Understand ALK Inhibitor Treatment of ALK positive Lung Cancer

Alcensa, Xalkori, and several other precision cancer medicines target ALK positive lung cancer and improve treatment.

ALK Inhibitor Treatment of Lung Cancer

by Dr. C.H. Weaver M.D. updated 11/2018

Approximately 5% of all NSCLC have an identified mutation referred to as the anaplastic lymphoma kinase (ALK) mutation. The ALK mutation is responsible for initiating and promoting cancer growth. Individuals with ALK+ lung cancer tend to be non-smokers or former light smokers; younger, and are a type of NSCLC referred to as adenocarcinoma (based upon the cells affected); and respond worse to standard chemotherapy regimens than patients who do not have the ALK mutation.(1)

Several precision cancer medicines have been developed for the treament of ALK positive NSCLC and these medications appear more effective than traditional chemotherapy.(2)

  • Zykadia® (ceritinib)
  • Alecensa (alectinib)
  • Xalkori (crizotinib)
  • Alunbrig (brigatinib)
  • Lorbrena (lorlatinib) - in development

Xalkori Targeted Therapy Replaces Standard Chemotherapy in ALK-Positive Lung Cancer

The ALK "inhibitor" Xalkori™ was determined to be more beneficial than chemotherapy for certain individuals with ALK positive lung cancer according to research published in the New England Journal of Medicine.

The clinical trial involved 343 NSCLC patients with overactive ALK who were divided into two groups and the results of their treatment directly compared. One group received Xalkori™ and the other group was treated with a standard chemotherapy regimen using pemetrexed, and either carboplatin or cisplatin.

On average, individuals treated with Xalkori™ experienced control of their cancer for almost 11 months compared to only 7 months for those receiving the chemotherapy treatment regimen. Xalkori™treated patients also experienced a greater reduction in symptoms related to their cancer and improved quality of life.

Alcensa Precision Medicine Approved for ALK Positive NSCLC

The Food and Drug Administration granted regular approval to Alcensa for treatment of patients with ALK-positive metastatic NSCLC in December 2015 based on research showing that 38% - 44% of patients intolerant to or failing Xalkori responded to Alcensa treatment.

Of interest 81% of patients with central nervous system involvement responded longer to Alcensa treatment compared to Xalkori.

Alcensa Provides Longer Symptom Improvement than Xalkori in ALK-positive Lung Cancer

Alecensa provides longer symptom improvement than Xalkori in ALK-positive NSCLC. Alcensa improved progression-free survival and prolonged the time to CNS progression compared to Xalkori, had a better toxicity profile than Xalkori, and fewer patients in the Alcensa group reported clinically meaningful worsening in treatment-related symptoms such as diarrhea, peripheral neuropathy, constipation, dysphagia, appetite loss, and nausea/vomiting.

The study authors concluded that “the improvement in survival combined with the patient-reported outcome data supports the use of Alcensa as a new standard of care in the front line treatment of patients with ALK-positive lung cancer.” (3,4)

Alecensa Superior to Xalkori in ALK positive NSCLC Involving the Brain

The results from two separate clinical studies comparing Alecensa® to Xalkori presented at the European Society for Medical Oncology in Madrid demonstrated that Alecensa® is superior for treating NSCLC that has spread to the brain in ALK gene positive NSCLC.

Findings from the ALUR trial1, as well as a secondary analysis of the ALEX trial2 both showed Alecensa can significantly decrease CNS progression of NSCLC in both the first-line as well as the second-line treatment setting.

Doctors presented results from the ALUR clinical trial, which included 107 ALK+ NSCLC patients whose disease had progressed after a previous first-line combination treatment of both platinum-based chemotherapy and Xalkori. These patients were treated with either standard relapse chemotherapy or Alecensa and directly compared.

The CNS overall response rate was 54.2% in those treated with Alecensa compared to zero for those treated with chemotherapy. Alecensa delayed cancer progression by 9.6 months compared to 1.4 months for Xalxori.

Zykadia® Approved for First-Line ALK-Positive NSCLC

The US FDA approved the expanded use of Zykadia® to include the first-line treatment of patients with NSCLC whose cancers are ALK-positive, as detected by an FDA-approved test.

Zykadia is an oral, selective inhibitor of ALK, a gene that can fuse with others to form an abnormal “fusion protein” that promotes the development and growth of certain tumors in cancers including NSCLC.

