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To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency. Highlights: This study provides the first detailed report in China on CNS adverse reactions induced by lorlatinib and its management. It emphasizes the scientific issues and objectives addressed in resolving CNS adverse reactions during lorlatinib treatment. The study reveals that CNS adverse reactions caused by lorlatinib can be effectively managed through dose adjustment. It fills the data gap on CNS adverse reactions to lorlatinib in the Asian population. The study highlights the importance and scientific value of optimizing lorlatinib treatment protocols to improve patient's quality of life. [ABSTRACT FROM AUTHOR]

Abstract To explore the presentation and control of CNS adverse reactions in patients with ALK-positive NSCLC treated with lorlatinib. This study includes a retrospective case report from Sir Run Run Shaw Hospital on a lorlatinib-treated patient with CNS adverse reactions and a systematic literature review of similar cases until January 2023. The report detailed a case of a 74-year-old male with Grade III CNS adverse reactions 25 days after starting lorlatinib, which were reversible with dose modification and pharmacotherapy. The review indicated a 19.39% occurrence rate of such reactions, with a 17% improvement rate post-dose adjustment. CNS adverse reactions frequently occur in ALK-positive NSCLC patients on lorlatinib, yet they are reversible with appropriate management. Research should continue to optimize treatment protocols to decrease these reactions' frequency.

In patients with advanced lung adenocarcinoma (LADC) harboring the echinoderm microtubule-associated protein-like 4 (EML4) -anaplastic lymphoma kinase (ALK) rearrangement, targeted therapy typically demonstrates superior efficacy as an initial treatment compared to chemotherapy. Following resistance to ALK-tyrosine kinase inhibitors (TKIs), regimens incorporating platinum-based dual agents or combined with bevacizumab often show effectiveness. However, therapeutic alternatives become constrained after resistance develops to both TKIs and platinumbased therapies. Given that the majority of ALK-positive non-small cell lung carcinomas (NSCLC) are LADC, the benefits of TKIs for patients with ALK-positive lung squamous cell carcinoma (LSCC) and the optimal treatment strategy for these patients remain a subject of debate. In this case study, we report on a patient with advanced LSCC, in whom the EML4-ALK rearrangement was identified via ARMS-PCR (Amplification Refractory Mutation System-Polymerase Chain Reaction). The patient underwent oral treatment with crizotinib and alectinib, showing effectiveness in both first-line and secondline ALK-TKI therapies, albeit with limited progression-free survival (PFS). Subsequent resistance to second-generation TKI was followed by the detection of tumors in the left neck region via computed tomography (CT). Biopsy pathology revealed non-squamous cell carcinoma, and subsequent treatment with platinum-based double-drug therapy proved ineffective. Further analysis through next-generation sequencing (NGS) indicated ALK negativity but a high expression of programmed death-ligand 1 (PD-L1). Immunotherapy was then initiated, resulting in a PFS of over 29 months and clinical complete remission (cCR). This case underscores the potential benefit of ALK-TKIs in patients with ALK-positive LSCC. Resistance to second-generation TKIs may lead to ALK negativity and histological transformation, highlighting the necessity of repeated biopsies post-TKI resistance for informed treatment decision-making. As of November 2023, imaging studies continue to indicate cCR in the patient, with a survival time exceeding 47 months. [ABSTRACT FROM AUTHOR]

Simple Summary: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Approximately 30% of patients treated with conventional chemotherapy experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL, such as the morphological pattern of the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL requires salvage therapy. Recently, targeted therapies such as ALK inhibitors and brentuximab vedotin have demonstrated dramatic responses in chemoresistant ALK-positive ALCL. Hematopoietic stem cell transplantation has also been reported to be an effective therapy. This article reviews pediatric ALK-positive ALCL, focusing on the risk factors associated with poor prognosis and treatment strategies for relapsed or refractory disease. Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL. [ABSTRACT FROM AUTHOR]

