Efficacy of platinum/pemetrexed combination chemotherapy in ALK-positive non-small cell lung cancer refractory to second-generation ALK inhibitors

Abstract

Background:

The current standard initial therapy for advanced ALK-positive non-small cell lung cancer (NSCLC) is a second-generation ALK tyrosine kinase inhibitor (TKI) such as alectinib. The optimal next-line therapy after failure of a second-generation ALK TKI remains to be established; however, standard options include the third generation ALK TKI lorlatinib or platinum/pemetrexed-based chemotherapy. The efficacy of platinum/pemetrexed-based chemotherapy has not been evaluated in patients refractory to second-generation TKIs.

Methods:

This was a retrospective study performed at three institutions. Patients were eligible if they had advanced ALK-positive NSCLC refractory to ≥1 second-generation ALK TKI(s) and had received platinum/pemetrexed-based chemotherapy.

Results:

Among 58 patients eligible for this study, 37 had scans evaluable for response with measurable disease at baseline. The confirmed objective response rate to platinum/pemetrexed-based chemotherapy was 29.7% (11/37; 95% CI, 15.9% to 47.0%), with median duration of response of 6.4 months (95% CI, 1.6 months to not reached). The median progression-free survival (PFS) for the entire cohort was 4.3 months (95% CI, 2.9 to 5.8 months). PFS was longer in patients who received platinum/pemetrexed in combination with an ALK TKI, compared to those who received platinum/pemetrexed alone (6.8 months vs 3.2 months, respectively; HR 0.33, p=0.025).

Conclusions:

Platinum/pemetrexed-based chemotherapy shows modest efficacy in ALK-positive NSCLC after failure of second-generation ALK TKIs. The activity may be higher if administered with an ALK TKI, suggesting a potential role for continued ALK inhibition.

INTRODUCTION

Tyrosine kinase inhibitors (TKIs) targeting anaplastic lymphoma kinase (ALK) are highly effective against ALK-rearranged (i.e., ALK-positive) non-small cell lung cancer (NSCLC).¹ Recently, second-generation ALK TKIs have replaced crizotinib as the standard-of-care initial therapy for patients with newly diagnosed advanced ALK-positive NSCLC.^2–6 Ceritinib and alectinib are both approved by the United States (US) Food and Drug Administration (FDA) for this indication on the basis of the ASCEND-4² and global ALEX⁴ trials, respectively. Most recently, first-line brigatinib demonstrated superior progression-free survival (PFS) compared to crizotinib (ALTA-1L), and may also receive regulatory approval in this setting.⁶ Despite the initial clinical benefit from second-generation ALK inhibitors, almost all patients ultimately develop resistance and experience disease relapse.

Optimal treatment options for patients following disease progression on second-generation ALK TKIs remain to be determined. Lorlatinib, a third-generation ALK inhibitor, represents one standard option in the US and Japan. In a phase II study, lorlatinib was associated with a confirmed objective response rate (ORR) of 40% and median PFS of 6.9 months among 139 patients who had received one or more second-generation ALK TKIs.^{7, 8} Based on these results, lorlatinib was granted FDA approval for second- or third-line treatment of ALK-positive NSCLC, including for patients who had failed alectinib or ceritinib as their initial ALK TKI. Of note, lorlatinib demonstrated significantly greater efficacy among patients with baseline ALK resistance mutations compared to those without ALK resistance mutations.⁸ Therefore, additional treatment options are needed for patients following progression on second-generation ALK inhibitors, particularly for those without ALK resistance mutations. Other potential options after the failure of a second-generation ALK TKI include alternative second-generation ALK TKI(s)—such as ceritinib or brigatinib following the failure of alectinib—selected based on the knowledge of ALK resistance mutation status. Both ceritinib and brigatinib have been evaluated in small numbers of patients following failure of at least one second-generation ALK inhibitor (such as alectinib), and have demonstrated ORRs ranging from 17% to 50%.^9–13

Most patients with advanced ALK-positive NSCLC will receive chemotherapy at some point during their disease course, especially once available TKI options are exhausted. In two separate phase III trials, PROFILE 1014 and ASCEND-4, platinum/pemetrexed chemotherapy showed efficacy in newly diagnosed patients with advanced ALK-positive NSCLC, with a median PFS of 7.0 and 8.1 months, respectively.^{2, 14} Similarly, in one retrospective analysis, first-line platinum/pemetrexed-based chemotherapy was associated with a median PFS of 8.5 months.¹⁵ However, there is little to no data on the efficacy of platinum/pemetrexed chemotherapy in patients once they have progressed on ALK inhibitors, including second-generation ALK TKI(s).

