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Cancer Prevention & Current Research

Mini Review Volume 8 Issue 3

ALK Inhibitors in NSCLC- Crizotinib and Beyond

Albaba Hamzeh, Moskovitz Mor

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Canada

Correspondence: Albaba Hamzeh, Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada

Received: May 19, 2017 | Published: August 2, 2017

Citation: Hamzeh A, Mor M (2017) ALK Inhibitors in NSCLC- Crizotinib and Beyond. J Cancer Prev Curr Res 8(3): 00275. DOI: 10.15406/jcpcr.2017.08.00275

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Abbreviations

EGFR, epidermal growth factor receptor; ALK-EML4, anaplastic lymphoma kinase echinoderm microtubule-associated protein-like 4; NSCLC, non-small cell lung cancer; PFS, progression free survival; RR, response rate; CNS, central nervous system; HR, hazard ratio; FDA, food and drug administration; mg, milligram

Introduction

Lung cancer is the most common cancer diagnosed in developed countries, and it is the leading cause of cancer related death worldwide.1. Over 70% of lung cancer patients are diagnosed with advanced disease at presentation, and receive palliative treatment only. Until a decade ago, the treatment included chemotherapy alone, with a limited survival benefit.2

The identification of molecular subtypes of NSCLC revolutionized the treatment for patients diagnosed with NSCLC harboring molecular alterations. The most common are the EGFR mutation; which is found at 10-15% of patient, and the ALK-EML4 rearrangement.3, which is found at 4-7% of patients. Several ALK tyrosine kinase inhibitors were developed in the last decade, and we hereby review the current and future ALK inhibitors and the up to date treatment of ALK-rearranged NSCLC.

Currently approved ALK inhibitors

The detection of ALK rearrangement has changed the treatment and prognosis in this subgroup of patients. Crizotinib, which was originally developed for treatment of anaplastic large-cell lymphoma.4 Table 1 was the first ALK inhibitor to be approved by the FDA in November 2014 for treatment of ALK rearranged NSCLC in the second line setting. The approval was based on the results of the PROFILE 1007, with PFS of 7.7 months, compare to 3months in the chemotherapy arm, and the RR was 65%.5 Crizotinib waslater on approved for the 1st line treatment based on the results of the PROFILE 1014 phase III trial, showing PFS of 10.9 months vs. 7 months, and RR of 74% vs. 45% in the Crizotinib and chemotherapy arm, respectively.6 The toxicity profile of crizotinib is different from chemotherapy, and includes vision disorders, diarrhea, nausea, vomiting, constipation, elevated liver aminotransferase levels and edema (Table 1). Currently, crizotinib is the standard 1st line treatment for NSCLC harboring ALK rearrangement, although most of the patients will develop resistance to treatment after a median of 10 months. Resistance to treatment is uasually related to the emergence of new resistant clones.7 About a quarter of patients with ALK-rearranged NSCLC will have CNS involvement at time of diagnosis, and that site is the most frequent site of disease progression.8 The inevitable resistance to treatment raised the need for new ALK inhibitors, with high penetrance of the blood-brain barrier and activity against the resistant clones in the second line setting and beyond.

Agent

Standard dose

Additional targets     

Mechanism of resistance

PFS in months    

Side effects

Crizotinib (Xalkori)16-20

250mg twice daily      

C-MET
ROS1

Mutations in L1196M (Gatekeeper), L1152R, C1156Y, 1151Tins,
G1202R, S1206Y, and G1269A, F1174L ALK/EGFR/KIT
amplification, KRAS mutation                                                                      

2nd line 7.7m

1st line 10.9m

Visual disturbance, nausea, diarrhea, elevated liver enzymes, lymphopenia, pneumonitis, hypophosphatemia, pulmonary embolism

Ceritinib (Zykadia)26-28, 74    

750mg once daily

IGF-1R
STK22D
PLT3 Alectinib resistant mutation I1171T/N/S

7m

diarrhea, vomiting, nausea, dehydration, elevated liver enzymes, hypophosphatemia

Alectinib (Alecensa) 34-37

600mg twice daily

RET
Crizotinib resistant mutation L1196M     

I1171T/N/S mutations

8.1-8.9m

Headache, neutropenia, fatigue, myalgia, peripheral edema, liver enzyme abnormality, hypophosphatemia.

Brigatinib (Alunbrig)

Arm A:90
Arm B:180 mg once daily

ROS1
EGFR
STK22D
PLT3

A: 8.8 m
B: 11.1 m

Nausea, diarrhea, fatigue, dyspnea, increased lipase, hypoxia, elevated liver enzymes and amylase. pneumonia, pyrexia, pulmonary embolism

Lorlatinib

100mg

ROS1
Crizotinib resistant mutation L1196M
LTK (TYK1)

L1198F

-

Hypercholesterole, peripheral edema

Table 1 Characteristics of different ALK inhibitors in NSCLC
NSCLC, non- small cell lung cancer; ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; KIT, tyrosine-protein kinase Kit; C-MET, tyrosine-protein kinase MET; ROS1, proto-oncogene tyrosine-protein kinase ROS; IGF-1R, insulin-like growth factor 1 receptor; STK22D, serine/threonine kinase; RET, RET proto-oncogene; PFS, progression free survival