Purpose: Anaplastic lymphoma kinase (ALK) mutations occurs in approximately 3–5% of patients with non-small cell lung cancer (NSCLC). Pleural involvement/effusion is common in ALK-positive patients with NSCLC at baseline. The aim of the study was to evaluate the characteristics of ALK-positive patients who have Ple-I/E. Methods: In this multicenter study, patients with ALK-positive NSCLC who have Ple-I/E were retrospectively analyzed. Clinical and demographic characteristics of the disease, response rates, median progression-free survival (PFS), and overall survival (OS) were evaluated in 362 ALK-positive patients with NSCLC. Results: Of the patients, 198 (54.7%) were male. The median age at the time of diagnosis was 54 (range 21–85) years. All patients' histology was adenocarcinoma (100%). At baseline, 57 (15.7%) patients had Ple-I/E. There was no association between Ple-I/E and gender, lung metastasis, or distant lymphadenopathy (LAP) metastasis. The frequencies of liver, brain, and bone metastases were significantly higher in ALK-positive patients without Ple-I/E compared to those with Ple-I/E (respectively 18.2% vs 4.8%, p = 0.008; 19.1% vs 4.8%, p = 0.001; 20.6% vs 8.9%, p = 0.002). The median PFS was longer in ALK-positive patients who had Ple-I/E (18.7 vs 10.6 months, p = 0.017). Similarly, the median OS was longer in ALK-positive patients who had Ple-I/E (44.6 vs 22.6 months, p = 0.051). Conclusion: Brain, liver, and bone metastases were lower in ALK-positive patients with Ple-I/E. Patients presented with Ple-I/E were prone to have better PFS and OS. [ABSTRACT FROM AUTHOR]

Brain metastases are especially common in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), with a cumulative incidence of over 50% and associated with a poor prognosis, high symptom burden, and decreased quality of life. Lorlatinib is a brain-penetrant, third-generation ALK tyrosine kinase inhibitor (TKI), which has a high potency against resistance mutations seen with earlier generation ALK TKIs. In 2018, lorlatinib was granted accelerated approval in second- and third-line treatment for use in patients with ALK-positive metastatic NSCLC on the basis of phase 1/2 study results. This initial approval was expanded for first-line treatment of patients with ALK-positive metastatic NSCLC on the basis of the interim analysis of the phase 3 CROWN study showing longer progression-free survival, time to intracranial progression, duration of response, and objective response rate compared with crizotinib. This manuscript is a transcript of our podcast, in which we discuss the clinical significance of controlling the onset of brain metastases, considerations in selecting a first-line therapy option, efficacy and safety observed in patients with and without brain metastases, and rationales for using lorlatinib upfront versus reserving for a later line in therapy. [ABSTRACT FROM AUTHOR]

Abstract Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings.

Mau Ern Poh,1 Soon Hin How,2,3 Gwo Fuang Ho,4 Yong Kek Pang,1 Harissa H Hasbullah,5,6 Lye Mun Tho,7 Ibtisam Muhamad Nor,6 Bee Chiu Lim,3 Kean Fatt Ho,8 Muthukkumaran Thiagarajan,6 Azlina Samsudin,9 Azza Omar,10 Choo Khoon Ong,11 Sing Yang Soon,12 Justin Yu Kuan Tan,9 Muhammad Adil Zainal Abidin2 1Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; 2Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan, Pahang, Malaysia; 3Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia; 4Clinical Oncology Unit, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia; 5Faculty of Medicine, Universiti Teknologi Mara, Sungai Buloh, Selangor, Malaysia; 6Oncology and Radiotherapy Department, General Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 7Department of Clinical Oncology, Beacon Hospital, Petaling Jaya, Selangor, Malaysia; 8Mount Miriam Cancer Hospital, Tanjong Bungah, Penang, Malaysia; 9Hospital Sultanah Nur Zahirah, Kuala Terengganu, Terengganu, Malaysia; 10Respiratory Unit, Medical Department, Hospital Raja Perempuan Zainab II, Kota Bharu, Kelantan, Malaysia; 11Gleneagles Penang, George Town, Penang, Malaysia; 12Sarawak Heart Centre, Kuching, Sarawak, MalaysiaCorrespondence: Mau Ern Poh, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, 50603, Malaysia, Tel +60-3-7841-4000, Email ernestpoh@gmail.comPurpose: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non–small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia.Methods: This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan–Meier method.Results: There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P< 0.01).Conclusion: Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.Keywords: ALK inhibitors, chemotherapy, ALK-positive, NSCLC

