Background
Lung cancer is the third most common cancer in the US, with NSCLC accounting for approximately 81% of all lung cancer diagnoses. NSCLC is the leading cause of cancer-associated death, contributing for approximately 25% of all cancer-associated deaths.1,2 In the past decade, the NSCLC treatment landscape has rapidly evolved with comprehensive genomic sequencing and targeted therapy.3-9
Anaplastic lymphoma kinase (ALK) fusion involves an inversion or translocation of the short arm of chromosome 2p (2p23), which activates downstream signaling pathways that promote tumor cell progression.10,11 Approximately 5% of NSCLC cases have ALK gene arrangements, most often with adenocarcinoma histology. Risk factors for ALK-positive NSCLC include younger age, non-smokers and East Asian descent. ALK-positive NSCLC is associated with more advanced disease, particularly brain metastases, compared to patients with ALK-negative NSCLC.12,13 There are currently five FDA-approved ALK-inhibitors for metastatic ALK-positive NSCLC, which include alectinib (Alecensa®), brigatinib (Alunbrig®), lorlatinib (Lorbrena®), ceritinib (Zykadia®), and crizotinib (Xalkori®). Alectinib, brigatinib, and lorlatinib have demonstrated superior efficacy over crizotinib based on phase 3 studies in metastatic ALK-positive NSCLC.4,5,7,14 Although they are all designated as category 1 recommendation in the National Comprehensive Cancer Network (NCCN) guidelines, alectinib is commonly used as the preferred first-line treatment for ALK-positive metastatic NSCLC, as it has been the first second-generation ALK inhibitors that was FDA approved, and it is fairly well-tolerated with good efficacy.4,5,13
Standard of care for early-stage ALK-positive NSCLC has been platinum-based combination chemotherapy until the FDA recently approved alectinib as adjuvant treatment for resected stage IB to IIIA NSCLC with ALK rearrangement based on the ALINA trial.15,16
ALINA
ALINA was a randomized, open-label, phase 3 trial that enrolled patients with completely resected stage IB (tumors > 4cm), II or IIIA NSCLC with ALK fusion who did not receive previous systemic anticancer therapy. Eligible patients were randomized 1:1 to receive either alectinib 600 mg twice daily or intravenous platinum-based chemotherapy every 21 days for four cycles. Platinum-based chemotherapy included a combination of cisplatin 75mg/m2 on day 1 with either gemcitabine 1250mg/m2 on days 1 and 8, pemetrexed 500mg/m2 on day 1, or vinorelbine 25mg/m2 on days 1 and 8. Carboplatin AUC of 5-6 was substituted for cisplatin in the event of cisplatin intolerance. Alectinib was given for 24 months or until disease progression, unacceptable toxicities, or withdrawal of consent, whichever occurred first. Patients were not allowed to cross over, and subsequent treatment after disease recurrence was determined at the discretion of the investigators. Efficacy was assessed in the intention-to-treat population, defined as all patients (stage IB, II or IIIA) who underwent randomization. Primary end point was median disease-free survival (DFS), which was defined as the time from randomization to first recurrence, new primary cancer, or death from any cause. Secondary end points included OS and safety.
From August 2018 to December 2021, 130 patients received alectinib, and 127 patients received chemotherapy. The patient characteristics of both groups were similar, although the alectinib group had higher percentage of female patients and never smokers. In both groups, the majority of patients were Asian or white, less than 65 years old and more than half of patients had stage IIIA disease.
After a median duration of follow-up of 27.8 months, the median DFS was significantly longer with adjuvant alectinib compared to chemotherapy in patients across all subgroups. The total 2-year DFS in patients with stage II or IIIA was 93.8% in the alectinib group and 63% in the chemotherapy group (HR 0.24; 95% CI, 0.13 to 0.45; P<0.001). The 2-year DFS in the intent-to-treat population (stage IB, II or IIIA) was 93.6% and 63.7% (HR 0.24; 95% CI, 0.13 to 0.43; P<0.001), respectively; 3-year DFS was 88.7% vs. 54%, respectively. Alectinib also demonstrated significantly lower CNS disease recurrence compared to chemotherapy (HR 0.22, 95% CI, 0.08 to 0.58). The DFS benefit of alectinib was consistent across all subgroups, which included race, sex, smoking status, performance status, and disease stage. Data for overall survival were incomplete at the data cutoff date.