Here we performed a multicenter retrospective analysis to determine the efficacy of platinum/pemetrexed-based combination chemotherapy in patients with advanced ALK-positive NSCLC refractory to at least one second-generation ALK TKI.

MATERIALS AND METHODS

Study population

Patients were identified at three participating institutions: Massachusetts General Hospital (MGH; n=37), Memorial Sloan Kettering Cancer Center (MSKCC; n=13), and University of California-Irvine (n=8). Patients were eligible if they had been diagnosed with advanced NSCLC with an ALK rearrangement identified by local molecular profiling [e.g., fluorescent in situ hybridization, immunohistochemistry, DNA-based next-generation sequencing (NGS), or targeted RNA sequencing]. Patients had to have previously received at least one second-generation ALK inhibitor with disease progression, and subsequently received platinum (PT)/pemetrexed (pem)-based combination chemotherapy. PT/pem could have been administered with bevacizumab, programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) checkpoint inhibitor, and/or an ALK TKI. Prior adjuvant or neoadjuvant chemotherapy was allowed. Up to two cycles of prior PT-based chemotherapy were allowed, if given before the ALK testing result became available with no evidence of disease progression. Treatment with the third-generation ALK TKI lorlatinib prior to PT/pem-based chemotherapy was not permitted. This study was approved by the Institutional Review Board at each participating institution.

Data collection

Medical records were reviewed to extract relevant clinical and pathologic data. Overall and intracranial responses to therapy were determined retrospectively using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 based on investigator assessment, with measurable extracranial or intracranial tumor lesions defined per the RECIST version 1.1 criteria (i.e., at least 10 mm in size, or if lymph node, then at least 15 mm in short axis).¹⁶ Previously irradiated tumor lesions were not measurable unless there had been unequivocal progression in those lesions.¹⁶ PFS was defined as the time from the start of PT/pem-based chemotherapy to first clinical/radiographic progression or death. Patients without documented disease progression were censored at their last follow-up. For those patients without scans available for objective tumor response review, PFS was determined by review of medical records. Duration of response was calculated from the date of the first documented response to the date of disease progression, or censored at last follow-up if no progression occurred. All data were updated as of February 15, 2019.

ALK resistance mutation genotyping

For a subset of patients, repeat biopsies were performed at the time of progression on a second-generation ALK inhibitor, and analyzed for the presence of ALK resistance mutations. Methods used to detect ALK mutations included the MGH SNaPshot NGS platform (n=5),¹⁷ FoundationOne NGS (n=7; Foundation Medicine, Inc.), MSK-IMPACT (n=1),¹⁸ MI Profile (n=2; Caris Life Sciences), tumor NGS at outside institutions (n=2), Sanger sequencing of cDNA for the ALK kinase domain (n=2).¹⁹ Four patients were evaluated for ALK resistance mutations using the Guardant360 cell-free DNA assay (Guardant Health, Inc.).

Statistical analysis

Fisher’s exact test and Wilcoxon rank-sum test were used to compare baseline characteristics between treatment groups. PFS and duration of response were estimated using the Kaplan-Meier method. 95% confidence intervals (CIs) were calculated using the log-log transformation. The Cox proportional hazards model was used to estimate the hazard ratio (HR) comparing PFS differences between treatment or genotype groups. The cumulative incidence of intracranial progression was estimated with extracranial progression treated as a competing risk, and Gray’s test was used to compare patients who received PT/pem with and without an ALK TKI. Median follow-up was calculated using the reverse Kaplan-Meier method. Data analysis was performed using SAS 9.4 (SAS Institute Inc., NC). P-values were reported for two-sided tests.