Approximately one‐third children with anaplastic large cell lymphoma (ALCL) relapse after completion of chemotherapy, particularly for those high‐risk patients. The introduction of novel therapeutic modalities is much needed for these sub‐group patients. Two groups (n = 3, n = 4) of ALCL patients were treated with crizotinib‐ and alectinib‐included ALCL‐99 therapy, respectively, achieving complete remission rates of 66.7% and 100%. Two patients of crizotinib group relapsed, while none relapsed among the alectinib‐treated patients. Adding alectinib instead of crizotinib sufficiently suppressed and maintained the deep NPM‐ALK molecular response. ALK inhibitors were well tolerated with only grade 1 adverse events in both groups. Though a relatively small case number, this study raised the possibility that alectinib‐included therapeutic regimens may benefit the early response, in‐depth molecular remission, and persistent remission to some extent. Further studies are warranted to validate our preliminary findings. [ABSTRACT FROM AUTHOR]

This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase–tyrosine kinase inhibitor, with chemotherapy, for patients with second-line or later advanced anaplastic lymphoma kinase–positive non–small cell lung cancer. The endpoints of interest were overall survival (OS) and progression-free survival (PFS). Evidence for lorlatinib was informed by the single-arm phase I/II trial B7461001. A systematic literature review (SLR) was performed to identify OS and PFS data for chemotherapy. Unanchored matching-adjusted indirect comparisons (MAICs) between lorlatinib and chemotherapy (pemetrexed/docetaxel, platinum-based, or systemic therapy) were performed. The SLR identified 3 relevant studies reporting PFS. Lorlatinib was associated with a significant decrease in the hazard of progression versus the 2 types of chemotherapy assessed. For PFS, the MAIC of lorlatinib versus the combined treatment arm of docetaxel or pemetrexed resulted in an adjusted hazard ratio (HR) of 0.22 (95% confidence interval [CI] 0.15-0.31). When lorlatinib was compared with platinum-based chemotherapy through an MAIC, the adjusted HR for PFS was 0.40 (95% CI 0.29-0.55). An exploratory comparison was performed for OS with evidence for systemic therapy (assumed equivalent to chemotherapy) not identified in the SLR. Lorlatinib provided a significant decrease in hazard of death (OS) versus systemic therapy, with HRs ranging from 0.12 (95% CI 0.05-0.27) to 0.43 (95% CI 0.27-0.60). Lorlatinib demonstrated a significant improvement in PFS compared with chemotherapy, although limitations in the analyses were identified. The evidence informing OS comparisons was highly limited but suggested benefit of lorlatinib compared with systemic therapy. • Previously, chemotherapy was the main treatment for patients who developed resistance to the available initial and subsequent anaplastic lymphoma kinase (ALK)–tyrosine kinase inhibitors. • The evidence for chemotherapy as second-line or later treatment in ALK-positive non–small cell lung cancer was limited; nevertheless, we were able to conduct indirect treatment comparisons between lorlatinib and chemotherapy for progression-free survival and between lorlatinib and systemic therapy (assumed approximately equivalent to chemotherapy) for overall survival. • Matching-adjusted indirect comparisons of treatment using the available evidence suggest that lorlatinib is an effective treatment alternative for second-line or later treatment of ALK-positive non–small cell lung cancer compared with chemotherapy. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) is an aggressive T-cell lymphoma characterized by large T-cells with strong CD30 and ALK expression. Although conventional chemotherapy is effective in most patients, approximately 30% experience a relapse or refractory disease and have a poor prognosis. Several risk factors associated with poor prognosis have been identified in pediatric ALK-positive ALCL. These include morphological patterns with the small cell variant or lymphohistiocytic variant, leukemic presentation, the presence of minimal disseminated disease, or involvement of the central nervous system. Relapsed or refractory ALK-positive ALCL is often resistant to conventional chemotherapy; therefore, salvage therapy is required. In recent years, targeted therapies such as ALK inhibitors and brentuximab vedotin (BV) have been developed. ALK inhibitors block the continuous activation of ALK kinase, a driver mutation that leads to cell proliferation in ALK-positive ALCL. Additionally, BV is an antibody–drug conjugate that targets CD30-positive cells. Both ALK inhibitors and BV have displayed dramatic effects in chemoresistant ALK-positive ALCL. Weekly vinblastine treatment and hematopoietic stem cell transplantation have also been reported to be effective therapies. This article reviews pediatric ALK-positive ALCL, focusing on risk factors and treatment strategies for pediatric patients with relapsed or refractory ALK-positive ALCL.

Abstract Background Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)‐rearranged non–small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)‐based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies. Methods A total of 75 eligible patients were enrolled from Sun Yat‐sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis‐free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log‐rank test was performed to describe the difference of BMFS risk. Results Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C‐index], 0.762; 95% confidence interval [CI], 0.663–0.861) and validation cohort (C‐index, 0.724; 95% CI, 0.601–0.847). Conclusion We have developed a CT‐based radiomics model to predict subsequent BM in patients with non‐brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.

