Advanced ALK-positive NSCLC Research Articles

Cost-effectiveness analysis of lorlatinib and crizotinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer

ABSTRACT Objectives To assess the economic value of lorlatinib and crizotinib in the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer at medical insurance negotiation prices from the viewpoint of China’s health system. Methods Based on data from the phase III clinical trial, a three-state partitioned survival model was established. In combination with parameters such as treatment costs, utility values, incidence of adverse reactions, and discount rates, the total incremental cost-effectiveness ratio (ICER) was simulated. Results The results of the fundamental analysis indicated that the patients in the lorlatinib group expended 709,671 yuan more than did the patients in the crizotinib group did but gained 3.09 quality-adjusted life years (QALYs). The ICER value was 229,782.6 yuan/QALY, which was lower than three times the per capita gross domestic product (GDP) of China. Conclusions Compared with crizotinib, lorlatinib may be a cost-effective first-line treatment choice for advanced ALK-positive NSCLC in China.

P3.08F.01 Interim Analysis of a Phase 2 Prospective Trial of Induction Lorlatinib in Locally Advanced ALK-Positive NSCLC (LORIN)

P3.08F.01 Interim Analysis of a Phase 2 Prospective Trial of Induction Lorlatinib in Locally Advanced ALK-Positive NSCLC (LORIN)

EP.09B.03 Salvage Surgery Following Inductiontherapy for Advanced ALK-Positive NSCLC: Pathological Response and Surgical Outcomes

EP.09B.03 Salvage Surgery Following Inductiontherapy for Advanced ALK-Positive NSCLC: Pathological Response and Surgical Outcomes

Analysis of Baseline Molecular Factors Associated With the Risk of Central Nervous System Progression Among Alectinib-Treated Patients With ALK–Positive NSCLC

IntroductionDespite receiving alectinib therapy, patients with ALK-rearranged NSCLC remain at risk of central nervous system (CNS) progression. Our retrospective study aimed to identify baseline clinical and molecular factors associated with the risk of CNS progression in this patient subset. MethodsWe analyzed the clinical, molecular, and imaging data of 318 patients with ALK-positive advanced NSCLC who received alectinib as first-line (1L-alectinib) or second-line (2L-alectinib) therapy at baseline (1L, n = 183; 2L, n = 135) and at disease progression (1L, n = 57; 2L, n = 75). ResultsThe incidence rates of CNS progression were 12.3% after 1L-alectinib treatment and 30.7% after 2L-alectinib treatment. Compared with patients who received 1L-alectinib, CNS progression was significantly higher in patients who received 2L-alectinib (p = 0.04), particularly those who had oligoprogression (p = 0.01). Oligoprogression was detected in 55.0% (44 of 80) of patients who progressed after first-line alectinib, with the remaining 45.0% (36 of 80) having nonoligoprogression. Univariate and multivariate analyses and stepwise regression analyses consistently identified a higher likelihood of CNS progression among (1) patients who received 2L-alectinib than 1L-alectinib, (2) patients with non-3a/b variant ALK fusion than those with echinoderm microtubule-associated protein-like 4–ALK variant 3a/b, and (3) patients with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or higher than PD-L1 TPS of less than 50%. ConclusionsOur study provided real-world evidence that patients who harbored PD-L1 TPS of 50% or higher were more likely to experience CNS progression during alectinib therapy. The association between CNS progression and breakpoint variants warrants further investigation. Our findings suggest that close monitoring and prompt intervention are crucial in prolonging the quality of life of this patient subset.

