The concept of matching a drug to a specific cell surface receptor, initially referred to as “side-chain theory”, dates back to Paul Ehrlich in 1901 (1). Over one hundred years later anaplastic lymphoma kinase (ALK) rearrangement was identified as a transforming oncogenic driver and potential therapeutic target in lung cancer (2). The successes of the modern versions of side-chain theory are well known, imatinib, erlotinib, ibrutinib, vemurafenib, rituximab, trastuzumab, etc., but despite the improved recognition of possible driver alterations few targeted therapies improve survival, and none are curative. Tumor heterogeneity, the ability of coexistent genomic alterations to modify response, and the invariable development of resistance have limited the therapeutic efficacy of molecularly directed therapies.
The oncogenic potential of ALK thus far requires chromosomal rearrangements leading to in-frame gene fusions, similar to the BCR-ABL paradigm, and single point mutations alone are not transformative. ALK gene fusions are translated into cytoplasmic chimeric proteins with constitutive, ligand-independent, tyrosine kinase activity. Beyond non-small cell lung cancer (NSCLC) ALK rearrangements have now been observed in renal cell carcinoma, inflammatory myofibroblastic tumors, thyroid, colorectal, and breast cancers, with over 20 unique fusions described, 11 in NSCLC (Table 1) (2-13). Early preclinical studies with ALK inhibitors conducted on cell lines derived from patients with ALK-rearranged (ALK+) NSCLC demonstrated potent growth arrest (14). Further in-vitro and in-vivo work confirmed the anti-proliferative effects of ALK inhibition in ALK+ mouse models, encouraging further clinical development (15). In 2010, the phase I clinical trial conducted by Kwak et al. explored the effects of the ALK inhibitor crizotinib in 82 pre-treated ALK-positive patients. This study showed an overall response rate (ORR) of 57% and stabilization of disease in an additional 33% (16). These promising results prompted a follow-up study expanding the original cohort by including 61 additional patients. The results from this study were similar with an ORR of 60.8% a median duration of response of 49.1 weeks and a median progression free survival (PFS) of 9.7 months (17). The results of these trials substantiated the FDA decision for accelerated approval of crizotinib in August 2011, followed by full approval in November 2013. A confirmatory second-line phase III study comparing crizotinib to chemotherapy, using either single agent pemetrexed or docetaxel, was conducted in 347 patients with progressive locally advanced or metastatic ALK+ lung cancer. The crizotinib treatment group showed a median PFS of 7.7 months compared to 3.0 months in the chemotherapy arm. The hazard ratio for progression or death in the crizotinib group vs. the chemotherapy group was 0.49 (95% CI, 0.37-0.64) with P<0.001 (18). In the recently published phase III PROFILE 1014, Solomon and colleagues demonstrated the superiority of crizotinib over modern first line platinum doublet therapy (cisplatin-pemetrexed or carboplatin-pemetrexed) in ALK+ NSCLC (19). The results themselves were not unexpected and served to confirm the previously presented crizotinib activity (16-18). The ORR of 74% vs. 45% and a median PFS of 10.9 vs. 7.0 months highlights the advantage of a molecularly directed therapy over broadly cytotoxic therapy (19).
In addition to first line justification, the PROFILE 1014 trial offers some important insights into the characteristics and natural history of ALK+ NSCLC. To our knowledge this is the largest and most well characterized cohort of treatment naïve ALK+ NSCLC. Interestingly, 26% of the population had known brain metastases at the time of presentation, a figure more than twice the rate of brain metastases in treatment naïve non ALK+ NSCLC (19,20). Prospective analysis of the intracranial efficacy from the PROFILE 1014 cohort demonstrated a trend toward improved intracranial TTP and statistically significant improvement in intracranial disease control rate (DCR) at 12 and 24 weeks (21). Whether or not ALK+ NSCLC has a particular tropism for early CNS spread cannot be concluded from PROFILE 1014, and crizotinib superiority over chemotherapy was not affected by the presence of CNS metastases (19). Importantly, later generation ALK inhibitors may offer further improvements in CNS activity.
Solomon and colleagues should be commended for the use of a modern platinum doublet (carboplatin or cisplatin plus pemetrexed) with known activity in ALK+ disease as the crizotinib comparator arm. The PFS reported for the chemotherapy arm of PROFILE 1014 (7.0 months) compares favorably with previously reported chemotherapy trials. Maintenance therapy in NSCLC has demonstrated improvements in PFS and OS, however, the median PFS from the pemetrexed maintenance arm of the phase III PARAMOUNT trial was 4.1 months, and increased to 7.4 months in the AVAPERL trial, and we would not predict maintenance therapy to significantly affect the PROFILE 1014 results (22,23).
Overall, the well-conducted PROFILE 1014 is an important and necessary addition to the management of ALK+ NSCLC, but also raises several concepts important for the future of ALK-directed therapies. First, the ORR of 74% is significantly greater than chemotherapy, but also suggests that 1 in 4 untreated patients with ALK+ NSCLC (by Vysis ALK Break Apart FISH) failed to achieve a RECIST response and/or have de-novo resistance. Second, while a PFS of 11 months is an improvement, why are these responses not more durable? Finally, if second and third generation inhibitors offer significant activity after crizotinib failure, then what is the optimal sequence of ALK-directed therapy in NSCLC?