Background: Brigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC. Methods: The pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model. Results: The pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events. Conclusion: Brigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types. [ABSTRACT FROM AUTHOR]

Objective: The aim of this economic evaluation was to assess the cost-utility of brigatinib versus alectinib in the treatment of naïve patients to anaplastic lymphoma kinase-positive advanced non-small cell lung cancer (ALK-positive aNSCLC) from the perspective of the Italian National Health Service (INHS). Methods: A partitioned survival model with four health states (progression-free [PFS], no central nervous system progression [CNS-PFS], central nervous system progression [CNS-PD] and death) was used. The clinical data (progression-free survival, overall survival and time to progression) was based on the ALTA-1L trial for brigatinib and on ALEX trial for alectinib. Utility values were derived from EORTC QLQ-C30 scores evaluated in the ALTA-1L trial and literature. Costs included frontline therapies, subsequent therapies, best supportive care (BSC), administration, concomitant medications, adverse events and health states. Direct medical costs and benefits (quality-adjusted life-years, QALYs) were discounted at a 3.0% annual rate. Uncertainty was assessed using deterministic (DSA) and probabilistic sensitivity analyses (PSA). Results: The analysis showed that brigatinib was dominant versus alectinib; brigatinib led to a gain of 0.216 QALYs and to a treatment cost reduction of € 85,635. The results of the DSA showed that no parameters of the model significantly modified the base case result. Conclusions: This economic evaluation suggested that, compared with alectinib, brigatinib can be considered a valid cost-utility option from the perspective of INHS in the treatment of patients with ALK-positive aNSCLC.

• Insight into the mutational landscape of ALK-positive advanced NSCLC. • EML4-ALK v3 and TP53 alterations correlate with unfavorable PFS on first-line crizotinib. • EML4-ALK v3 demonstrates a distinct resistance landscape from the non-v3 subset. • Bypass and downstream signaling pathway alterations as potential resistance mechanisms to first-line crizotinib. Crizotinib remains one of the most commonly used targeted therapies for ALK fusion-positive patients. However, the mutational profiles and mechanisms of resistance to first-line crizotinib treatment remain to be thoroughly examined. We retrospectively reviewed 125 ALK -positive patients with histological and/or cytological diagnosis of NSCLC. Of these, baseline samples were available from 62 patients and 63 had resistance samples following first-line crizotinib treatment, with 18 patients having paired baseline and resistance samples. All patients were genetically profiled by NGS using a 139 lung cancer gene panel (Pulmocan®, Nanjing Geneseeq Technology Inc.). Survival associations of progression-free survival (PFS) and resistance mechanisms were evaluated in relation to ALK fusion variants and background genetic alterations. The median age of the cohort was 53 years old (range 26–78; 46.4 % females). Three novel ALK fusion partners were identified, including PSME4, cullin3 (CUL3) and coiled-coil domain containing 85A (CCDC85A). Among the different ALK fusion genes, patients carrying the v3 variant experienced worse PFS outcome compared with other non-v3 fusions (P = 0.01) in response to first-line crizotinib. Profiling of the genetic landscape revealed TP53 as the most frequently co-mutated gene, alterations of which were associated with unfavorable outcome (P = 0.024) and were among the secondary acquired mutations in the resistance samples. Examinations of the resistance mechanisms showed that the v3 variant was more likely to acquire ALK activating mutations (P = 0.04). Off-target resistance mechanisms included mutations in genes in the RAS/MAPK and its parallel pathway genes, such as ERBB2 , BRAF , KRAS , FGFR3 , NF1 and CREBBP. In this study, through profiling of the mutational landscape of ALK-positive advanced NSCLCs both at baseline and disease progression, we characterized resistance mechanisms and molecular correlations of PFS in response to first-line crizotinib. Our findings may facilitate rational selection of subsequent ALK TKIs in the clinic. [ABSTRACT FROM AUTHOR]

Introduction: Alectinib 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. Methods: Adults 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. Results: In 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). Conclusions: The 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.

