Analysis of Condition
Lung cancer is the leading cause of cancer death in the United States (U.S.) with more than 80%
of all lung cancer cases classified as NSCLC. In 2018, an estimated 234,030 new cases of lung and bronchial cancer will be diagnosed in the US, with 154,050 deaths estimated to occur due to this disease1; lung cancer accounted for approximately 27% of cancer deaths in 2014.2 Eight-five percent of cases are diagnosed at later stages, and for patients with distant metastasis, the 5-year relative survival rate is less than 5%.2
The ALK gene was first identified as a lung adenocarcinoma oncogene in 2007 when a small number of NSCLC cells were found to have a small inversion within chromosome 2p resulting in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene (referred to hereafter as ALK rearrangement).3 This EML4-ALK fusion transcript results in a constitutively active tyrosine kinase that promotes angiogenesis, cell survival, and cell cycle progression.4 Preclinical and clinical studies
demonstrated that cancer cells harboring an ALK rearrangement are sensitive to ALK inhibition.5
The estimated incidence of ALK rearrangements in NSCLC is 2-7%. Clinical characteristics of patients with ALK rearrangements include adenocarcinoma histology, never or light smokers, more likely to be men, and younger age. In these populations, approximately 30% of patients will have ALK rearrangements.6
Crizotinib, the first FDA-approved ALK kinase inhibitor (hereafter referred to as ALK inhibitor), was approved in 2011 for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive (i.e., positive for ALK rearrangement). The initial approval of crizotinib was based on the results from two multicenter single arm studies of crizotinib in 255 patients with
advanced NSCLC demonstrating overall response rates (ORRs) of 50% and 61%. The majority of patients in these studies had metastatic disease (95%) and had received prior systemic
treatment for locally advanced or metastatic disease (94%).7 In 2013, the crizotinib USPI was updated with the results of a randomized trial comparing crizotinib to chemotherapy
(pemetrexed or docetaxel) in 347 patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen, which demonstrated an
improvement in median progression-free survival (PFS) for patients treated with crizotinib (7.7 months vs 3.0 months; hazard ratio [HR] 0.49 [95% confidence interval {CI} 0.37, 0.64]).8 The crizotinib USPI was further updated in 2015 with results from a randomized trial of crizotinib compared to pemetrexed-platinum combination chemotherapy in 343 patients with ALK-positive non-squamous NSCLC who had not received any previous systemic therapy for
advanced NSCLC. There was a significant improvement in median PFS for patients in the crizotinib arm (10.9 months vs 7.0 months; HR 0.45 [95% CI 0.35, 0.60]).9
Development of resistance to crizotinib is possible, and in approximately 28% of patients progressing on crizotinib, secondary mutations distributed throughout the ALK domain, including resistance mutations located in the solvent-exposed region of the adenosine
triphosphate (ATP)-binding pocket have been identified; amplification of the ALK fusion gene is also a mode of resistance.10 Furthermore, approximately one-third of patients treated with crizotinib develop brain metastases within the first year of treatment, with the central nervous system (CNS) representing the most common site of progression.11 Since the approval of crizotinib, later generation ALK inhibitors, discussed in Section 2.2 below, have been developed to address the problems of crizotinib resistance and/or CNS metastasis.
Analysis of Current Treatment Options
Ceritinib and alectinib were granted accelerated approval for the treatment of patients with ALK-positive metastatic NSCLC who progressed on or were intolerant to crizotinib in 2014 and 2015, respectively. Regular approval for the treatment of patients with ALK-positive metastatic NSCLC was granted to both ceritinib and alectinib in 2017, after confirmatory trials
demonstrated benefit (a large, clinically meaningful and statistically robust improvement in progression-free survival) in the first-line setting. Brigatinib is the only FDA-approved ALK inhibitor with an indication limited to the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. Brigatinib is not considered available therapy, as defined in the FDA Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics, because it is approved under the provisions of accelerated approval.