The approval of Zykadia is based on results from the ASCEND-4 clinical trial which demonstrated that patients treated with first-line Zykadia had an average progression-free survival of 16.6 months compared to 8.1 months for patients treated with standard first-line pemetrexed-platinum chemotherapy and pemetrexed maintenance.1,3

Overall intracranial response rate in patients with measurable brain metastases was 57% for patients treated with Zykadia, versus 22% for patients treated with chemotherapy.

About ASCEND-4 compared Zykadia to standard chemotherapy, including maintenance, in adult patients with Stage IIIB or IV ALK-positive advanced NSCLC who received no prior therapy for their advanced disease. Patients received Zykadia orally or standard pemetrexed-based platinum doublet chemotherapy followed by pemetrexed maintenance and were directly compared.

Of 376 patients, 189 (59 with brain metastases) were treated with Zykadia and 187 (62 with brain metastases) with chemotherapy. Patients treated with first-line Zykadia had a median time to cancer progression of 16.6 months, compared to 8.1 months for patients treated with standard first-line pemetrexed-platinum chemotherapy with pemetrexed maintenance. Patients without brain metastases receiving Zykadia experienced an average time to cancer progression of 26.3 months compared with 8.3 months among patients treated with chemotherapy.

Higher Dose Alunbrig ALK Inhibitor Improves Outcomes

Doubling the dose of the ALK inhibitor Alunbrig improved outcomes in patients with Xalkori refractory NSCLC according to a study published in the Journal of Clinical Oncology.

In the current study patients who started treatment at 90 mg/day and had their dose gradually increased to 180 mg/day experienced an improved response rate (54% versus 45%) and this translated into a delay in cancer progression and prolonged survival. Importantly these better outcomes occurred with limited additional side effects.

Higher doses of chemotherapy drugs ofter kill more cancer cells than lower doses. When higher doses of therapy kill more cancer than lower doses, doctors say there is a “dose response effect.” Additional post FDA approval clinical trials are performed to refine dosing regimens and drug combinations.



  1. Zykadia® (ceritinib) Full Prescribing Information.
  2. Lovly, C., L. Horn, W. Pao. 2016. Molecular Profiling of Lung Cancer. My Cancer Genome. . (Updated March 28). Accessed March 22, 2017.
  3. Soria JC, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): A randomized, open-label Phase 3 study. The Lancet. 2017; 389(10072):917-929.

Novel ALK-Inhibitor AP26113 Active in NSCLC with Brain Metastasis

The novel targeted agent AP26113 shows strong anti-tumor activity in Xalkori® resistant and Xalkori-naïve patients with NSCLC.

AP26113 is a novel targeted agent known as a tyrosine kinase inhibitor. It potently inhibits mutant activated forms of ALK and epidermal growth factor receptor (EGFRm), but does not inhibit native EGFR.

Researchers conducted a phase 1/2 open-label dose finding multi-center study of AP26113 in ALK positive patients and determined that AP26113 was generally well tolerated. An objective response was observed in 22 (65%) of 34 ALK-positive NSCLC patients. The response rate in patients previously treated with Xalkori was 61%; all three Xalkori-naive patients responded (100%), one with a complete response. Eight of 10 patients (80%) with preexisting brain metastasis had radiographic evidence of regression, and ongoing improvements lasting more than 40 weeks were reported.

The researchers note that the data is immature, but 80 percent of patients remain on therapy after six months and there is a marked response in brain metastases.

Interim Results of Ensartinib (X-396) in ALK positive NSCLC Appear Promising

Preliminary results from a small phase 1 study of X-396 showed that X-396 is well tolerated and has antitumor activity in patients with ALK positive non-small cell lung cancer (NSCLC).

X-396 is being developed for the treatment of solid tumors where ALK is deregulated. The interim results were recently presented from a dose-escalation phase 1 study evaluating X-396 in patients with advanced solid tumors. The NSCLC patient group was comprised of ALK-positive patients (n=18) who were either Xalkori® (crizotinib)-naïve (n=5) or Xalkori-resistant (n=13).

Among 11 ALK positive patients evaluable for response 6 patients had a partial response (55%) and 2 had stable disease (18%). Of the three patients with progressive disease, and acquired resistance to Xalkori anti-cancer activity was also observed

The clinical safety profile for X-396 is thus far favorable and different from other ALK inhibitors. This and other studies are ongoing to better determine what role X-396 will play in the management of NSCLC. X-396 is currently only available through participation in clinical trials.

Zykadia Highly Active in Advanced ALK-Positive NSCLC

Zykadia is highly active in patients with advanced ALK-positive NSCLC according to the results of a study published in the New England Journal of Medicine.