Introduction: The Blood First Assay Screening Trial revealed the clinical applicability of blood-based next-generation sequencing to identify patients with ALK-positive NSCLC for alectinib treatment. To understand the relationship between tissue-based versus blood-based testing, we retrospectively investigated concordance between VENTANA ALK (D5F3) CDx immunohistochemistry and the FoundationACT (FACT; Foundation Medicine, Inc.) plasma assay, and compared clinical efficacy between phase 3 ALEX study subpopulations. Methods: Patients with advanced ALK-positive (by immunohistochemistry) NSCLC were randomized 1:1 to alectinib 600 mg or crizotinib 250 mg, twice daily. Assessable baseline plasma samples were analyzed for ALK positivity by FACT; positive percent agreement with immunohistochemistry was evaluated. Progression-free survival (PFS), duration of response, and objective response rate were compared between intention-to-treat (ITT) and biomarker-evaluable populations, and plasma ALK-positive and plasma ALK-negative subpopulations. Results: In the ITT population (303 patients; alectinib, 152; crizotinib, 151), all patients had ALK-positive tumors by immunohistochemistry. In the biomarker-evaluable population (149 patients; alectinib, 76; crizotinib, 73), 105 had plasma ALK-positive and 44 had plasma ALK-negative tumors. Positive percent agreement between immunohistochemistry and FACT was 70.5% (105 of 149; 95% confidence interval: 62.5–77.7). Baseline characteristics were generally balanced, with some exceptions, notably tumor burden. Median PFS in plasma ALK-positive and ALK-negative patients was 22.4 months and not estimable with alectinib and 7.3 months and 12.9 months with crizotinib, respectively; median duration of response was 25.9 months and not estimable with alectinib and 5.6 months and 11.5 months with crizotinib, respectively. Conclusions: Reasonable concordance between FACT and immunohistochemistry was observed; both methods are valuable in identifying ALK-positive patients, separately or concurrently. Alectinib was found to have superior PFS in the plasma ALK-positive population, as in the ITT population.

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)‐rearranged non–small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)‐based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies. Methods: A total of 75 eligible patients were enrolled from Sun Yat‐sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis‐free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log‐rank test was performed to describe the difference of BMFS risk. Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C‐index], 0.762; 95% confidence interval [CI], 0.663–0.861) and validation cohort (C‐index, 0.724; 95% CI, 0.601–0.847). Conclusion: We have developed a CT‐based radiomics model to predict subsequent BM in patients with non‐brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM. [ABSTRACT FROM AUTHOR]

European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II basket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. After central reference pathology, eligible ALK- positive and ALK -negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or systemic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed centrally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or partial response). If ≥6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confidence interval [CI] 34.9–90.1%) in ALK -positive patients and 14.3% (95% CI 0.0–57.9%) in ALK -negative patients. In the ALK -positive and ALK -negative patients, the median progression-free survival was 18.0 months (95% CI 4.0–NE) and 14.3 months (95% CI 1.2–31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2–95.6) and 34.3% (95% CI 4.8–68.5). Safety results were consistent with previously reported data. These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK -positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. EORTC 90101, NCT01524926. • No molecular agent has been approved for advanced, inoperable IMT. • In this updated analysis, crizotinib achieved an ORR of 66.7% in ALK positive IMT. • In ALK -positive IMT, the median PFS with crizotinib was 18.0 months (95% CI 4.0–NE). • In ALK -positive IMT, the 3-year overall survival rate was 83.3% (95% CI 48.2–95.6). • Crizotinib should be considered for approval in advanced ALK -positive IMT. [ABSTRACT FROM AUTHOR]

We report a case of anaplastic lymphoma kinase-positive anaplastic large T-cell lymphoma (ALK+ALCL) presenting primarily as a sinonasal mass with pseudoproptosis in an 11-year-old boy. The diagnosis was based on histopathological and immunohistochemical (IHC) evaluation, which is indispensable for determining tumor type. On the basis of clinicoradiological findings, provisional differential diagnoses of angiofibroma and rhabdomyosarcoma were made. Upon histopathological examination of the biopsy sent, the diagnosis of lymphoma in the sinonasal region was considered. Upon IHC, the tumor cells showed immunoreactivity for vimentin, CD45, CD30, and ALK. The tumor cells showed focal immunoreactivity for CD3 and CD68. Ki-67 labeling index was 70%. They were nonimmunoreactive for PAN cytokeratin, epithelial membrane antigen, cluster of differentiation (CD) 20, CD15, CD56, S100, smooth muscle actin, and myogenin. The diagnosis of ALK+ALCL was rendered. The studied IHC markers confirmed the histopathological diagnosis and helped in further subtyping. To the best of our knowledge, this is the first case of ALCL presenting primarily as a sinonasal mass with pseudoproptosis. [ABSTRACT FROM AUTHOR]