Ceritinib was the next agent to demonstrate high anti-tumor activity for patients who progressed on crizotinib, as well as higher rate of CNS penetration. The drug was approved by the FDA in the second line setting in April 2014 in accelerated process after a phase I trial- the ASCEND 1 trial, which showed high RR among both crizotinib naïve and pretreated patients, of 58% and 56%, respectively.9 Ceritinib has also showed prolonged duration of response, more than 8 months in the pretreated patientsIn the first line setting, ceritinib demonstrated superiority over chemotherapy, with PFS of 16.6 months vs. 8.1 months on the chemotherapy arm (HR=0.55). The toxicity profile of ceritinib included mostly GI toxicity, with diarrhea, nausea and vomiting (Table 1).10

The third ALK inhibitor approved in December 2015 was Alectinib, after 2 phase II clinical trials.11 demonstrating PFS of 8.1 to 8.9 months and RR around 50% in pretreated patients. The toxicity profile of alectinib is considered favorable, and includes headache, neutropenia, fatigue, myalgia, peripheral edema, liver enzyme abnormality and hypophosphatemia. Alectinib also has improved CNS activity (Table 1).

Future ALK inhibitors

Additional ALK inhibitor approved in April 2017 was Brigatinib.12 (Table 1), which demonstrated PFS of 8.8 months with the daily dose 90 mg, and 11.1 months with the 180 mg dose, although the starting dose will be 90 mg. The overall RR was 46% and 54% in each arm, respectively. Several other ALK inhibitors are currently under investigation (Table 1), such as Lorlatinib,13 which similarly to Crizotinib, also acts as a ROS-1 inhibitor, and results from phase II and phase III clinical trials are pending.

Sequence of treatment

The best sequence of treatment for ALK-rearranged NSCLC patients is not clear yet, and several trials are comparing the different ALK inhibitors in first line setting to establish the preferred order of agents. The multinational phase III ALEX trial is comparing alectinib to crizotinib in the first line setting, and data from the Japanese subgroup has showen significant improvement in the PFS in the alectinib group, with HR=0.34 and a PFS of 10.2 months in the crizotinib arm vs. PFS not reached in the alectinib arm.14 The final data from this trial demonstrated favorable PFS of alectinib (not reached vs. 11.1months with crizotinib), and hazard ratio of 0.47.15

Acknowledgments

None.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Funding

None.

References

  1.  Siegel RL, Miller KD, Jemal A.  Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.
  2. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non–small–cell lung cancer. N Engl J Med. 2012;346(2):92–98.
  3. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014;311(19):1998–2006.
  4. Li Y, Ye X, Liu J, et al.  Evaluation of EML4–ALK fusion proteins in non–small cell lung cancer using small molecule inhibitors. Neoplasia. 2011;13:1–11.
  5. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus Chemotherapy in Advanced ALK –Positive Lung Cancer. N Engl J Med. 2013;368(25):2385–2394.
  6. Solomon BJ, Mok T, Kim DW, et al. al. First–Line Crizotinib versus Chemotherapy in ALK –Positive Lung Cancer. N Engl J Med. 2014;371(23):2167–2177.
  7. Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non–small cell lung cancers harboring the fusion oncogene EML4–ALK. Proc Natl Acad Sci U S A. 2011;108(18):7535–7540.
  8. Costa DB, Shaw AT, Ou SH, et al. Clinical Experience With Crizotinib in Patients With Advanced ALK–Rearranged Non–Small–Cell Lung Cancer and Brain Metastases. J Clin Oncol. 2015;33(17):1881–1888.
  9. Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK–rearranged non–small–cell lung cancer. N Engl J Med. 2014;370(13):1189–1197.
  10. Soria JC, Tan DS, Chiari R, et al. First–line ceritinib versus platinum–based chemotherapy in advanced ALK –rearranged non–small–cell lung cancer (ASCEND–4):a randomised, open–label, phase 3 study, Lancet. 2017;389(10072):917–929.
  11. Shaw AT, Gandhi L, Gadgeel S, et al. investigators study, Alectinib in ALK–positive, crizotinib–resistant, non–small–cell lung cancer:a single–group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–242.
  12. Dong–Wan Kim, Marcello Tiseo, Myung–Ju Ahn, et al. Brigatinib in Patients With Crizotinib–Refractory Anaplastic Lymphoma Kinase–Positive Non–Small–Cell Lung Cancer:A Randomized, Multicenter Phase II Trial. J Clin Oncol. 2017;35(22):2490–2498.
  13. B Solomon, T Bauer, E Felip, et al. Safety and efficacy of lorlatinib (PF–06463922) from the dose–escalation component of a study in patients with advanced ALK+ or ROS1+ non–small cell, cell lung cancer (NSCLC. Journal of Clinical Oncology. 2016;34(15suppl):9009–9009.
  14. H Nokihara, T Hida, M Kondo, et al. Alectinib (ALC) versus crizotinib (CRZ) in ALK–inhibitor naive ALK–positive non–small cell lung cancer (ALK+ NSCLC):Primary results from the J–ALEX. ASCO Annu Meet. 2016.
  15.  Shaw AT, Peters S, Mok T, et al. Alectinib versus crizotinib in treatment–naive advanced ALK –positive non–small cell lung cancer (NSCLC):Primary results of the global phase III ALEX study. J Clin Oncol. 2017;35(18 suppl).
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