RESULTS

Patient characteristics

We identified 58 patients with advanced ALK-positive NSCLC eligible for this study. Baseline characteristics are summarized in Table 1. The median age at diagnosis of advanced disease was 50 years (range, 22–75 years), the majority of patients (74%) were never smokers, and all patients had adenocarcinoma histology. The chemotherapy regimens included (Supplemental Table 1): PT/pem (32/58, 55%), PT/pem/bevacizumab (7/58, 12%), PT/pem/PD-1 inhibitor (4/58, 7%), PT/pem with ALK TKI (8/58, 14%), PT/pem/bevacizumab with TKI (6/58, 10%), and PT/pem/PD-1 inhibitor with TKI (1/58, 2%). At the time of starting PT/pem chemotherapy, 31 (53%) patients had known metastases in the central nervous system (CNS), five of whom (9%) had leptomeningeal disease.

Table 1.

Baseline clinical and pathologic features of the study cohort.

Characteristic	N=58, n (%)
Age at diagnosis of advanced disease, years
Median (range)	50 (22–75)
Sex
Male	22 (38)
Female	36 (62)
Race
White	42 (72)
Asian	9 (16)
Other	7 (12)
Smoking history
Never	43 (74)
Light (≤10 pack-years)	13 (22)
Heavy (>10 pack-years)	2 (3)
Histology
Adenocarcinoma	58 (100)
Stage at diagnosis#
Stage I–III	8 (14)
Stage IV	50 (86)
Brain metastases at diagnosis
Present	15 (26)
Absent	37 (64)
Not assessed^	6 (10)
Brain metastases prior to PT/pem-based chemo
Present	31 (53)
Absent	22 (38)
Not assessed%	5 (9)
Line of therapy for PT/pem-based chemo
2	7 (12)
3	36 (62)
≥4	15 (26)
Prior exposure to chemo
Prior neoadjuvant	3 (5)
Prior adjuvant	3 (5)
Other*	5 (9)
None	47 (81)
Number of prior ALK TKIs
1	7 (12)
2	39 (67)
≥3	12 (21)

^#Staging based on the AJCC TNM 7^th edition.

^{^,%}No MRI brain or CT head with contrast obtained, at the time of advanced disease diagnosis (^) or starting PT/pem-based chemotherapy (%).

^*Received one cycle of PT/pem (n=1), one cycle of PT/pem/bev (n=2), two cycles of PT/paclitaxel (n=1), or two cycles of PT/gem prior to the ALK testing results, without evidence of disease progression.

PT, platinum; pem, pemetrexed; bev, bevacizumab; gem, gemcitabine; chemo, chemotherapy; TKI, tyrosine kinase inhibitor.

Most patients (88%) had received at least two prior ALK TKIs. Thirty-three patients (57%) received prior crizotinib followed by a second-generation ALK TKI (ceritinib, alectinib, or brigatinib) (Supplemental Table 2). Twelve patients (21%) received three or more prior ALK TKIs; in all of these cases, crizotinib was followed by two or three second-generation ALK inhibitors. Most (55; 95%) received PT/pem-based chemotherapy as the immediate next line of therapy following a second-generation ALK inhibitor. Three patients received intervening investigational therapies with AUY922 (n=1), an AKT inhibitor (n=1), and an ALK TKI combined with a MEK inhibitor (n=1), respectively. All patients had disease progression on the immediate preceding therapy (extracranial only: 39, 67%; CNS only: 4, 7%; CNS and extracranial: 14, 24%; pattern unknown: 1, 2%). The median duration between the time of progression on the last ALK TKI and the initiation of PT/pem chemotherapy was 24 days (range, 3 to 559 days). The median duration on the immediately preceding ALK TKI was 6.2 months (range, 1.5 to 36.9 months).

Six patients received prior neoadjuvant or adjuvant PT-based chemotherapy. Additionally, five patients received 1–2 cycles of prior PT-based chemotherapy at diagnosis before their ALK testing results became available, and switched therapies without evidence of disease progression on chemotherapy (Table 1). Among 10 of the 11 patients with prior exposure to chemotherapy, the median interval between the last dose of prior chemotherapy and the start of PT/pem-based chemotherapy for advanced disease was 22.7 months (range, 10.0 to 88.1 months); the remaining one patient started PT/pem-based chemotherapy at a minimum of 38.7 months after the prior chemotherapy, but the exact time interval could not be determined.