Ceritinib was received accelerated approval in 2014 based on the results of a multicenter, single arm study in 163 patients with metastatic ALK-positive NSCLC who progressed on or were intolerant to crizotinib. The results demonstrated an ORR of 44% (95% CI 47%, 62%) as assessed by Blinded Independent Central Review Committee (BICR) with a median duration of response (DOR) of 7.4 months (95% CI 5.4, 10.1). Approximately 60% of patients initiating treatment with ceritinib at the recommended dose of 750 mg daily required at least one dose reduction, and dose modification related to gastrointestinal toxicities of nausea, vomiting, diarrhea or abdominal pain occurred in 38% of patients.12 The USPI was updated in May 2017 with the conversion to regular approval based on the results of an open-label, randomized, active-controlled, multicenter study of ceritinib versus chemotherapy (pemetrexed with cisplatin or carboplatin). The median PFS in the ceritinib arm was 16.6 months (95% CI 12.6, 27.2) versus 8.1 months (95% CI 5.8, 11.1) in the chemotherapy arm, with a HR of 0.55 (95% CI 0.42, 0.73).13 Alectinib was granted accelerated approval in 2015 based on the results of two single-arm
Results included ORRs of 38% (95% CI 28%, 49%) and 44% (95% CI 36%, 53%) as assessed by Independent Central Review (IRC). Median DOR was 7.5 months (95% CI 4.9, not estimable [NE]) and 11.2 months (95% CI 9.6, NE).14 The USPI was updated in November 2017 with the conversion to regular approval based on the results of an open-label, randomized, active-controlled, multicenter study in 303 patients who were randomized to receive alectinib or crizotinib. The median PFS in alectinib-treated patients was 25.7 months (95% CI 19.1, not estimable [NE]) compared to 10.4 months (95% CI 7.7, 14.6) in crizotinib-treated patients.
Permanent discontinuation of alectinib for adverse reactions occurred in 11% of patients.
Adverse drug reactions that led to discontinuation of alectinib were renal impairment (2.0%), hyperbilirubinemia (1.3%), increased ALT (1.3%), and increased AST (1.3%). Dose reductions and drug interruption due to adverse reactions occurred in 16% and 19% of patients, respectively, in the alectinib arm. The most frequent adverse reactions that led to dose modifications in the alectinib arm were hyperbilirubinemia (6%), increased aspartate aminotransferase (AST) (5%), increased alanine aminotransferase (ALT) (4.6%), and pneumonia (3.3%).15
Other classes of therapy that are available for the treatment of patients with ALK-positive metastatic NSCLC with progression on a prior ALK inhibitor include anti-programmed cell death (PD-1)/programmed cell death ligand (PD-L1) monoclonal antibodies and chemotherapy.
Pembrolizumab, an anti-PD-1 antibody, was granted accelerated approval in October 2015 for the treatment of patients with metastatic NSCLC that has progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for ALK or EGFR mutations, and any evidence of PD-L1 expression by a clinical trial immunohistochemistry assay.16 In October 2016, regular approval was granted based on results from a randomized, multicenter, open-label study in which 1033 patients whose tumors had PD-L1 expression of 1% or greater were randomized 1:1:1 to receive one of two doses of pembrolizumab or docetaxel. The results demonstrated an improvement in median overall survival (OS) in pembrolizumab-treated patients who received 2 mg/kg every 3 weeks (10.4 months vs 8.5 months; HR 0.71 (95% CI 0.58, 0.88). The ORR of pembrolizumab in patients with a PD-L1 tumor proportion score of ≥ 1%
was 18% (95% CI: 14, 23) in the 2 mg/kg arm compared to 19% (95% CI: 15, 23) in the 10 mg/kg arm. Pembrolizumab was discontinued due to adverse reactions in 14% of patients. The primary toxicities of concern are related to the class of drug and include immune-mediated
pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and infusion-related reactions.17 Initially approved for metastatic NSCLC with squamous histology only, nivolumab, an anti-PD-1 monoclonal antibody, was subsequently approved for patients with any histology NSCLC and progression on or after platinum-based chemotherapy, including those with EGFR or ALK genomic tumor aberrations after progression on FDA-approved therapy for these aberrations, in October 2015. The approval was based on the results of a randomized open-label multicenter trial in which 582 patients received either nivolumab or docetaxel. The ORR of nivolumab for second-line treatment of metastatic non-squamous NSCLC was 19% (95% CI: 15, 24) compared to 12% (95% CI: 9,17) in the docetaxel arm. Median OS demonstrated an improvement in nivolumab-treated patients (12.2 months vs 9.4 months; HR 0.73 (95% CI 0.60, 0.89).