Improvements in diagnostic sensitivity has led to the recognition that a subset of malignant clones in epidermal growth factor receptor (EGFR) mutant tumor carry de-novo T790M resistance mutations, and that patients with pre-existing T790M mutations derive less benefit from first line erlotinib (24). In fact, 66% of patients harbored de-novo T790M mutations and the PFS was 9.7 months for T790M+ vs. 15.8 months for T790M-tumors in the pivotal EURTAC trial (24). Crizotinib resistance mechanisms include the gatekeeper L1196M mutation, solvent front mutations such as G1202R and S1206Y, ALK fusion gene amplification, EGFR and c-KIT pathway activation, and likely several others yet to be identified (4). Increasingly sensitive tests may identify subsets of ALK+ patients harboring de-novo resistance mutations, perhaps underlying the variability in response duration observed clinically. The second generation ALK inhibitors ceritinib and alectinib can overcome some of the resistance mechanisms, which may partly explain the improved response rates observed in early trials (6,25-28). Comprehensive profiling assays will continue to refine the mutational landscape of ALK+ NSCLC and identify co-existent alterations that may modify response and resistance to ALK-directed therapies. Sequencing-based approaches have the additional advantage of identifying novel fusion partners, something that cannot be done with immunohistochemistry or gold standard FISH testing.
The superiority of crizotinib to first line chemotherapy is likely to be eclipsed by other ALK inhibitors but represents an important advance and proof that understanding tumor biology translates to improved outcomes. If crizotinib represents a first try at one of Ehrlich’s “silver bullets”, then we hope the future of ALK-therapies parallels the pace of weapons advancements since 1900.
The authors would like to acknowledge the important contributions of other investigators whose work could not be cited due to space constraints.
Provenance: This is a Guest Editorial commissioned by the Editorial Board Member Ying Liang [Department of Medical Oncology, Sun Yat-sen University Cancer Center (SYSUCC), Guangzhou, China].
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Drews J. Paul Ehrlich: magister mundi. Nat Rev Drug Discov 2004;3:797-801. [PubMed]
- Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561-6. [PubMed]
- Horn L, Pao W. EML4-ALK: honing in on a new target in non-small-cell lung cancer. J Clin Oncol 2009;27:4232-5. [PubMed]
- Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. J Clin Oncol 2013;31:1105-11. [PubMed]
- Majewski IJ, Mittempergher L, Davidson NM, et al. Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 2013;230:270-6. [PubMed]
- Ou SH, Klempner SJ, Greenbowe JR, et al. Identification of a novel HIP1-ALK fusion variant in Non-Small-Cell Lung Cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK-rearranged NSCLC patients with resistance to Alectinib. J Thorac Oncol 2014;9:1821-5. [PubMed]
- Jung Y, Kim P, Jung Y, et al. Discovery of ALK-PTPN3 gene fusion from human non-small cell lung carcinoma cell line using next generation RNA sequencing. Genes Chromosomes Cancer 2012;51:590-7. [PubMed]
- Choi YL, Lira ME, Hong M, et al. A novel fusion of TPR and ALK in lung adenocarcinoma. J Thorac Oncol 2014;9:563-6. [PubMed]
- Drilon A, Wang L, Arcila ME, et al. Broad, Hybrid Capture-Based Next-Generation Sequencing Identifies Actionable Genomic Alterations in Lung Adenocarcinomas Otherwise Negative for Such Alterations by Other Genomic Testing Approaches. Clin Cancer Res 2015;21:3631-9. [PubMed]
- Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-4. [PubMed]
- Debelenko LV, Raimondi SC, Daw N, et al. Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum. Mod Pathol 2011;24:430-42. [PubMed]
- Rikova K, Guo A, Zeng Q, et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 2007;131:1190-203. [PubMed]
- Lin E, Li L, Guan Y, et al. Exon array profiling detects EML4-ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol Cancer Res 2009;7:1466-76. [PubMed]
- McDermott U, Iafrate AJ, Gray NS, et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res 2008;68:3389-95. [PubMed]
- Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci USA 2008;105:19893-7. [PubMed]
- Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. [PubMed]
- Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study. Lancet Oncol 2012;13:1011-9. [PubMed]
- Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94. [PubMed]
- Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77. [PubMed]
- Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. [PubMed]
- Solomon B, Felip E, Blackhall FH, et al. Overall and intracranial efficacy results and time to symptom deterioration in PROFILE 1014: 1st line crizotinib vs pemetrexed platinum chemotherapy in patients with advanced ALK-positive non-squamous non-small cell lung cancer. Ann Oncol 2014;25:iv426-70.
- Paz-Ares L, de Marinis F, Dediu M, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol 2012;13:247-55. [PubMed]
- Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31:3004-11. [PubMed]
- Costa C, Molina MA, Drozdowskyj A, et al. The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. Clin Cancer Res 2014;20:2001-10. [PubMed]
- Shaw AT, Kim DW, Mehra R, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med 2014;370:1189-97. [PubMed]
- Friboulet L, Li N, Katayama R, et al. The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer. Cancer Discov 2014;4:662-73. [PubMed]
- Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119-28. [PubMed]
- Seto T, Kiura K, Nishio M, et al. CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study. Lancet Oncol 2013;14:590-8. [PubMed]