Efficacy of PT/pem-based chemotherapy

Median follow-up was 11 months. Forty patients in the cohort had scans available for radiology review and were evaluable for objective tumor response. The remaining 18 patients did not have scans available for response review (Supplemental Figure 1). Of the 40 patients with evaluable scans, 37 patients had measurable disease at baseline (Figure 1). Confirmed partial responses (PRs) were observed in 11 patients, with an objective response rate (ORR) of 29.7% (95% CI, 15.9% to 47.0%). Thirteen patients had stable disease (SD) as the best tumor response, two of which were unconfirmed PRs. The remaining 13 patients had progressive disease (PD). Three additional patients with evaluable scans had nonmeasurable disease at baseline, of whom two had non-complete response (CR)/non-PD and one had CR. Among 19 patients with measurable and/or nonmeasurable CNS disease at baseline who had scans evaluable for CNS objective responses, the CNS ORR was 15.8% (95% CI, 3.4% to 39.6%). Three of the 19 patients had measurable CNS lesions at baseline, and of these, one had CNS PR.

Figure 1. Best confirmed tumor response to platinum-pemetrexed-based combination chemotherapy in ALK-positive NSCLC refractory to second-generation ALK TKIs.

The bars show best overall tumor response represented as the percent change in the target tumor burden from baseline. The dotted horizontal line shows the 30% threshold for partial response. The dot indicates patients who received an ALK TKI together with platinum-pemetrexed chemotherapy.

The median duration of response among 11 patients who had confirmed PRs was 6.4 months (95% CI, 1.6 months to not reached), with two ongoing responses at data cutoff (Figure 2). The median overall PFS on PT/pem-based chemotherapy for the entire cohort was 4.3 months (95% CI, 2.9 to 5.8 months) (Figure 3A). The risk of intracranial progression at one year was 30% (95% CI, 18% to 44%), while the median was not reached.

Figure 2. Duration of objective response to platinum-pemetrexed-based chemotherapy.

The bars show the duration of response to chemotherapy among 11 patients in the cohort who had confirmed objective responses. Arrows indicate ongoing responses at the time of data cutoff. Asterisks indicate patients who discontinued chemotherapy per patient preference despite ongoing responses.

Figure 3. Progression-free survival (PFS) on chemotherapy.

(A) Overall PFS on platinum (PT)-pemetrexed (pem)-based chemotherapy for the entire study cohort. Dotted lines show the median PFS. (B) PFS for patients who received PT/pem only (red) versus those who received PT/pem with an ALK TKI (blue).

In the subgroup of patients who received PT/pem plus bevacizumab (n=7), there was a modest trend towards improved PFS compared to those who received PT/pem only (n=32) (median PFS: 4.6 months vs 3.2 months; HR: 0.40). However, the difference was not strictly statistically significant (p=0.062) due to low power (Supplemental Figure 2). Among the five patients who received PT/pem plus a PD-1 inhibitor (of whom one received PT/pem plus PD-1 inhibitor together with brigatinib), the median PFS was 4.7 months (95% CI, 1.0 month to not reached). Four of these patients were evaluable for tumor response; of these, one had PR, one had SD, and two had PD as best response.

Continuation of an ALK TKI with chemotherapy

A total of 15 patients in the cohort received a PT/pem-based chemotherapy regimen in combination with an ALK TKI (Supplemental Table 1). Nine patients (60%) continued on the same immediate preceding second-generation ALK TKI (alectinib, n=7; brigatinib, n=2) when they started chemotherapy (Supplemental Table 3). Of the remaining 6 patients, two went on PT/pem plus alectinib, which they had previously received though not as the immediate preceding TKI. Three patients went back to crizotinib, which they had previously received. The remaining one patient went on crizotinib for the first time, after having received prior brigatinib and ceritinib.

We observed that the receipt of any PT/pem-based combination chemotherapy plus an ALK TKI (n=15) was associated with a significant increase in PFS compared to PT/pem-based chemotherapy alone (n=43) (median PFS: 7.7 months vs 3.6 months; HR: 0.31, p=0.002). Baseline characteristics of patients who received the chemotherapy combination regimen with vs without ALK TKI were overall comparable (Supplemental Table 4). This PFS difference was also seen when comparing those who received PT/pem (without bevacizumab or anti-PD-1/PD-L1 agent) plus an ALK TKI (n=8) vs PT/pem only (n=32), with a median PFS of 6.8 months vs 3.2 months, respectively (HR: 0.33, p=0.025) (Figure 3B). The ORR was numerically higher for those with baseline measurable disease receiving PT/pem plus ALK TKI vs PT/pem alone [3/5 (60%) vs 4/21 (19%)], but this difference did not reach strict statistical significance (p=0.101) due to low power. When the baseline characteristics of patients who received PT/pem with an ALK TKI (n=8) were compared to those of patients who received PT/pem alone without an ALK TKI (n=32), they were found to be largely comparable without statistically significant differences (Supplemental Table 5). It is worth noting that a higher percentage of patients who received PT/pem with an ALK TKI [7/8 (88%)] had known prior history of brain metastases at the time of starting therapy compared to those who received PT pem alone without an ALK TKI [15/28 (54%)] (p=0.115). Nevertheless, the incidence of CNS disease progression on PT/pem was similar for those who received it together with an ALK TKI (28% at one year) vs without an ALK TKI (38% at one year) (p=0.598).

