Alecensa (Alectinib), an Oral Tyrosine Kinase Inhibitor, Approved for Metastatic Non–Small-Cell Lung Cancer with ALK Mutation

2016 Oncology Pharmacy Guide to New FDA Approvals - Drug Profiles

 

Lung cancer is the second most common cancer in the United States.1 In 2015, an estimated 221,200 new cases of lung cancer were diagnosed, representing 13.3% of all new cancer cases.1 Furthermore, lung cancer is the leading cause of cancer mortality in men and women, responsible for 27% of all cancer deaths, and claiming more lives than breast, colon, prostate, and ovarian cancers combined.1,2 From 2007 to 2011, there was a slight decline in lung cancer incidence and deaths.3

The 2 major types of lung cancer include non–small-cell lung cancer (NSCLC) and small-cell lung cancer.4 Approximately 85% to 90% of all lung cancers are NSCLC, which comprise squamous-cell carcinoma and non–squamous-cell carcinoma, including adenocarcinoma and large-cell carcinoma.4,5 Less common types of NSCLC include carcinoid tumor, pleomorphic, salivary gland carcinoma, and unclassified carcinoma.5 Squamous-cell carcinomas account for 25% to 30% of all lung cancers, and adenocarcinomas account for 40% of all lung cancers.4

As with other cancers, the earlier that lung cancer is detected and treated, the better the prognosis.2 Nevertheless, approximately 22% of lung cancers have already spread to regional lymph nodes at diagnosis, and 57% have metastasized to a distant site.1 The 5-year relative survival rate for patients with lung cancer that has spread regionally is 27.4%, and only 4.2% for patients with metastatic disease.1

The treatment of metastatic NSCLC typically includes chemotherapy, targeted therapy, immunotherapy, or a combination of these options.6 The majority of targeted therapies are either small-molecule compounds designed for targets inside the cell, or monoclonal antibodies designed for targets on the outer surface of cancer cells.6

Advances in cell biology and gene expression have fostered the development of new targeted therapies and have changed the landscape of NSCLC treatment.7 Several predictive biomarkers have emerged.7 Some of these biomarkers include the sensitizing epidermal growth factor receptor (EGFR) mutations (eg, exon 19 deletion or exon 21 L858R mutation) and the anaplastic lymphoma kinase (ALK) fusion gene.7

Sensitizing EGFR mutations are harbored in an estimated 10% of Caucasian patients with NSCLC, and in up to 50% of Asian patients with NSCLC.7 ALK gene rearrangements are found in an estimated 2% to 7% of patients with NSCLC.7 Oncology practice guidelines recommend testing for EGFR mutations and ALK gene rearrangements for select patients with NSCLC.7,8 Other biomarkers are being studied for their potential response to targeted therapies.7

Molecular profiling and the evolving development of targeted, patient-precise treatments are transforming the therapeutic options for patients with NSCLC. In 2015, several targeted therapies—including immunotherapies, angiogenesis inhibitors, tyrosine kinase inhibitors, and monoclonal antibodies—were approved for the treatment of patients with NSCLC.9,10 Several of those approvals were new indications for drugs already available on the market, and several approvals were for novel targeted therapies. Altogether, 2015 was a banner year for the approval of new therapies for NSCLC, significantly increasing the treatment options available for patients with lung cancer.

Alectinib Approved for Metastatic NSCLC with ALK Mutation

On December 11, 2015, alectinib (Alecensa; Genentech), an oral tyrosine kinase inhibitor, was approved by the US Food and Drug Administration (FDA) for the treatment of patients with metastatic NSCLC and the ALK mutation whose disease had progressed while taking crizotinib (Xalkori) or who were unable to tolerate treatment with crizotinib.11-13 Alectinib was granted an accelerated regulatory pathway by the FDA, based on data that suggest clinical benefit.11

ALK gene mutations occur in some cancer cells, including lung cancer cells. In patients with ALK mutation metastatic NSCLC, the cancer often spreads to the brain. Alectinib targets and blocks the activity of the ALK protein.11

Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, commented, “Today’s approval provides a new therapy for a group of patients who would have few treatment options once their disease no longer responds to treatment with Xalkori.” Dr Pazdur added, “In addition to the primary effect on tumors in the lung, Alecensa clinical trials provide evidence of an effect on tumors that had spread to the brain, which is an important effect for clinicians to understand.”11