Ceritinib is a highly selective ALK-inhibitor that has shown promise in early trials. The majority of patients hacw experienced a clinical response to ceritinib. The overall response rate among patients with ALK-positive NSCLC was 58 percent and the median progression-free survival was seven months.

Xalkori® Approved for Lung Cancer with ROS-1 Gene Alterations

The United States FDA approved Xalkori as treatment for patients with NSCLC whose cancer has an alteration within the ROS-1 gene. Xalkori is already approved for the treatment of patients with NSCLC that have a mutation in the ALK gene.

Lung cancer causes more cancer-related deaths worldwide than any other type of cancer. Approximately 75% of lung cancers are categorized as NSCLC, referring to certain types of cells in the lung from which the cancer arises.

Within all cellular subgroups of lung cancer, however, researchers have begun to identify several different genetic mutations and/or alterations that are associated with the growth and/or the progression of cancer.

Recently, targeted drugs for lung cancer have been developed that inhibit the cancer-stimulating effects caused by specific genetic mutations. It is now standard for samples of a patient’s lung cancer to undergo genetic testing to determine if the cancer has specific mutations for which anti-cancer drugs have been approved. Results of these tests guide treatment options for patients with NSCLC.

Recent data has indicated that 1% of all patients with NSCLC have mutations within the ROS-1 gene. These specific mutations result in an abnormal protein that is involved in abnormal cellular growth, including the growth and/or development of NSCLC. Through blocking the activity of this abnormal protein, Xalkori reduces the growth and spread of cancer cells.

The clinical trial leading to the approval of Xalkori for ROS-1 positive NSCLC included 50 patients with NSCLC that had spread to distant sites in the body. All patients had mutations within the ROS-1 gene.

  • A complete or partial reduction in cancer was achieved in 66% of patients.
  • The median time to cancer progression was 18.3 months.
  • Treatment with Xalkori was generally well tolerated, with side effects remaining consistent to those seen when Xalkori is used for treatment of ALK-positive NSCLC.

The approval of Xalkori for the treatment of NSCLC with a mutation in the ROS-1 gene represents another example of the fast-growing list of targeted agents in the treatment of NSCLC. Patients with NSCLC should speak with their healthcare provider regarding testing of their cancer for specific genetic mutations.


  1. N Engl J Med. 2017 Jun 6. doi: 10.1056/NEJMoa1704795.
  2. Shaw AT, Kim DW, Mehra R, et al: Ceritinib in ALK-rearranged non–small-cell lung cancer. New England Journal of Medicine. 2014; 370: 1189-1197.
  3. Peters S, Camidge DR, Shaw AT, et al. Alcensa versus Xalkori in Untreated ALK-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(9):829–838. doi: 10.1056/NEJMoa1704795.
  4. Abstract 138PD_PR “Patient-reported outcomes (PROs) in ALEX: A phase III study of Alcensa (ALEC) vs Xalkori (CRIZ) in non-small-cell lung cancer (NSCLC)” presented by Maurice Pérol during the Poster Discussion session “Immunotherapy and next-generation TKIs: from second to frontline treatment” on Thursday 12 April, 07:45 to 09:00 (CEST) in Room A. Journal of Thoracic Oncology, Volume 13, Issue 4, Supplement, April 2018
  5. Abstract 1298O_PR “Alectinib vs crizotinib in treatment-naïve ALK+ NSCLC: CNS efficacy results from the ALEX study.
  6. Abstracts 1299O_PR ‘Primary results from the phase III ALUR study of alectinib versus chemotherapy in previously treated ALK+ non-small-cell lung cancer (NSCLC).
  7. Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). Presented at the 37th Congress of the European Society for Medical Oncology (ESMO), Vienna, Austria, September 28-October 2, 2012. Abstract LBA1.
  8. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). Alexander E. Drilon et al. Journal of Clinical Oncology 2016 34:15_suppl, 108-108
  9. Solomon, B., et al. (2014). First-Line Crizotinib versus Chemotherapy in ALK-Positive Lung Cancer. New England Journal of Medicine, 371 (23), 2167-2177 DOI: 10.1056/NEJMoa1408440
  10. Camidge DR, Bazhenova L, Salgia R, et al. Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. 2013 European Cancer Congress. Abstract 3401.
  11. Horn L, Infante J, Blumenshcein G, et al. A phase I trial of X-396, a novel ALK inhibitor, in patients with advanced solid tumors. J Clin Oncol 32:5s, 2014 (suppl; abstr 8030)
  12. United States Food FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. Available at: . Accessed March 11, 2016.

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