Efficacy according to baseline ALK mutation status

Twenty-three patients (40%) had undergone a repeat biopsy following disease progression on the immediately preceding second-generation ALK inhibitor. On the basis of tumor (n=19) or plasma (n=4) genotyping, 12 patients (52%) had a detectable ALK resistance mutation, whereas 11 patients (48%) did not (Supplemental Figure 3A). Among these patients, the median PFS on PT/pem-based chemotherapy was 4.1 months and 3.6 months for those with and without ALK mutations, respectively (HR: 1.02, p=0.966) (Supplemental Figure 3B). Among patients with measurable baseline disease, objectives responses were observed in 14.3% (1/7) and 37.5% (3/8) for those with and without ALK mutations, respectively (p=0.569).

DISCUSSION

The current standard first-line therapy in advanced ALK-positive NSCLC is a second-generation ALK inhibitor such as alectinib. Progression-free survival with first-line alectinib significantly exceeds that of crizotinib,^{2, 4} with median PFS of first-line alectinib reaching 34.8 months based on an updated analysis of the phase III global ALEX trial.²⁰ Despite these impressive results, acquired TKI resistance remains a major challenge. For patients experiencing disease relapse on alectinib or other second-generation ALK inhibitors, the optimal next-line therapy remains to be established.

Here we evaluated the efficacy of PT/pem-based chemotherapy in patients with advanced ALK-positive NSCLC refractory to second-generation ALK TKI(s). We found that PT/pem-based chemotherapy demonstrated modest clinical activity in this setting, with an ORR of 29.7% and median PFS of 4.3 months. While the response rate is overall comparable to what has been reported in prior phase III trials of treatment-naïve ALK-positive patients, the median PFS is shorter than the 6.7–7.0 months previously observed in treatment-naïve patients.^{2, 14} This finding suggests that ALK-positive tumors may be less sensitive to chemotherapy once they have become resistant to ALK TKI(s). Indeed, in advanced EGFR-mutant NSCLC, a similarly short median PFS of 4.4 months (95% CI, 4.2 to 5.6 months) with platinum/pemetrexed was reported among patients resistant to earlier-generation EGFR TKIs due to an EGFR T790M mutation.²¹ It is not yet known whether prior—in many cases, sequential—TKI therapies could enhance genomic instability and tumor heterogeneity leading to diminished sensitivity to cytotoxic chemotherapy. Additionally, in at least a subset of tumors, prior treatment with TKIs could contribute to chemotherapy (or overall drug) resistance by promoting epithelial to mesenchymal transition (EMT).^{22, 23}

These findings should be interpreted in the context of emerging efficacy data with next-generation ALK TKIs in patients refractory to prior second-generation ALK inhibitor(s). The second-generation inhibitors ceritinib and brigatinib have been evaluated in small numbers of patients who have failed prior alectinib or other second-generation ALK inhibitor(s), and have shown some activity with a median PFS ranging 3.7–6.4 months.^10–13 Certain tumors harboring alectinib-resistant but ceritinib- or brigatinib-sensitive ALK mutations may have more favorable responses to these latter second-generation ALK inhibitors,^{11, 24} although this remains to be validated in larger studies. The third-generation ALK TKI lorlatinib has demonstrated overall as well as intracranial efficacy in patients who failed one or more prior second-generation ALK inhibitors,⁷ and has received FDA approval for second- or third-line treatment of advanced ALK-positive NSCLC. While the efficacy was significantly greater for patients with baseline ALK mutations compared to those without ALK mutations (median PFS: 11.0 months vs 4.0 months; ORR: 69% vs 31%, respectively), reflecting the continued ALK dependency of the tumors harboring ALK mutations, it is noteworthy that lorlatinib did show modest clinical activity in the ALK mutation-negative, second-generation TKI-refractory patients.⁸ This activity appears comparable to that seen with PT/pem-based chemotherapy among ALK mutation-negative patients in our study (lorlatinib: ORR 31%, median PFS 4.0 months; PT/pem-based chemotherapy: ORR 37.5%, median PFS 3.6 months). However, it must be emphasized that our study was a small retrospective study and not a trial designed to directly compare the efficacy of PT/pem-based chemotherapy versus lorlatinib in this clinical context.

