Figure 1H,3D, Figure 3C).…”

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study)

“…Median PFS by BICR was NR (95 % CI, NR-NR) with lorlatinib and 9.3 months (95 % CI, 7.6-11.1 months) with crizotinib (HR, 0.27; 95 % CI, 0.184-0.388). Notably, PFS at 36 months was 63.5 % and 18.9 % for lorlatinib and crizotinib respectively [40].…”

Lorlatinib: new therapeutic options for ALK-positive patients

“…), Senior Researcher of the Department of Oncological Medicinal Methods of Treatment No. 17 (Chemotherapeutic), Blokhin National Medical Research Center of Oncology; 24, Kashirskoye Shosse, Moscow, 115478, Russia; evreutova@rambler.ru Обновленные результаты исследования CROWN после трех лет наблюдения были представлены весной 2022 г. Лорлатиниб продолжает демонстрировать убедительное преимущество над кризотинибом по критерию времени без прогрессирования (HR 0.27) со снижением риска прогрессирования и смерти на 73% [22]. Обращает на себя внимание длительность контроля за интракраниальными проявлениями болезни (рис.…”