Robert Ali,1 Junaid Arshad,1 Sofia Palacio,1 Raja Mudad2 1Department of Medicine, Division of Oncology, Jackson Memorial Hospital, University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Centre, Miami, FL 33131, USA; 2Department of Medicine, Division of Oncology, University of Miami, Miller School of Medicine, Sylvester Comprehensive Cancer Centre, Miami, FL 33136, USA Abstract: Despite the benefits of first and second generation anaplastic lymphoma kinase (ALK) inhibitors in the management of ALK-rearranged advanced non-small-cell lung cancer (NSCLC), the development of acquired resistance poses an ongoing dilemma. Brigatinib has demonstrated a wider spectrum of preclinical activity against crizotinib-resistant ALK mutant advanced NSCLC. The current review narrates a brief history of tyrosine kinases, the development and clinical background of brigatinib (including its pharmacology and molecular structure) and its use in ALK-positive NSCLC. Keywords: non-small cell lung cancer, ALK positive, ALK inhibitors, brigatinib, TKI

We present here a case of ALK-positive lung adenocarcinoma that has been started on Alectinib. Treatment has been initiated at the recommended initial dose, but it subsequently required a dose adjustment following adverse drug events. Alectinib is a second-generation, CNS-active, tyrosine kinase inhibitor used in the treatment of ALK-positive non-small cell lung cancer. Its efficacy as a first-line treatment and as a second-line agent after Crizotinib has been proven across several trials both in terms of overall response rate and progression-free survival. The use of Alectinib is associated with side effects that occasionally lead to treatment discontinuation, interruption, or dose adjustment. Several studies have used two starting doses – 300 mg and 600 mg twice daily – across different populations and have consistently shown efficacy of Alectinib for both treatment doses. Results of these studies have also revealed that body weight, rather than race, affect the pharmacokinetics of Alectinib. Randomized trials have shown that the 600 mg dose is associated with more grade ≥3 adverse events and more changes in treatment in contrast to the 300 mg dose. A lower dose of Alectinib may limit treatment disruptions and dose reductions particularly for specific patient populations—particularly those with a lower body weight.

Background: Alectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited., Methods: This retrospective cohort study included fifteen patients with ALK -positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance., Results: Among fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT)., Conclusions: The continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK -positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-798/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32e0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46e0.98). The 5-year OS rate was 62.5% (95% CI 54.3e70.8) with alectinib and 45.5% (95% CI 33.6e57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34e1.00)] and those without [HR 0.76 (95% CI 0.45 e1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALKpositive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

• Final PFS data and second pre-planned interim analysis of OS and safety from J-ALEX. • Sustained improvement in IRF-assessed PFS demonstrated with alectinib. • Superiority of alectinib to crizotinib not concluded at second interim OS analysis. • Fewer alectinib-treated patients experienced grade ≥3 adverse events. • Alectinib continued to demonstrate superiority in IRF-assessed PFS vs crizotinib. The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK -positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018. Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26–0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35–1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib). At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK -positive NSCLC, with a favorable safety profile. OS follow-up continues. [ABSTRACT FROM AUTHOR]