Ultimately, when evaluating next-line treatment options for patients progressing on a second-generation ALK inhibitor, clinicians will need to consider various parameters including baseline ALK resistance mutation status, CNS disease burden, co-morbidities, drug tolerability, in addition to patient preference and access to/eligibility for clinical trials. In general, for patients relapsing on a second-generation ALK inhibitor and known to harbor a secondary ALK resistance mutation, lorlatinib may be preferable to PT/pem-based chemotherapy based on the demonstrated efficacy of lorlatinib in these patients.^{7, 8} For patients relapsing on a second-generation ALK inhibitor with tumor genotyping showing no ALK mutation, either lorlatinib or PT/pem-based chemotherapy could be considered at this time, in the absence of prospective trial data directly comparing lorlatinib versus chemotherapy.

Interestingly, in this study cohort, those patients receiving PT/pem with an ALK TKI had a significantly longer PFS compared to those receiving PT/pem alone. This finding contradicts prior results in advanced EGFR-mutant NSCLC. In the phase III IMPRESS trial, EGFR-mutant NSCLC patients with progression on gefitinib were randomized to cisplatin/pemetrexed with gefitinib vs placebo, and no significant PFS difference was observed between the treatment arms.²⁵ Of note, all patients in the IMPRESS trial had previously received gefitinib only, a first-generation EGFR inhibitor, without additional lines of therapy. Whether the same conclusion would be reached in the context of next-generation TKIs (such as osimertinib or alectinib)—which have improved CNS activity and can suppress or delay the emergence of CNS metastases²⁶—, or following multiple prior sequential TKIs, is unknown. Our study included patients who had received at least one prior second-generation ALK inhibitor, with the majority having received two or more prior ALK TKIs. Given the small and retrospective nature of our study and the variety of ALK TKIs that were administered in combination with PT/pem chemotherapy, further investigation is needed to better address whether concurrent administration of an ALK TKI with chemotherapy may improve outcomes compared to chemotherapy alone.

Our study had a number of limitations, several of which are inherent in any retrospective study. First, as aforementioned, the study included a small number of patients. Since all participating centers were tertiary academic institutions, patients may not be representative of the general ALK-positive population. Second, patients received a range of PT/pem-based regimens, including regimens with or without bevacizumab, PD-1 inhibitor, or an ALK TKI. The decision of the treating physician to administer PT/pem in combination with bevacizumab, PD-1 inhibitor, or an ALK TKI may have been influenced by multiple factors, including the patient’s performance status, extent of CNS and extracranial disease, tumor genotyping results, smoking history, and/or the degree of response to and tolerability of prior ALK TKIs. These confounders, in turn, could have affected the PFS comparisons performed herein. Similarly, the exact ALK TKIs the patients previously received were variable, although all were required to have received at least one prior second-generation ALK TKI. Third, because this was a retrospective analysis, there was no standardized schedule for tumor assessments, and imaging was not subjected to centralized review, both of which may have impacted the PFS and ORR outcomes. Finally, because crizotinib was the standard initial therapy for advanced ALK-positive NSCLC until recently, a majority of the patients in this study received prior crizotinib followed by next-generation ALK TKI(s). The efficacy of PT/pem-based chemotherapy may in theory be different among patients who receive prior second-generation ALK inhibitors without preceding crizotinib.

In summary, our findings suggest limited efficacy of PT/pem-based chemotherapy in advanced ALK-positive NSCLC after failure of a second-generation ALK inhibitor. Efficacy may be higher in patients who receive chemotherapy in combination with an ALK TKI, suggesting a potential role for ongoing ALK inhibition. This study underscores the need to develop more effective therapeutic strategies for ALK-positive NSCLC patients progressing on next-generation ALK inhibitors.