Navigating treatment sequencing in ALK-positive non-small cell lung cancer: lorlatinib as a key to prolonged survival?

Anaplastic lymphoma kinase-positive (ALK⁺) non-small cell lung cancer (NSCLC) occurs in 3–8% of NSCLC cases (1), primarily affecting adenocarcinoma patients, often females, and never smokers (1-3). The development of ALK-directed therapy with tyrosine kinase inhibitors (ALK-TKIs) has significantly improved the treatment of ALK⁺ NSCLC. The first-generation ALK-TKI, crizotinib, demonstrated superior efficacy compared to chemotherapy in the first-line setting (4), establishing a new standard of care. This breakthrough paved the way for the introduction of second- and third-generation ALK-TKIs. Ceritinib demonstrated superior efficacy to chemotherapy (5), while alectinib (6), brigatinib (7), and lorlatinib (3,8) outperformed crizotinib in randomized clinical trials. These treatment options improved progression-free survival (PFS) and overall survival (OS) and enhanced control of metastasis in the central nervous system (CNS) when used in the first-line setting compared to crizotinib (3,9,10). While OS data on alectinib, brigatinib, and lorlatinib remain immature, alectinib has shown promising long-term outcomes (6), and lorlatinib has demonstrated promising long-term PFS and CNS progression benefits (8). Despite high response rates, resistance inevitably develops, and the optimal treatment sequence after first-line treatment remains unclear.

The global phase 2 study (NCT01970865-study) by Solomon et al. (11) evaluated the third-generation ALK-TKI lorlatinib in patients with ALK- or C-ros Oncogene 1, receptor tyrosine kinase (ROS1)-positive advanced NSCLC with or without CNS metastasis. The trial included multiple cohorts based on ALK and ROS1 status and previous treatments, assessing lorlatinib’s efficacy and safety. Lorlatinib demonstrated significant overall and intracranial efficacy in ALK⁺ NSCLC, both in treatment-naïve patients and those who had received previous ALK-TKI treatment with or without prior chemotherapy.

In a brief report, Ou and colleagues (12) have, after a minimum follow-up period of five years, evaluated the long-term efficacy and safety of lorlatinib in ALK⁺ NSCLC patients from the NCT01970865-study mentioned above (11). Participants were categorized into expansion cohorts (EXP) based on prior treatments to receive lorlatinib. If the investigator determined a clinical benefit, lorlatinib continued until progressive disease (PD) or beyond PD. The median OS was not reached among treatment-naïve patients (EXP1), indicating sustained efficacy for lorlatinib when used in the first-line. These findings align with the updated data from the CROWN study, where lorlatinib demonstrated superior PFS compared to crizotinib, with a 5-year PFS rate of 60% [95% confidence interval (CI): 51–68%] versus 8% for crizotinib (95% CI: 3–14%), and median PFS for lorlatinib was not reached (8).

In patients with disease progression after crizotinib ± chemotherapy (EXP2-3A), the median OS was also not reached, reflecting lorlatinib’s substantial efficacy in this cohort. In a previously reported cohort of patients receiving alectinib after prior crizotinib treatment, Ou and colleagues (13) conducted a pooled analysis of two open-label phase 2 studies involving 225 patients with ALK⁺ NSCLC, with a median follow-up of approximately 21 months. The study reported a median OS of 29.1 months (95% CI: 21.3–39.0) for patients treated with Alectinib. The most common all-grade adverse events (AEs) were constipation (39.1%), fatigue (35.1%), peripheral edema (28.4%), and myalgia (26.2%). AEs leading to treatment discontinuation (TTD) were reported in 6.2% and fatal AEs in 3.1% of the pooled population (13).

Gettinger et al. (14) investigated the long-term efficacy and safety from the phase 1/2 (79 patients) and phase 2 (222 patients) ALTA trials for brigatinib treatment in patients with crizotinib refractory ALK⁺ NSCLC. The median follow-up was 27.7 months, and they reported a median OS of 30.1 months and a 5-year OS probability of 35% in these patients. The most common AEs reported were gastrointestinal events and elevated blood creatine phosphokinase levels. Any AEs leading to TTD were reported in 10% of the phase 1/2 study cohort and 17% of the study 2 cohort. Deaths were reported in 3 patients: 2 in the phase 1/2 cohort and 1 in the ALTA cohort (14).

The open-label multicenter ALTA3-trial (15) randomized patients with ALK⁺ NSCLC previously treated with or without chemotherapy to receive either alectinib or brigatinib after progression on crizotinib. Median follow-up was 15.9 months for brigatinib and 16.9 months for alectinib. The median PFS for brigatinib was 19.3 months [95% CI: 15.7–not estimable (NE)] and 19.2 months for alectinib (95% CI: 12.9–NE). Neither brigatinib nor alectinib demonstrated superiority in PFS for crizotinib-pretreated ALK⁺ NSCLC patients. The OS was not reached, showing a sustained effect of both treatments in patients pre-treated with crizotinib. The most common treatment-related AEs (TRAEs; more than 30% of the patients) in the brigatinib arm were increased blood creatine phosphokinase (CPK; 70%), increased aspartate aminotransferase (AST; 53%), and increased alanine aminotransferase (ALT; 40%) levels. In the alectinib arm, AST (38%) and ALT (36%) levels were increased. AEs leading to TTD occurred in six patients (5%) in the brigatinib arm and three (2%) in the alectinib arm.