• PRO data from the randomized ALEX study of two ALK inhibitors in ALK -positive NSCLC. • QoL and lung cancer symptom improvement prolonged with alectinib versus crizotinib. • Better patient-reported tolerability with alectinib on treatment-related symptoms. • PRO findings support the primary outcome results of the ALEX study. Alectinib demonstrated superior efficacy and a safety profile that compared favorably with crizotinib in treatment-naïve ALK + non-small-cell lung cancer (NSCLC) in the phase III ALEX study. We present patient-reported outcomes (PROs) from ALEX to assess disease burden, treatment-related symptom tolerability, and health-related quality of life (HRQoL) with alectinib versus crizotinib. Patients were randomized to receive alectinib 600 mg or crizotinib 250 mg twice daily until disease progression, death, or withdrawal. Pre-specified PRO endpoints were: mean change from baseline in symptoms, HRQoL, and functioning; and time to deterioration (TTD) in cough, dyspnea, chest pain, arm/shoulder pain, fatigue, and a composite of three symptoms (cough, dyspnea, chest pain). PRO data were collected using EORTC QLQ-C30 and LC13 questionnaires. Raw scores were standardized to a 0–100-point range, with a ≥10-point score change defined as clinically meaningful. TTD was defined as the time from randomization until confirmed clinically meaningful deterioration (i.e., a ≥10-point score change from baseline). Baseline completion rates and characteristics were balanced in the PRO-evaluable population (alectinib n = 100, 66%; crizotinib n = 97, 64%). On average, alectinib-treated patients reported clinically meaningful improvements in lung cancer symptoms for longer than crizotinib-treated patients. Between-treatment differences in lung cancer symptoms tended to favor alectinib from 11.1 months (45 weeks) onwards, around the time of median PFS with crizotinib (11.1 months). TTD in lung cancer symptoms was similar between treatment arms, despite longer duration of symptom improvement with alectinib; composite symptom endpoint (hazard ratio 1.10 [95% confidence interval: 0.72–1.68]). Duration of clinically meaningful improvement in HRQoL was longer with alectinib versus crizotinib (Week 88 vs. Week 68, respectively). Better patient-reported tolerability was observed with alectinib versus crizotinib on common treatment-related symptoms. PRO data support the superior efficacy and tolerability of alectinib relative to crizotinib demonstrated in the ALEX study. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the prognostic utility of inflammation-based prognostic scores in patients with ALK-positive metastatic or non-resectable non-small-cell lung cancer (NSCLC) treated with crizotinib., Patients and Methods: A total of 82 patients with ALK-positive metastatic or non-resectable NSCLC who received ALK TKI crizotinib were included. Pre-treatment modified Glasgow prognostic score (mGPS), prognostic nutritional index (PNI), and systemic immune-inflammation index (SII) were calculated. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment mGPS, PNI, and SII on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR)., Results: The ORR was 77.2%, while 1-year OS and PFS rates were 95.0% and 93.5%, respectively. The univariate analysis revealed significantly higher 1-year PFS (89.4 vs. 64.4%, p=0.043) and OS (92.0 vs. 83.3%, p=0.01) rates in patients with low (<934.7) vs. high (≥934.7) SII scores. Multivariate analysis revealed that PNI ≥0.09 was a significant determinant of poorer 1-year OS rates (hazard ratio [HR]: 2.46, 95% confidence interval [CI] 0.88-4.85, p=0.035). No significant difference was observed in survival rates according to gender, age, smoking status, prior lines of therapy, or mGPS scores, while higher mGPS scores (odds ratio [OR]: 0.1, 95%CI 0.16-1.04; p=0.009) and higher PNI scores (OR: 0.16, 95% CI 0.02-0.55; p=0.035) were associated with poorer ORR., Conclusion: Our findings indicate the prognostic significance of PNI and SII in terms of survival outcome and the impact of mGPS and PNI on treatment response in patients with ALK-positive NSCLC treated with crizotinib., Competing Interests: Conflicts of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

We conducted a large‐scale surveillance study as a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK‐positive non–small‐cell lung cancer (NSCLC) in Japan. Patients receiving 300 mg twice‐daily alectinib (September 2014 to June 2015) were monitored until termination of alectinib or completion of 18 months of treatment at 519 Japanese study sites. The primary endpoint was the incidence of adverse drug reactions (ADR), which are important identified risks for alectinib in Japanese patients. Overall survival (OS), a key secondary endpoint, was assessed according to information on outcome. Overall, 1251 patients were enrolled. The median patient age was 62.0 years; 12.9% of patients were aged ≥75 years. At baseline, 63.0% of patients had received crizotinib and 40.6% had brain metastases. Altogether, 1512 ADR occurred in 654 patients (53.6%), with 164 grade ≥3 ADR in 123 patients (10.1%). Commonly occurring ADR were hepatic disorders (all grades, 19.8%; grade ≥3, 2.0%), decreased neutrophil and/or white blood cell count (all grades, 7.6%; grade ≥3, 1.1%), and interstitial lung disease (all grades, 3.8%; grade ≥3,.7%). Median OS was not estimable. The 18‐month cumulative OS rate was longer in patients with ECOG performance status ≤1 (vs 2 or ≥3; 83.7% vs 44.5% or 27.2%), without prior crizotinib (vs with; 81.1% vs 73.4%), receiving first‐line alectinib (vs second and third or later line; 83.0% vs 79.2% or 71.9%), without brain metastases (vs with; 79.5% vs 71.5%). These data confirm the favorable safety and effectiveness of alectinib in patients with ALK‐positive NSCLC in Japan. The highly selective ALK inhibitor alectinib is approved as the standard of care for advanced anaplastic lymphoma kinase (ALK)‐positive non–small‐cell lung cancer (NSCLC). This large‐scale surveillance study was implemented as part of a post–marketing commitment to investigate the safety and effectiveness of alectinib in patients with ALK‐positive NSCLC in Japan. Data from this real‐world study confirm the favorable safety and effectiveness profile of alectinib in Japanese patients with ALK‐positive NSCLC. [ABSTRACT FROM AUTHOR]