Table 1

Mechanism of Action

Alectinib is a tyrosine kinase inhibitor that blocks the activity of the protein made by the mutated ALK gene—a process that may prevent the growth and spread of NSCLC cells.11,12,14 Alectinib also targets the RET protein, a receptor tyrosine kinase that has a role in cell growth and differentiation. RET is a potential therapeutic target in advanced NSCLC.12,15

Dosage and Administration

Alectinib is available as a 150-mg capsule. The recommended dosage of alectinib is 600 mg twice daily taken orally with food. Alectinib is administered until disease progression or until unacceptable toxicity. The contents of the capsule should not be opened or dissolved. A detailed dose-reduction schedule and criteria for dose modification are included in the full prescribing information for alectinib.12

Clinical Studies

The FDA approval of alectinib was based on 2 studies (Study 1 and Study 2) that established its safety and efficacy in patients with locally advanced or metastatic NSCLC with the ALK mutation whose disease progressed during treatment with crizotinib.12,16,17

Study 1 was a phase 2, single-arm, open-label study in North America that included 87 patients (median age, 54 years) who received alectinib 600 mg orally twice daily.12,16

Study 2 was a phase 2, single-arm, international, open-label, multicenter study involving 138 patients (median age, 52 years) who received alectinib 600 mg orally twice daily.12,17

The primary efficacy outcome for both studies was the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by a central independent review committee.12,16-18 The secondary efficacy end points included the duration of response and efficacy against the spread of disease to the central nervous system.12,16,17

The objective response rates, as assessed by an independent review committee, were 38% in Study 1 and 44% in Study 2 (Table 1). The investigator-assessed objective response rates for patients receiving alectinib were 46% in Study 1 and 48% in Study 2 (Table 1).12

An assessment of the objective response rate and the duration of response in the subgroup of 51 patients (in Studies 1 and 2) with baseline measurable lesions in the central nervous system revealed that 61% of patients experienced a complete or partial reduction of their brain tumors, with a median duration of response of 9.1 months (Table 2).12,16,17

Table 2

 

Adverse Reactions

The safety of alectinib was assessed in 2 clinical studies (Study 1 and Study 2), and involved 253 patients with advanced NSCLC and the ALK mutation who received alectinib 600 mg orally twice daily. These patients were exposed to alectinib for a median duration of 9.3 months. The most common adverse reactions (incidence ≥20%) associated with alectinib therapy included fatigue (41%), constipation (34%), edema (30%), and myalgia (29%).12

The most common grade 3 or 4 adverse reactions included dyspnea (3.6%), fatigue (1.2%), myalgia (1.2%), and diarrhea (1.2%).

Serious adverse reactions occurred in 19% of patients, and most often included pulmonary embolism (1.2%), dyspnea (1.2%), and hyperbilirubinemia (1.2%).

Adverse reactions that led to the permanent discontinuation of alectinib occurred in 6% of patients, and most often included hyperbilirubinemia (1.6%), increased alanine transaminase (ALT) levels (1.6%), and increased aspartate transaminase (AST) levels (1.2%).12

Alectinib has no contraindication, and there are no known drug interactions associated with alectinib that require dosage adjustments.12

Warnings and Precautions

Hepatotoxicity. Elevated AST levels and elevated ALT levels, some serious, have been reported in patients receiving alectinib. Alectinib should be withheld and resumed at a lower dose or permanently discontinued in patients with severe elevations in ALT levels and in AST levels.12

Interstitial lung disease and pneumonitis. Any patient with worsening respiratory symptoms, including dyspnea, cough, and fever, should be monitored closely. Treatment with alectinib should be withheld in patients with interstitial lung disease, and permanently discontinued if no other causes for this condition have been determined.12

Bradycardia. Symptomatic bradycardia has been reported in patients who were exposed to alectinib. The patients’ heart rate and blood pressure should be monitored regularly. Alectinib should be withheld in patients with symptomatic bradycardia, and permanently discontinued for life-threatening bradycardia.12

Severe myalgia and elevated creatine phosphokinase levels. Myalgia or musculoskeletal pain has been reported in patients receiving alectinib. Creatine phosphokinase levels should be assessed every 2 weeks in the first month of treatment, and in patients reporting symptoms (eg, unexplained muscle pain, tenderness, or weakness). Depending on the severity of creatine phosphokinase levels, alectinib should be withheld and then resumed, or the dose should be reduced, as recommended in the prescribing information.12