Consolidation ALK Tyrosine Kinase Inhibitors Versus Durvalumab or Observation After Chemoradiation in Unresectable Stage III ALK-Positive NSCLC

IntroductionPatients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation. MethodsWe conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related adverse events (trAEs) were classified by Common Terminology Criteria for Adverse Events version 5.0. Outcomes were assessed by multivariable Cox regression analysis. ResultsA total of 67 patients were included, of whom 39 (58%) were female. Median age was 57 (interquartile range: 49–67) years. Furthermore, 15 received consolidation ALK TKI, 30 received durvalumab, and 22 underwent observation. Baseline characteristics were similar across the three groups other than differences in race. After adjusting for stage, age, and nodal status, median rwPFS was significantly longer for ALK TKI (rwPFS not reached, 95% confidence interval [CI]: 22.7– not reached) versus durvalumab (11.3 mo, 95% CI: 8.9–18.5, hazard ratio [HR] = 0.12, 95% CI: 0.026–0.5, p-adjusted [p-adj] = 0.006) or observation (7.2 mo, 95% CI: 3.4–10.6, HR = 0.04, 95% CI: 0.009–0.2, p-adj < 0.0001). Durvalumab significantly improved median rwPFS compared with observation (HR = 0.37, 95% CI: 0.19–0.71, p-adj = 0.002). Median OS in the ALK TKI and durvalumab cohorts was significantly improved compared with patients on observation (ALK TKI-observation: p = 0.04; durvalumab-observation: p = 0.03). TrAE of any grade occurred in eight (53%) and 11 (37%) patients treated with ALK TKI and durvalumab, respectively. Grade greater than or equal to three trAEs occurred in 27% (n = 4) of patients treated with ALK TKI and 6.7% of patients treated with durvalumab. ConclusionsPatients with ALK-positive NSCLC experience significantly improved rwPFS when treated with consolidation ALK TKI therapy, surpassing outcomes found with either durvalumab or observation. Although both ALK TKI therapy and durvalumab offer an extension in OS compared with observation alone, it seems that ALK TKI therapy is the superior choice, underscoring its pivotal role in enhancing patient survival.

Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study

IntroductionPrevious results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the “last patient in” date. MethodsAdult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. ResultsAt the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23–0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08–0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. ConclusionsWith four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALK-Positive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE)

IntroductionIruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC. MethodsIn this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758). ResultsFrom September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7–37.7) in the iruplinalkib group and 25.9 months (range: 0.5–35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3–not estimable] versus 14.6 mo [95% CI: 11.1–16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23–0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5–96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1–93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7–99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3–83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group. ConclusionsIruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC. FundingThis study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People’s Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

MA06.11 Lorlatinib for Previously Treated ALK-positive Advanced NSCLC: Updated Efficacy and Safety Data from a Phase 2 Study in China

MA06.11 Lorlatinib for Previously Treated ALK-positive Advanced NSCLC: Updated Efficacy and Safety Data from a Phase 2 Study in China

Efficacy of Lorlatinib in Treatment-Naive Patients With ALK-Positive Advanced NSCLC in Relation to EML4::ALK Variant Type and ALK With or Without TP53 Mutations

IntroductionLorlatinib, a third-generation ALK tyrosine kinase inhibitor, improved outcomes compared with crizotinib in patients with previously untreated ALK-positive advanced NSCLC in the phase 3 CROWN study. Here, we investigated response correlates using plasma circulating tumor DNA (ctDNA) and tumor tissue profiling. MethodsALK fusions and ALK with or without TP53 mutations were assessed by next-generation sequencing. End points included objective response rate (ORR), duration of response, and progression-free survival (PFS) by blinded independent central review on the basis of EML4::ALK variants and ALK with or without TP53 or other mutation status. ResultsALK fusions were detected in the ctDNA of 62 patients in the lorlatinib arm and 64 patients in the crizotinib arm. ORRs were numerically higher with lorlatinib versus crizotinib for EML4::ALK variant 1 (v1; 80.0% versus 50.0%) and variant 2 (v2; 85.7% versus 50.0%) but were similar between the arms for variant 3 (v3; 72.2% versus 73.9%). Median PFS in the lorlatinib arm was not reached for EML4::ALK v1 and v2 and was 33.3 months for v3; in the crizotinib arm, median PFS was 7.4 months, not reached, and 5.5 months, respectively. ORRs and PFS were improved with lorlatinib versus crizotinib regardless of TP53 mutation status and in patients harboring preexisting bypass pathway resistance alterations. In the lorlatinib arm, PFS was lower in patients who had a co-occurring TP53 mutation. Results from ctDNA analysis were similar to those observed with tumor tissue samples. ConclusionsPatients with untreated ALK-positive advanced NSCLC derived greater clinical benefits, with higher ORRs and potentially longer PFS, when treated with lorlatinib compared with crizotinib, independent of EML4::ALK variant or ALK mutations, TP53 mutations, or bypass resistance alterations.

