ESMO 2022 Phase III CROWN Study 3-year follow-up results updated, Asian subgroup data published

Editor: Xiaoyuan

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The European Society for Medical Oncology (ESMO) Annual Meeting is the most prestigious and influential oncology conference
in Europe.
The 2022 ESMO Conference will be held offline (Paris, France) and online from September 9 to 13, 2022, covering basic research, translational research and the latest clinical research progress, and will provide a broad and excellent academic platform
for clinical practice and multidisciplinary discussion.
A number of blockbuster studies in the field of lung cancer were presented at this year's ESMO Conference
.

At this year's ESMO conference, the updated results of the Phase III CROWN study were announced, and the team of Professor Wu Yilong of Guangdong Provincial People's Hospital announced the results
of the Asian subgroup of the CROWN study.
Details are as follows:

The team of Professor Wu Yilong and Professor Zhou Qing: The results of the Asian subgroup of the phase III CROWN study were announced

Background:

Lolatinib is a third-generation ALK TKI
with blood-brain barrier penetration.
Previous phase III CROWN studies (NCT03052608) have shown that lorlatinib improves progression-free survival (PFS)
in patients with treatment-naïve advanced ALK rearrangement-positive non-small cell lung cancer (NSCLC).
。 At a median follow-up of 18.
3 months, the median PFS in the lorlatinib group and crizotinib group was not reached and 9.
3 months, respectively (HR=0.
28, P<0.
001), and lorlatinib showed good intracranial (IC) antitumor activity in patients with measurable brain metastases at baseline, with an objective response rate (ORR) of 82%, and an ORR of 23%<b12> in the crizotinib group.
At this year's ESMO conference, the team of Professor Wu Yilong and Professor Zhou Qing announced the results
of the 36-month follow-up of the Asian subgroup.

Method:

Enrolled patients were randomized to receive lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily) in a 1:1 ratio, with stratified factors including brain metastases (yes/no) and ethnicity (Asian/non-Asian).

The primary endpoint was PFS
assessed by an Independent Central Review of Blinding (BICR).
Key secondary endpoints included ORR, intracranial ORR (IC ORR), TIME TO IC PROGRESSION (IC TTP), AND SAFETY
.

Study design

Outcome:

In the Asian subgroup, a total of 120 patients were randomized to lorlatinib (n=59) or crizotinib (n=61).

As of the data cut-off on 20 September 2021, the median PFS (as assessed by BICR) was not achieved in the lorlatinib and crizotinib groups (HR=0.
40; 95% CI, 0.
230-0.
710),
respectively.

PFS results

Lolatinib significantly improves ORR (78 versus 57 percent) and IC ORR (73 versus 20 percent)
compared with crizotinib.

Efficacy analysis

Compared with crizotinib, the median IC TTP was better in the lorlatinib and crizotinib groups, with median IC TTP not reaching and 16.
6 months, respectively (HR=0.
03, 95% CI, 0.
004-0.
200).

IC TTP results

80% and 8% vs 62% and 13% of patients in the lorlatinib and crizotinib groups experienced adverse events (TEAEs) and TEAE leading to treatment discontinuation in all-cause grade 3/4 treatment
, respectively.
No new adverse events
were identified.

Security analysis

Conclusion:

The efficacy and safety results of the CROWN study in the Asian subgroup were consistent
with the general population.
Research data support lorlatinib as a first-line treatment option
for patients with baseline ALK rearrangement positive Asian NSCLC with or without brain metastases.

Phase III CRAM study: an update on long-term intracranial safety and efficacy results

Background:

Results from the Phase III CROWN study (NCT03052608) confirm that lorlatinib, a third-generation ALK inhibitor, provides durable systemic and intracranial antitumor activity
in patients with treatment-naïve ALK-rearranged-positive NSCLC compared with crizotinib.
Previous analysis of the CROWN study found an increase
in CNS toxicity in the lorlatinib group compared with the crizotinib group.
Therefore, the investigators performed a 3-year follow-up to further evaluate the long-term intracranial safety and efficacy
of lorlatinib.

Method:

A total of 296 patients were randomized 1:1 to oral lorlatinib (100 mg once daily) or crizotinib (250 mg twice daily).

CNS adverse events (AEs) were classified and the incidence of
cognitive, emotional, speech, and psychotic events was calculated between treatment with lorlatinib.
Secondary endpoints included IC-TTP, with IC-TTP landmark analysis
based on 16-week dose reduction.

Outcome:

For patients with baseline brain metastases, the IC-TTP HR for lorlatinib (n=37) vs crizotinib (n=39) was 0.
10 (95% CI, 0.
04-0.
27).

For patients with anencephalacial metastases, the IC-TTP HR of lorlatinib (n=112) versus crizotinib (n=109) was 0.
02 (95% CI, 0.
002-0.
14).

IC TTP in patients with baseline brain metastases

IC TTP in patients without brain metastases at baseline

Among the 149 patients treated with lorlatinib, 37 (24.
8%) patients had all-cause CNS adverse events
at less than 6 months, 14 (11%) patients at 6 months to 1 year of treatment, 18 (15%) patients during 1-2 years of treatment, 10 (10%) patients during 2-3 years of treatment, and only 2 (2%) patients with more than 3 years of treatment.
A total of 103 CNS adverse events
were identified.
Of these, events were controlled in 61 (59.
2%) without any intervention: spontaneous resolution in 32 (31.
1%) patients, improvement in 1 (1.
0%) and no resolution in 28 (27.
2%) patients
.
Twenty-six events were managed
with dose reduction and/or interruption.
CNS adverse events led to discontinuation of 2 patients
.

Over 3 years, the incidence and incidence of adverse events in CNS gradually decreased
over time.

Adverse events gradually decreased over 3 years

IC-TTP landmark analysis showed comparable efficacy in patients with or without lolatinib dose reduction at 16 weeks
.

Landmark analysis

Conclusion:

The follow-up results of the phase III CROWN study showed that in patients with and without brain metastases NSCLC at baseline, the intracranial disease progression time was better in the lorlatinib group than in the crizotinib group, and the CNS adverse events led to discontinuation of treatment in only 2 patients
.
Over 3 years, the incidence and incidence of adverse events in CNS gradually decreased
over time.
Long-term follow-up confirmed that central nervous system adverse events remained manageable and that the reduction of lorlatinib did not affect intracranial efficacy
.


Reference:
992P-Updated analyses from the CROWN study of first-line lorlatinib vs crizotinib in Asian patients with ALK-positive non-small cell lung cancer （NSCLC）.

2022 ESMO.
979P Long-term intracranial safety and efficacy analyses from the phase III CROWN study.
2022 ESMO.