Embryo-fetal toxicity. There is a risk for fetal harm when alectinib is administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus.12

Use in Specific Populations

Pregnancy. Alectinib exposure may cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus.12

Lactation. No data are available on the presence of alectinib in breast milk, its effects on the breast-fed infant, or its effects on milk production.12

Females and males of reproductive potential. Alectinib can cause harm to a fetus when administered to pregnant women. Women of reproductive potential should be advised to use effective contraception during treatment with alectinib, and for 1 week after the final dose of alectinib. Men with women partners of reproductive potential should be advised to use effective contraception while receiving alectinib, and for 3 months after the final dose of alectinib.12

Pediatric use. The safety and effectiveness of alectinib in pediatric patients have not been determined.12

Geriatric use. Clinical studies did not include a sufficient number of patients aged ≥65 years to determine whether they respond differently to alectinib compared with younger patients.12

Renal impairment. Patients with mild or moderate renal impairment do not require a dosage adjustment of alectinib. The safety of alectinib has not been studied in patients with severe renal impairment or with end-stage renal disease.12

Hepatic impairment. No dosage adjustment of alectinib is required in patients with mild hepatic impairment. The safety of alectinib has not been studied in patients with moderate or severe hepatic impairment.12

Conclusion

With the FDA approval of alectinib, an oral tyrosine kinase inhibitor, a new therapeutic option became available for patients with metastatic NSCLC with ALK mutation whose disease progressed while taking crizotinib, or those who could not tolerate crizotinib. Clinical trials with alectinib showed that patients with advanced NSCLC with ALK mutation experienced significant tumor shrinkage, including tumor responses in the central nervous system. In addition to its effect on lung tumors, alectinib has been shown to have a positive effect on tumors that have spread to the brain.


References

  1. National Cancer Institute. SEER stat fact sheets: lung and bronchus cancer. http://seer.cancer.gov/statfacts/html/lungb.html. Accessed February 2, 2016.
  2. Mayo Clinic staff. Diseases and conditions: lung cancer. September 25, 2015. www.mayoclinic.org/diseases-conditions/lung-cancer/basics/causes/con-20025531. Accessed February 3, 2016.
  3. American Cancer Society. Cancer facts & figures 2015. 2015. www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed February 3, 2016.
  4. American Cancer Society. Lung cancer (non-small cell). Revised February 8, 2016. www.cancer.org/acs/groups/cid/documents/webcontent/003115-pdf.pdf. Accessed February 12, 2016.
  5. National Cancer Institute. Non-small cell lung cancer treatment (PDQ®). Updated May 12, 2015. www.cancer.gov/types/lung/patient/non-small-cell-lung-treatment-pdq. Accessed February 4, 2016.
  6. National Cancer Institute. Targeted cancer therapies. www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet. Accessed February 4, 2016.
  7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): non-small cell lung cancer. Version 4.2016. January 12, 2016. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed February 3, 2016.
  8. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. J Clin Oncol. 2014;32:3673-3679.
  9. American Cancer Society. Lung cancer (non-small cell): immunotherapy for non-small cell lung cancer. Revised February 8, 2016. www.cancer.org/cancer/lungcancer- non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-immunotherapy. Accessed February 12, 2016.
  10. American Cancer Society. Lung cancer (non-small cell): targeted therapy drugs for non-small cell lung cancer. Revised February 8, 2016. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-treating-targeted- therapies. Accessed February 12, 2016.
  11. US Food and Drug Administration. FDA approves new oral therapy to treat ALK-positive lung cancer. Press release. December 11, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm476926.htm. Accessed January 22, 2016.
  12. Alecensa (alectinib) capsules [prescribing information]. South San Francisco, CA: Genentech USA; December 2015.
  13. Xalkori (crizotinib) capsules [prescribing information]. New York, NY: Pfizer; September 2015.
  14. National Cancer Institute. Alectinib. NCI Dictionary of Cancer Terms. www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=777448. Accessed February 2, 2016.
  15. Pirker R, Filipits M. Alectinib in RET-rearranged non-small cell lung cancer—another progress in precision medicine? Transl Lung Cancer Res. 2015;4:797-800.
  16. Shaw AT, Gandhi L, Gadgeel S, et al; for the Study Investigators. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17:234-242.
  17. Ou SH, Ahn JS, De Petris L, et al. Alectinib in crizotinib-refractory ALK-rearranged non–small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34:661-668.
  18. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
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Last modified: May 18, 2016