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis.

To compare the efficacy and safety of alectinib with other ALK inhibitorsin treating patients with metastatic or locally advanced ALK-positive NSCLC. A systematic literature review was conducted up to November 2021. Network meta-analyses were performed using the frequentist method (random effects). GRADE evidence profile was conducted. 13 RCTs were selected. For overall survival, alectinib was found to reduce the risk of death compared with crizotinib. In progression-free survival, alectinib reduced the risk of death or progression compared with crizotinib and ceritinib. Subgroup analysis by brain metastasis at baseline showed the superiority of alectinib over crizotinib and a similar effect compared with second-and third-generation inhibitors. Alectinib showed a good safety profile compared with the other ALK inhibitors.

Real-World Comparative Effectiveness of First-Line Alectinib Versus Crizotinib in Patients With Advanced ALK-Positive NSCLC With or Without Baseline Central Nervous System Metastases

IntroductionAlectinib was found to have superior efficacy to crizotinib in the phase 3 ALEX study and is a preferred initial treatment for patients with advanced ALK-positive NSCLC. To understand the efficacy of alectinib in U.S. clinical practice, we conducted a retrospective real-world comparative effectiveness analysis of first-line alectinib versus crizotinib. MethodsAdults with advanced ALK-positive NSCLC who received first-line alectinib (from December 11, 2015) or crizotinib (from January 1, 2014) were included from a real-world database. Propensity scores were applied to balance baseline characteristics. Real-world data (RWD), including real-world progression-free survival (rwPFS), real-world overall survival, real-world time to new central nervous system (CNS) metastases, and outcomes in patients with or without baseline CNS metastases were analyzed. The ALEX-like RWD cohort (filtered by ALEX laboratory eligibility criteria) was used to compare real-world comparative effectiveness with ALEX. ResultsThe RWD cohort comprised 364 patients (141 alectinib; 223 crizotinib); rwPFS (weighted hazard ratio [wHR] = 0.46, 95% confidence interval [CI]: 0.33–0.65) and real-world overall survival (wHR = 0.46, 95% CI: 0.31–0.69) were significantly improved with alectinib versus crizotinib. In patients with baseline brain scans, a substantial rwPFS benefit was found regardless of baseline CNS metastases. Real-world time to new CNS metastases was delayed with alectinib versus crizotinib in patients with (wHR = 0.28, 95% CI: 0.16–0.52) and without (wHR = 0.42, 95% CI: 0.24–0.76) baseline CNS metastases. The ALEX-like RWD cohort comprised 325 patients (120 alectinib; 205 crizotinib); alectinib was found to have similar rwPFS benefits with ALEX. ConclusionsOutcomes were significantly improved with first-line alectinib versus crizotinib in patients with advanced ALK-positive NSCLC in the U.S. real-world setting.

First-Line Lorlatinib Versus Crizotinib in ALK-Positive NSCLC: Japanese Subgroup Analysis of CROWN