Background The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK +) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX. Patients and methods Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression. Results In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n  =   64; crizotinib, n  =   58), 43 had measurable lesions (alectinib, n  =   21; crizotinib, n  =   22), and 46 had received prior radiotherapy (alectinib, n  =   25; crizotinib, n  =   21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25–0.64] and those without (HR 0.51, 95% CI: 0.33–0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P  <   0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not. Conclusion Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK + NSCLC, irrespective of prior CNS disease or radiotherapy. Clinical trial registration ClinicalTrials.gov NCT02075840 [ABSTRACT FROM AUTHOR]

Introduction: Alectinib is an oral tyrosine kinase inhibitor currently recommended by the National Comprehensive Cancer Network (NCCN) as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase (ALK) gene rearrangement-positive non-small cell lung cancer (NSCLC). Skin toxicity is a known adverse effect of this medication, yet current recommendations are unclear regarding how to best manage patients who develop severe skin toxicity while taking alectinib. Case report: Here, we describe a case of successful rechallenge with alectinib by utilizing a desensitization procedure in a patient who had developed severe alectinib-induced skin toxicity about two weeks into treatment. Management and outcome: Upon resolution of the initial skin toxicity symptoms, the patient was rechallenged with alectinib using a modified version of a previously published desensitization procedure. The patient tolerated the rechallenge with no recurrence of skin toxicity or other adverse effects and was able to continue treatment with alectinib. Discussion: Alectinib is currently recommended as the preferred first-line treatment option for the treatment of metastatic anaplastic lymphoma kinase gene rearrangement-positive NSCLC due to improved progression-free survival when compared to crizotinib. The development of skin toxicity can lead to early discontinuation of alectinib treatment, forcing providers and patients to select alternative, potentially less effective options. This case report provides evidence that patients who have experienced severe skin toxicity due to alectinib may be able to continue this first-line treatment option by rechallenging them using a desensitization procedure. [ABSTRACT FROM AUTHOR]

Objectives We determined the central nervous system (CNS) efficacy of alectinib by calculating time to CNS progression and cumulative incidence rates (CIRs) of CNS progression, non-CNS progression and death in patients with anaplastic lymphoma kinase ( ALK )-positive non-small-cell lung cancer (NSCLC) enrolled in the J-ALEX phase III study. Materials and methods Japanese patients aged ≥20 years with ALK -positive NSCLC who were ALK inhibitor-naïve and chemotherapy-naïve, or who had received one previous chemotherapy regimen, were enrolled. Patients with treated or untreated asymptomatic CNS metastases were eligible. Treatment comprised oral alectinib 300 mg twice daily or crizotinib 250 mg twice daily until progressive disease, unacceptable toxicity, death or withdrawal. Imaging scans (computed tomography/magnetic resonance imaging) were taken at baseline and at regular intervals throughout the study. The CIRs for CNS progression, non-CNS progression and death were calculated for patients with and without baseline CNS metastases using a competing risks method. Results The hazard ratio for time to CNS progression in patients with and without baseline CNS metastases was 0.51 (95% confidence interval [CI]: 0.16–1.64; P  = 0.2502) and 0.19 (95% CI: 0.07–0.53; P  = 0.0004), respectively. The CIRs of CNS progression and non-CNS progression were lower in the alectinib group than in the crizotinib group at all time points. The 1-year CIRs of CNS progression were 16.8% and 5.9% with crizotinib and alectinib, respectively, and the 1-year CIRs of non-CNS progression were 38.4% and 17.5%, respectively. Comparable findings were obtained in patients with or without baseline CNS metastases. Conclusion Alectinib appears to avert the progression of CNS metastases in patients with ALK -positive NSCLC and baseline CNS metastases, and to prevent the development of new CNS lesions in patients without baseline CNS disease. [ABSTRACT FROM AUTHOR]