Nivolumab was discontinued in 13% of patients for an adverse reaction.18
Atezolizumab, an anti-PD-L1 monoclonal antibody, was approved for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy, including those with EGFR or ALK genomic tumor aberrations after progression on FDA-approved therapy for these aberrations, in October 2016. The approval was based on the results of a randomized, open-label multicenter trial in which 1137 patients received either atezolizumab or docetaxel. The ORR observed in the first 850 patients randomized to receive atezolizumab for the second-line treatment of metastatic NSCLC in the OAK trial was 14% (95%
CI: 11, 17), with a median duration of response of 16.3 months (95% CI 10, NE) in the
atezolizumab arm (n=450). The median OS observed amongst all 1225 randomized patients was 13.3 months (95% CI 11.3, 14.9) in the atezolizumab arm (n=613) and 9.8 months (95% CI 8.9, 11.3) in the docetaxel arm (n=612).19
The primary toxicities of concern for nivolumab and atezolizumab, as for all anti-PD-1/anti-PD-L1 directed antibodies are immune-related adverse reactions, as described above for
pembrolizumab.
Finally, chemotherapy (including platinum-based doublets) in patients who are chemotherapy-naïve is another option for patients with ALK-positive NSCLC with progression of disease following treatment with an ALK inhibitor. Median OS observed for first-line treatment with platinum-based combination chemotherapy in earlier studies, which included patients with NSCLC regardless of histology, ranged from approximately 8 to 11 months with response rates of 15% to 32%.20 A subsequent randomized study comparing cisplatin plus pemetrexed to cisplatin plus gemcitabine for the first-line treatment of NSCLC demonstrated response rates close to 30% in both arms; this study included a pre-specified analysis of OS by histology, and the median OS for the subset of patients with adenocarcinoma histology receiving cisplatin plus pemetrexed was 12.6 months.21 In a randomized trial comparing crizotinib to platinum-based combination chemotherapy for the first-line treatment of advanced ALK-positive NSCLC, the ORR observed in the chemotherapy arm was 45% with a median duration of response of less than 6 months and median progression-free survival (PFS) of 7.0 months.22 These findings were in patients who had received no prior systemic therapy for advanced NSCLC. Another study randomized patients with ALK-positive NSCLC who had already received one prior platinum-based regimen to treatment with crizotinib versus either pemetrexed or docetaxel and
demonstrated an ORR of 20% in the chemotherapy arm.23 There is insufficient data available to determine the potential impact of prior treatment with an ALK inhibitor on response to
treatment with platinum-based combination chemotherapy. The major toxicities of
chemotherapy regimens most commonly used for NSCLC include hematologic toxicities (e.g., cytopenias), gastrointestinal toxicities (e.g., nausea, vomiting), and neurotoxicity (e.g., peripheral neuropathy with taxanes, ototoxicity with cisplatin).
Table 1: Summary of treatment armamentarium relevant to proposed indication
APPEARS THIS WAY ON ORIGINAL
Product (s)
Nivolumab Metastatic
Platinum-based
chemotherapy Metastatic
NSCLC N/A Various
regimens Range 15-32%i Myelosuppressi on, peripheral
a: PROFILE 1007; USPI crizotinib 2013 b: ASCEND-1; USPI ceritinib 2014
c: NP28761 and NP28673; USPI alectinib 2015 d: ALTA, USPI brigatinib 2017
e: KEYNOTE-010; USPI pembrolizumab 2016 f: CheckMate-057; USPI nivolumab 2015 g: OAK; USPI atezolizumab 2016
h: Mok, et al 2014 i: Ramalingam, et al 2008