IntroductionLorlatinib, a third-generation ALK inhibitor, was found to have improved efficacy versus crizotinib in patients with previously untreated, advanced ALK-positive NSCLC in the ongoing, global, randomized, phase 3 CROWN study. MethodsThe study’s primary end point was progression-free survival assessed by blinded independent central review. Secondary end points included objective and intracranial response. Here, we report efficacy and safety data of the Japanese subgroup of the CROWN study (lorlatinib 100 mg once daily, n = 25; crizotinib 250 mg twice daily, n = 23). ResultsProgression-free survival was not reached (95% confidence interval [CI]: 11.3 mo–not reached) for lorlatinib and 11.1 months (95% CI: 5.4–14.8) for crizotinib (hazard ratio = 0.44, 95% CI: 0.19–1.01). Objective response (lorlatinib versus crizotinib) was 68.0% (95% CI: 46.5–85.1) versus 52.2% (95% CI: 30.6–73.2) in all patients, and intracranial response was 100.0% (three of three, 95% CI: 29.2–100.0) versus 28.6% (two of seven; 95% CI: 3.7–71.0) in patients with brain metastases at baseline. The most common adverse events with lorlatinib were hypertriglyceridemia, hypercholesterolemia, and weight increase; 28.0% and 8.0% of patients had cognitive and mood effects (all grades 1 or 2), respectively. Lorlatinib was associated with more grade 3 or 4 events than crizotinib (80.0% versus 72.7%). Treatment was discontinued owing to adverse events in 16.0% and 27.3% of patients in the lorlatinib and crizotinib groups, respectively. ConclusionsThe efficacy and safety of lorlatinib in the Japanese subgroup were similar to those in the CROWN global population, revealing improved outcomes versus crizotinib in Japanese patients with previously untreated, advanced ALK-positive NSCLC.

Clinical Profile, Practice Pattern, and Outcomes With First-Line Therapy in ALK-Positive Lung Cancer: Real-World Data From Resource-Constrained Settings

IntroductionALK inhibitors are one of the success stories in precision medicine for treating patients with advanced ALK-positive NSCLC. Nevertheless, developing countries have substantial constraints in using ALK inhibitors, with limited data from India. MethodsAn audit of a prospectively collected database of patients with advanced ALK-positive NSCLC treated from January 2013 to March 2018 was conducted. The SPSS version 20.0 was used for statistical analysis. ResultsA total of 441 patients were available for analysis; 62.5% were males, median age was 50 (range: 19–75) years, and 78.3% had Eastern Cooperative Oncology Group performance status of 0 to 1. When all the lines of therapies were included in the analysis, ALK inhibitors could be used in 379 (85.9%) of the total ALK-positive patients and 292 patients (66.2%) received ALK inhibitors in the first line in any strategy. The major reason for not starting ALK inhibitors upfront was financial constraints in 69% of the patients. The median progression-free survival on first-line therapy for the entire cohort was 14.1 months (95% confidence interval [CI]: 12.2–15.9), with a significant difference between patients receiving ALK inhibitor in first line in any strategy versus not in first line (17.2 mo [95% CI: 14.5–19.9] versus 5.9 mo [95% CI: 4.2–7.6], p < 0.001). The median overall survival was 30.7 months (95% CI: 27.3–34.2), with 37.6 months (95% CI: 28.1–47.1) for ALK inhibitor in the first line versus 20.5 months (95% CI: 15.8–25.1) for subsequent lines of therapy (p < 0.001). ConclusionsMost of our patients with ALK-positive NSCLC were exposed to ALK inhibitors through various support mechanisms. Those patients who could receive ALK inhibitors in the first line had a significant survival advantage as compared with others.

320MO Envonalkib vs crizotinib in treatment-naïve advanced ALK-positive NSCLC: A randomized, multicenter, phase III trial

Envonalkib (TQ-B3139, Env) is a novel small molecule ALK/ROS1/c-Met inhibitor. Here, we presented the primary analysis results of a phase III trial, aiming to evaluate the efficacy and safety of Env versus crizotinib (Cri) in advanced ALK-positive NSCLC patients (pts) who had not received a prior ALK inhibitor.

Cost-effectiveness of ensartinib, crizotinib, ceritinib, alectinib, brigatinib and lorlatinib in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer in China.

