WCLC 2022｜Subsequent treatment exploration and drug resistance mechanism of ALK-positive NSCLC patients

The 2022 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer (WCLC) will be held in offline + online format from August 6 to 9, 2022

Research Background

Alectinib is the standard treatment option for patients with ALK-positive NSCLC

Research methods

ALTA-2 (NCT03535740) and J-ALTA (NCT03410108) are open-label, single-arm, multicenter studies in patients with advanced or metastatic ALK-positive NSCLC

Figure 1 Study Design

Research result

The analysis included 133 patients (ALTA-2, n=86; J-ALTA main cohort, n=47) with a median follow-up of 11.

Table 1 Patient baseline information

As shown in Table 2, after brigatinib treatment, the ORR of patients was 30.

Table 2 Treatment benefits of patients

The median PFS assessed by BIRC was 5.
2 months (95% CI, 3.
7-7.
3).
The PFS performance is shown in Figure 2, and the median OS was not reached
.

Figure 2 PFS manifestations of patients

The safety analysis showed that 66.
2% of patients experienced ≥ grade 3 adverse events during treatment, the most common being increased serum creatine phosphokinase (11.
3%), hypertension (10.
5%), and increased lipase (7.
5%) and pneumonia (5.
3%)
.

Interstitial lung disease/pneumonitis of any grade occurred in 8 (6.
0%) patients, of which 2 (1.
5%) were early-onset
.

12% of patients discontinued due to adverse events
.

Analysis conclusion

In the ALTA-2 and J-ALTA trials, brigatinib demonstrated clinical benefit in patients with advanced or metastatic ALK+ NSCLC whose disease had progressed after treatment with ALK inhibitors such as alectinib
.

Safety results were consistent with known analyses of brigatinib, and no new safety signals were observed
.

Progression patterns, drug resistance mechanisms and subsequent treatment of ALK-positive NSCLC²

Research Background

In the real world, data on progression patterns, resistance mechanisms, and subsequent therapy in patients with ALK-positive NSCLC are limited
.

Research methods

The investigator's center retrospectively collected data on patients who failed treatment with second-generation ALK-TKIs, including patients with disease progression after first-line alectinib therapy and enrolled in cohort 1 (n=20), followed by crizotinib Patients with disease progression after treatment with second-generation ALK-TKIs were included in cohort 2 (n=52)
.

Research result

The proportion of patients with central nervous system (CNS) progression (15% vs.
57.
7%, p=0.
001) and symptomatic CNS progression (5% vs.
32.
7%, p=0.
016) in cohort 1 was much lower than first-line crizole patients treated with tinib
.

The main resistance mechanism of second-generation ALK-TKIs is the resistance mutation in the ALK kinase domain (24/43, 55.
8%), especially G1202R (15/43, 34.
9%)
.

In addition, MET amplification, BRAF fusion, BRAF V600E mutation, KRAS amplification, KRAS mutation, and squamous cell transformation may also contribute to drug resistance
.

Subsequent ALK-TKIs were more effective in patients with ALK secondary mutations (excluding patients with ALK compound mutations) than those without ALK secondary mutations (242d vs.
75d, p=0.
05, HR=0.
46, 95%CI: 0.
18- 1.
2)
.

The ALK compound mutation that emerges after multiple ALK-TKIs treatment is the main mechanism of lorlatinib resistance
.

Some patients who received ALK-TKIs without a second biopsy had a poor response to subsequent ALK-TKIs, and biopsy results after multiple lines of therapy in such patients suggest that patients may be in the process of initial ALK-TKI therapy.
resistance has developed
.

For patients without ALK resistance mutations, 57.
2% of the overall population and 51.
8% of the deceased population received at least first-line chemotherapy, and chemotherapy resulted in better PFS than ALK-TKIs (median PFS 168d vs.
.
75d, p=0.
035, HR=0.
47, 95%CI: 0.
19-1.
2)
.

Analysis conclusion

Patients receiving first-line alectinib were less likely to have CNS and symptomatic CNS progression than first-line crizotinib
.

In the era of second-generation ALK-TKIs, secondary biopsy should be highly valued, and secondary biopsy may be beneficial to the selection of clinical programs and the evaluation of subsequent treatment effects
.

Patients should not lose the opportunity to chemotherapy, which remains an important treatment strategy, especially for patients who are not sensitive to targeted therapy
.

references

1.
MA13.
03 - Integrated Efficacy and Safety of Brigatinib Following Alectinib Treatment in the ALTA-2 and J-ALTA Studies.

2.
EP08.
02-009 - Progression Pattern, Resistance Mechanism and Subsequent Therapy for ALK Positive NSCLC in the Era of Second—Generation ALK—TKIs.

Edit: Youshi

Reviewer: Jiang Zhou

Typography: Youshi

Execution: Uni