Current and developing therapies for the treatment of non-small cell lung cancer with ALK abnormalities: update and perspectives for clinical practice

ABSTRACT

Introduction: The treatment of patients with ALK-rearranged non-small-cell lung cancer was completely revolutionized by the introduction of Crizotinib, a small molecule inhibiting ALK, MET and ROS1. Given that resistance occurs within approximately 12 months, in order to develop more potent inhibitors and to increase drug penetration to CNS, innovative ALK-inhibitors were developed. Second-generation ALK inhibitors Ceritinib (LDK378), Alectinib (CH5424802/RO5424802) and Brigatinib (AP26113) have shown significant clinical activity, and were rapidly approved by regulatory agencies. In addition, early clinical data demonstrated that 3^rd generation ALK-inhibitors Lorlatinib (PF-06463922), Entrectinib (RxDx-101) and Ensartinib (X-398) provided promising advantages in terms of both clinical activity and safety.

Areas covered: In this review, the efficacy and tolerability of Crizotinib for 1^st and 2^nd-line treatment, and the clinical and preclinical data that led to the development of innovative second and third generation ALK-inhibitors are described.

Expert opinion: The better characterization of the mechanisms of resistance to Crizotinib led to the development of newest drugs, which are active both after Crizotinib failure and in patients naïve from ALK-inhibitors. Tumor characterization at disease progression will allow to further personalize the treatment by establishing optimal sequences, which represent tough challenges for the future research in this field of cancer treatment.

KEYWORDS:

• Lung cancer
• ALK inhibitors
• Crizotinib
• resistance

Article highlights

• ALK rearrangements are common driver oncogenic alterations in cancer. The most frequent translocation usually involves EML-4 gene, with subsequent activation of downstream signalling pathways controlling cell proliferation, survival and angiogenesis.

• ALK translocation is present in the 3-7% of patients with NSCLC and in 30% of never/light smoker EGFR WT patients. ALK rearrangement seems to be associated with adenocarcinoma histology, younger age and never smoking history.

• FISH is the gold standard diagnostic assay to detect ALK translocations in NSCLC, however IHC showed comparable sensitivity and specificity, being more rapid, less expensive and laborious. RT-PCR is an alternative technique, particularly useful for cytological samples.

• Crizotinib is the first-generation ALK inhibitor showing an acceptable safety profile, impressive responses and improved survival compared to chemotherapy in first and second treatment line.

• Distinct variants of ALK-EML-4 translocations can differently influence Crizotinib survival benefit, in particular, variant-1 seems to be associated with a longer PFS compared to other ALK-EML-4 genotypes.

• ALK secondary mutations (20-40%), activation of bypass tracks (30%) and amplification of ALK gene (15%) were identified as the three main mechanisms of acquired resistance to Crizotinib, however, almost 50% of the mechanisms of secondary resistance remain unknown.

• Ceritinib, Alectinib and Brigatinib are extremely selective second-generation ALK inhibitors, more potent than Crizotinib against native ALK protein and able to inhibit also gatekeeper mutations. Lorlatinib is a third generation ALK inhibitor with a clinical activity also against G1202R, a mutation that usually confers acquired resistance to first and second-generation ALK inhibitors. Entrectinib and Ensartinib are multi-kinases inhibitors currently under clinical development.

• Second and third generation ALK inhibitors showed remarkably encouraging responses and survival benefit both in Crizotinib-naïve and -resistant patients, and a dramatic activity on brain metastases, thanks to the high penetration through the brain-blood barrier.

• Although HSP-90 modulation of ALK activation and stabilization represents a promising therapeutic opportunity, to date HSP-90 inhibitors failed to significantly impact upon lung cancer survival.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was partially supported by a grant of the Italian Association for Cancer Research (AIRC-MFAG 14282) and a fellowship award of the International Association for the Study of Lung Cancer (IASLC).