ObjectiveSix anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs), including one domestic (ensartinib) and five imported ALK-TKIs (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib), have been recommended as first-line treatments for advanced ALK-positive NSCLC in China. This study sought to examine the cost-effectiveness of these six novel therapies in Chinese patients.Material and methodsWe constructed a Markov model to compare the cost-effectiveness of the six ALK-TKIs as a first-line treatment for patients with advanced ALK-positive NSCLC from the perspective of the Chinese healthcare system. Transition probabilities were estimated by synthesizing data from the PROFILE 1,029 trial and a network meta-analysis. Health state utilities and costs were sourced from published literature, publicly available national databases, and local general hospitals. The robustness of model was assessed via deterministic sensitivity analyses and probabilistic sensitivity analyses.ResultsCompared with crizotinib, ensartinib achieved additional 0.12 quality-adjusted life-year (QALY) with marginal costs of $3,249, resulting in an incremental cost-effectiveness ratio (ICER) of $27,553/ QALY. When compared with ceritinib and brigatinib, ensartinib achieved additional 0.06 and 0.03 QALYs with substantially reduced costs. When compared with lorlatinib and alectinib, ensartinib was associated with a lower QALY and decreased total costs; the ICERs for lorlatinib and alectinib were $934,101/ QALY and $164,888/ QALY, respectively.ConclusionFor Chinese patients with advanced ALK-positive NSCLC, ensartinib was a cost-effective option compared with crizotinib, and was a dominant alternative to ceritinib and brigatinib. Although lorlatinib and alectinib were associated with prolonged survival compared with ensartinib, they were less cost-effective than ensartinib due to the overwhelming total costs.

Efficacy of Brigatinib in Patients With Advanced ALK-Positive NSCLC Who Progressed on Alectinib or Ceritinib: ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2)

IntroductionBrigatinib is a potent next-generation ALK tyrosine kinase inhibitor approved for treatment-naive and crizotinib-refractory advanced ALK-positive (ALK+) NSCLC. We evaluated brigatinib after other next-generation ALK tyrosine kinase inhibitors. MethodsIn this single-arm, phase 2, ALK in Lung Cancer Trial of brigAtinib-2 (NCT03535740), patients with advanced ALK+ NSCLC whose disease progressed on alectinib or ceritinib received brigatinib 180 mg once daily (after 7-d 90-mg lead-in). Primary end point was independent review committee (IRC)-assessed overall response rate (ORR). Circulating tumor DNA (ctDNA) was analyzed. ResultsAmong 103 patients (data cutoff: September 30, 2020; median follow-up [range]: 10.8 [0.5–17.7] mo), confirmed IRC-ORR was 26.2% (95% confidence interval [CI]: 18.0–35.8), median duration of response, 6.3 months (95% CI: 5.6–not reached), and median progression-free survival (mPFS), 3.8 months (95% CI: 3.5–5.8). mPFS was 1.9 months (95% CI: 1.8–3.7) in patients with ctDNA-detectable baseline ALK fusion (n = 64). Among 86 patients who progressed on alectinib, IRC-ORR was 29.1% (95% CI: 19.8–39.9); mPFS was 3.8 months (95% CI: 1.9–5.4). Resistance mutations were present in 33.3% (26 of 78) of baseline ctDNA; 54% (14 of 26) of mutations were G1202R; 52% (33 of 64) of patients with detectable ALK fusion had EML4-ALK variant 3. Most common all-grade treatment-related adverse events were increased creatine phosphokinase (32%) and diarrhea (27%). The mean dose intensity of brigatinib (180 mg once daily) was 85.9%. ConclusionsIn ALK in Lung Cancer Trial of brigAtinib-2, brigatinib was found to have a limited activity in patients with ALK+ NSCLC post-ceritinib or post-alectinib therapy. mPFS was longer with brigatinib in patients without baseline detectable plasma ALK fusion.

The percentage of ALK-positive cells and the efficacy of first-line alectinib in advanced non-small cell lung cancer: is it a novel factor for stratification? (Turkish Oncology Group Study).