Treatment-related adverse events of any grade occurred in 93.5% in the alectinib group and 89.2% in the chemotherapy group. In the alectinib arm, most common grade 1 or 2 events included increased creatinine kinase level (43%) and constipation (42.4%). Nausea (72.5%) and decreased appetite (29.2%) were the common side effects in the chemotherapy arm. Grade 3 or 4 treatment-related toxicities occurred in 18% and 27.5% in the alectinib and chemotherapy group, respectively. The most common grade 3 and 4 adverse effects were elevated creatinine (6.2%) in the alectinib group and decreased neutrophils (10%) in the chemotherapy group. Serious toxicities occurred in 1.6% and 6.7 % in the alectinib and chemotherapy arms, respectively. No grade 5 treatment-related toxicities were reported. Adverse events leading to treatment discontinuation were reported in 5.5% in the alectinib group and 12.5% in the chemotherapy group. Median duration of treatment was 23.9 months for the alectinib arm and 2.1 months for the chemotherapy arm.16
Discussion
The ALINA trial demonstrated that patients with stage IB, stage II or IIIA ALK-positive NSCLC who received adjuvant alectinib had significantly longer DFS and lower intracranial disease recurrence compared to adjuvant platinum-based chemotherapy. In the intent-to-treat population, alectinib demonstrated 76% lower risk for disease recurrence or death compared to chemotherapy. Additionally, alectinib had better tolerability and longer duration of treatment compared to the chemotherapy arm.16 The excellent safety profile of alectinib reported in this study is consistent with previously reported trials in the metastatic setting.4,5,13 Along with better safety and efficacy profile, adjuvant alectinib may improve quality of life and convenience for patients by avoiding the need for infusion visits that would be needed for chemotherapy regimens.
The results from ALINA has established alectinib as a category 1 recommendation in the NCCN for patients with stage II-IIIA or stage IIIB (T3, N2) NSCLC positive for ALK rearrangement.17 This is the second oral targeted therapy along with osimertinib (Tagrisso ®) that have been FDA approved for early stage NSCLC.9 There are currently ongoing trials investigating the use of other ALK inhibitors for adjuvant ALK-positive NSCLC, including ensartinib (NCT05241028), which is an investigational agent, and crizotinib (NCT02201992). It would also be interesting to assess brigatinib and lorlatinib in this setting, since these agents are deemed to be comparable to alectinib regarding efficacy and toxicity.
Future trials are warranted to assess long-term toxicities and optimal duration of adjuvant alectinib and the potential benefit of adding chemotherapy to alectinib in patients with early stage, ALK-positive NSCLC.
Bibliography
1. Howlader N NA, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA. Cancer Stat Facts: Lung and Bronchus Cancer. SEER Cancer Statistics Review, 1975-2018, National Cancer Institute. Accessed May 24, 2024. https://seer.cancer.gov/csr/1975_2018/
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820
3. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of Selpercatinib in. N Engl J Med. Aug 27 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
4. Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. Jul 01 2017;390(10089):29-39. doi:10.1016/S0140-6736(17)30565-2
5. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. Aug 31 2017;377(9):829-838. doi:10.1056/NEJMoa1704795
6. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated,. N Engl J Med. Jan 02 2020;382(1):41-50. doi:10.1056/NEJMoa1913662
7.Shaw AT, Bauer TM, de Marinis F, et al. First-Line Lorlatinib or Crizotinib in Advanced. N Engl J Med. Nov 19 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187
8. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for Lung Cancers with. N Engl J Med. Jun 24 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695
9.Wu YL, Tsuboi M, He J, et al. Osimertinib in Resected. N Engl J Med. Oct 29 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071
10. Du X, Shao Y, Qin HF, Tai YH, Gao HJ. ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. Apr 2018;9(4):423-430. doi:10.1111/1759-7714.12613
11. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. Oct 28 2010;363(18):1693-703. doi:10.1056/NEJMoa1006448
12. Christopoulos P, Endris V, Bozorgmehr F, et al. EML4-ALK fusion variant V3 is a high-risk feature conferring accelerated metastatic spread, early treatment failure and worse overall survival in ALK. Int J Cancer. Jun 15 2018;142(12):2589-2598. doi:10.1002/ijc.31275
13. Camidge DR, Dziadziuszko R, Peters S, et al. Updated Efficacy and Safety Data and Impact of the EML4-ALK Fusion Variant on the Efficacy of Alectinib in Untreated ALK-Positive Advanced Non-Small Cell Lung Cancer in the Global Phase III ALEX Study. J Thorac Oncol. Jul 2019;14(7):1233-1243. doi:10.1016/j.jtho.2019.03.007
14. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus Crizotinib in ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. Nov 22 2018;379(21):2027-2039. doi:10.1056/NEJMoa1810171
15. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA/CEDR resources page; 2024.
16. Wu YL, Dziadziuszko R, Ahn JS, et al. Alectinib in Resected. N Engl J Med. Apr 11 2024;390(14):1265-1276. doi:10.1056/NEJMoa2310532
17. National Comprehensive Cancer Network: Non-Small Cell Lung Cancer (Version 5.2024). © National Comprehensive Cancer Network, Inc. 2024; 2024.