The long-term follow-up in the NCT01970865-study (12) showed that for patients previously treated with one or more second-generation ALK-TKIs (EXP3B, EXP4-5, and EXP3B-5), with or without chemotherapy, the median OS varied. For patients previously treated with one second generation ALK-TKI +/− chemotherapy, the median OS was 37.4 months [95% CI: 12.3–not reached (NR)]. The heavily pretreated patients had a median OS of 19.2 months in EXP4-5 (95% CI: 15.4–30.2), and for EXP3B-5, the median OS was 20.7 months (95% CI: 16.1–30.3). These promising results show the clinical significance of the sequential treatment of ALK⁺ NSCLC with ALK-TKIs. Treating ALK⁺ NSCLC beyond PD is relatively common, especially in cases where the patient shows clinical benefit despite disease progression (12,13). Sometimes, this can be done by treating with radiotherapy for oligo-metastatic disease (16). Hence, the decision to treat beyond PD depends on factors such as the patient’s overall condition, progression sites, and resistance mechanisms.

It is common clinical practice to switch to another generation of ALK-TKI in the case of PD and use sequential treatment with different ALK-TKIs. Schmid and colleagues (17) demonstrated the latter in a real-world study on 148 patients with ALK⁺ NSCLC, showing that sequential treatment with ALK-TKIs is a viable strategy that can prolong both the quality and duration of life for patients. However, approximately 20% of patients succumbed within two years.

The studies above highlight the clinical relevance of sequential ALK-TKI therapy. The brief report by Ou et al. (12) highlights the potential for sustained responses with a sequential treatment strategy following first-line ALK-TKI therapy. No definitive sequencing strategy has emerged as the optimal approach, as the data of the studies discussed above are still maturing.

A recent retrospective study evaluated outcomes in ALK⁺ NSCLC patients treated between 2015 and 2022, comparing those who received third-line ALK-TKIs (n=85) with non-ALK therapies (n=43) after progression on two prior ALK-TKIs (18). Patients in the third-line ALK-TKI group had significantly longer time to TTD [6.2 vs. 2.4 months, hazard ratio (HR) 0.61, P=0.049] and OS (17.6 vs. 6.5 months, HR 0.57, P=0.042), compared to the third-line non-ALK TKI group. Further insight was provided by Wu et al., who studied ALK-TKI sequencing in two cohorts of patients with PD following alectinib alone or crizotinib followed by second-generation ALK-TKIs (19). Among patients with resistance to second-generation ALK-TKIs, 60.3% underwent rebiopsy and sequencing, revealing ALK resistance mutations in 56.8% of cases. Those with detectable ALK resistance mutations had significantly improved PFS (8.6 vs. 2.7 months; HR 0.43, P=0.021) and a trend toward better OS when treated with subsequent ALK-TKIs, compared to patients without such mutations. No significant survival difference was observed between chemotherapy and further ALK-TKI therapy in patients lacking ALK resistance mutations. The findings from the studies underscore the potential clinical benefit of sequential ALK-TKI use and suggest that this approach may be preferable to chemotherapy. Additionally, the sequential ALK-TKI strategy may particularly benefit ALK mutation-positive cases. This highlights the need for studies exploring these insights to refine treatment strategies based on resistance profiles.

However, the clinical value of sequential ALK-TKI therapy must be weighed against the treatment-related toxicities, especially given the typically long survival of this patient population. The toxicity profiles differ between second generation ALK-TKIs like alectinib/brigatinib and the third generation ALK-TKI lorlatinib. Ou et al. (12) reported that treatment all-cause AEs leading to treatment end occurred in 13% of the cohort, and the most frequent all-cause AEs leading to dose reductions were peripheral edema, cognitive disorder, and hypertriglyceridemia. Weight gain, hypertriglyceridemia, and hypercholesterolemia were the most frequently reported treatment-related grade 3 AEs. Treatment-related edema was reported in 45%, peripheral neuropathy in 35%, cognitive effects in 24%, and weight gain in 24% of the cohort.

As the development of ALK-TKIs and, hence, survival keeps improving for these patients, the management of toxicities can significantly impact the quality of life of the patients. A recent retrospective observational analysis from John et al. (20) of 43 patients with ALK and ROS1-positive NSCLC treated with lorlatinib demonstrated that 81% experienced weight gain. In addition, 91% developed an increase in total cholesterol, and 68% developed an increase in triglycerides. The incidence rates observed were comparable to those reported in the CROWN trial (21). Weight gain and dyslipidemia are frequently associated with lorlatinib, and these effects accumulate over time (3,8). However, we still do not know the long-term impact, emphasizing the importance of pharmacologic and non-pharmacologic interventions to manage these side effects. With a 60% five-year PFS demonstrated in CROWN, managing treatment-related toxicities is essential for preserving patient quality of life and minimizing non-cancer-related health risks. Toxicity management is crucial for this subgroup of NSCLC patients with relatively favorable long-term outcomes.

Additionally, they tend to be younger, often balancing evolving careers and family responsibilities. Another thing to consider is patients with pre-existing metabolic risk factors—these might not be suitable for lorlatinib. Sequential treatment with ALK-TKIs is a key therapeutic approach; however, it is essential to balance the benefits against potential side effects while considering the impact on patient quality of life.

The brief report by Ou et al. (12) underscores the clinical importance of switching ALK-TKI therapy after PD to extend survival. The efficacy of lorlatinib in later lines of treatment suggests that, despite progression, tumor growth is still driven by the ALK fusion, supporting continued ALK-TKIs use to improve survival. This treatment strategy offers hope for further optimizing treatment and prolonging survival in this patient group. However, OS tends to decrease with an increasing number of prior therapies, and data concerning optimal sequencing are limited. This emphasizes the importance of continuing research and gaining a deeper molecular understanding of ALK⁺ NSCLC to establish the best sequence for ALK-TKIs, hoping to identify biomarkers that can inform personalized treatment strategies.

Acknowledgments

None.

Footnote

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