Alectinib is an effective second-generation ALK tyrosine kinase inhibitor (TKI) used in the first-line treatment of patients with advanced ALK-positive NSCLC. Recent studies demonstrated that the percentage of ALK-positive tumor cells in patient groups receiving crizotinib might affect outcomes. This study aimed to investigate whether the percentage of ALK-positive cells had a predictive effect in patients with advanced NSCLC who received first-line Alectinib as ALK-TKI. This retrospective study included patients with advanced-stage NSCLC who received alectinib as a first-line ALK-TKI and whose percentage of ALK-positive cells was determined by FISH at 27 different centers. Patients who received any ALK-TKI before alectinib were not included in the study. Patients were separated into two groups according to the median (40%) value of the percentage of ALK-positive cells (high-positive group ≥ 40% and low-positive group < 40%). The primary endpoint was PFS, and the secondary endpoints were OS, ORR, and PFS of the subgroups based on different threshold values for the percentage of ALK-positive cells. 211 patients were enrolled (48.3% female, 51.7% male) to study. 37% (n = 78) of the patients had received chemotherapy previously. After a median of 19.4months of follow-up, the median PFS was not reached in the high-positive group (n = 113), but it was 10.8months in the low-positive group (n = 98) (HR 0.39; 95% CI 0.25-0.60, p < 0.001). The median OS in the high-positive group was not reached, whereas it was 22.8months in the low-positive group (HR 0.37; 95% CI 0.22-0.63, p < 0.001). ORR was significantly higher in the high-positive group (87.2 vs. 68.5%; p = 0.002). According to the cut-off values of < 20%, 20-39%, 40-59%, and ≥ 60%, the median PFS was 4.5, 17.1, and 26months, respectively, and could not be reached in the ≥ 60% group. Our study demonstrated that the efficacy of alectinib varies significantly across patient subgroups with different percentages of ALK-positive cells. If these findings are prospectively validated, the percentage of ALK-positive cells may be used as a stratification factor in randomized trials comparing different ALK-TKIs.

EP08.02-131 Alectinib after Crizotinib Failure in Patients with Advanced ALK-Positive NSCLC: Results from the Spanish Early Access Program

Survival of patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (ALK+ NSCLC) has significantly improved in the last 5 years, following the incorporation of new generation ALK-tyrosine kinase inhibitors into the therapeutic armamentarium. However, there is still scarce information on the effect of patient clinical features, real-world treatment patterns and management of central nervous system (CNS) metastases on survival rates. We performed this real-world study to describe our experience with the use of alectinib in heavily pre-treated patients.

Brief Report: Safety and Antitumor Activity of Alectinib Plus Atezolizumab From a Phase 1b Study in Advanced ALK-Positive NSCLC

IntroductionAlectinib is a preferred first-line treatment option for advanced ALK-positive NSCLC. Combination regimens of alectinib with immune checkpoint inhibitors are being evaluated for synergistic effects. MethodsAdults with treatment-naive, stage IIIB/IV, or recurrent ALK-positive NSCLC were enrolled into a two-stage phase 1b study. Patients received alectinib 600 mg (twice daily during cycle 1 and throughout each 21-d cycle thereafter) plus atezolizumab 1200 mg (d8 of cycle 1 and then d1 of each 21-d cycle). Primary objectives were to evaluate safety and tolerability of alectinib plus atezolizumab. Secondary objectives included assessments of antitumor activity. ResultsIn total, 21 patients received more than or equal to 1 dose of alectinib or atezolizumab. As no dose-limiting toxicities were observed in stage 1 (n = 7), the starting dose and schedule were continued into stage 2 (n = 14). Median duration of follow-up was 29 months (range: 1–39). Grade 3 treatment-related adverse events occurred in 57% of the patients, most often rash (19%). No grade 4 or 5 treatment-related adverse events were reported. Confirmed objective response rate was 86% (18 of 21; 95% confidence interval [CI]: 64–97). Median progression-free survival was not estimable (NE) (95% CI: 13 mo–NE), neither was median overall survival (95% CI: 33 mo–NE). ConclusionsThe combination of alectinib and atezolizumab is feasible, but increased toxicity was found compared with the individual agents. With small sample sizes and relatively short follow-up, definitive conclusions regarding antitumor activity cannot be made.