ALK Inhibitors Help to Define Precision Medicine

Ravi Salgia, MD, PhD

Anaplastic lymphoma kinase (ALK)–targeted therapies have increased the survival time for patients with ALK-translocated non–small cell lung cancer (NSCLC). Can ALK inhibitors have the same impact on other malignancies that harbor ALK rearrangements?

“One thing I should say about our ALK-positive patients [is that] we’re very hopeful because there have been great breakthroughs in terms of survival. So, we’re so excited for our patients and we want to also utilize this experience in this paradigm from our ALK-positive patients and apply to other patients who are non–ALK[-positive] and make a difference there as well,” said Ravi Salgia, MD, PhD, a professor in the Department of Medical Oncology and Therapeutics Research and the Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope in Duarte, California, in an interview with Targeted Therapies in Oncology™.

ALK and Cancer

“We’ve been really excited in pediatric oncology after the discovery [of ALK and ALK inhibitors]. The history goes back quite some time and it’s a fascinating story. The ALK gene was first cloned in 1994 from a cell line derived from a pediatric patient with anaplastic large cell lymphoma [ALCL],” explained Yael P. Mossé, MD, in an interview with Targeted Therapies in Oncology™. Mossé is an attending physician at the Children’s Hospital of Philadelphia’s Cancer Center in Pennsylvania.

Investigators analyzing a protein called p80, which had previously been described in ALCL, and found that it consisted of a fusion of parts of 2 proteins: the kinase domain of ALK fused to the N-terminal region of the nucleophosmin (NPM) protein (FIGURE1).

This fusion results from a chromosomal translocation, and NPM was the first of many ALK fusion partners to be described. NPM and the other fusion partners drive dimerization of the fusion protein in the absence of ligand, which activates the ALK kinase.

ALK fusions have been described in many cancer types, such as ALCL, NSCLC, inflammatory myofibroblastic tumor (IMT), diffuse large B-cell lymphoma, esophageal squamous cell carcinoma, renal medulla carcinoma, renal cell carcinoma, breast cancer, colorectal carcinoma, serous ovarian carcinoma, and anaplastic thyroid carcinoma (ATC).^1,2

A year after the identification of ALK fusions in NSCLC, “my lab made the discovery of a very different mechanism by which ALK gets activated, which is through point mutations in the kinase domain in the rare families where neuroblastoma is inherited,” Mossé said. This type of ALK activation is also seen in some ATCs. More than 35 different ALK alterations have been identified in neuroblastoma, most of which are point mutations.¹

ALK is a receptor tyrosine kinase protein and consists of functional regions including an extracellular ligand-binding domain, which in humans binds to the small, secreted peptide/protein ligands ALKAL1 (FAM150A or AUGβ) and ALKAL2 (FAM150B or AUGα), and an intracellular tyrosine kinase domain, which is highly similar to that of the insulin receptor.¹

ALK Inhibitors in NSCLC

“Lung cancer has become the poster child for precision oncology,” said Vivek Subbiah, MD, in an interview with Targeted Therapies in Oncology™. Subbiah is an associate professor in the Investigational Cancer Therapeutics Department and clinical medical director of the Clinical Center for Targeted Therapy, Cancer Medicine Division, at The University of Texas MD Anderson Cancer Center in Houston.

Although the ALK rearrangement was first identified in ALCL, most of the information investigators have comes from ALK rearrangements in NSCLC, of which the echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most prevalent.¹ ALK rearrangements occur in only 5% of NSCLC cases. However, since NSCLC is the most common malignancy worldwide, there are approximately 40,000 new cases of NSCLC with an EML4-ALK rearrangement per year. This high number of cases has resulted in more ALK-directed therapies being developed and tested for NSCLC than for other cancers. Additionally, there have been many advances in the understanding of the NSCLC biology and genomics, which led to the identification of various mutations and the development of drugs to target them.³

“We were very fortunate because Pfizer had a drug in phase 1 clinical trial that was developed to inhibit [the mesenchymal epithelial transition factor] (MET) and instead they started to see responses in adults and it turned out that those were actually patients with NSCLC harboring ALK fusions,” Mossé said. There are now 3 generations of approved ALK inhibitors including first-generation crizotinib (Xalkori); second-generation ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig); and the third-generation lorlatinib (Lorbrena).³

In 2011, crizotinib was the first ALK inhibitor to be approved by the FDA for ALK-positive NSCLC after it showed an objective response rate (ORR) greater than 50% and a median duration of response of 42 to 48 weeks. Later, the PROFILE-1014 trial (NCT01154140) showed an impressive ORR (74%) for crizotinib as a first-line therapy with a median progression-free survival (PFS) of 10.9 months.³

ALK Inhibitors in Other Malignancies

Since ALK rearrangements and mutations occur in other types of cancer, there is an interest to see whether ALK inhibitors would also provide benefits for patients. With the increase in genetic testing for cancers, it is becoming more feasible to identify the patients who have ALK (and other) alterations and to target these tumors directly.

Anaplastic Large Cell Lymphoma

ALCL is a type of non-Hodgkin lymphoma that occurs primarily in children and young adults.5 Most pediatric cases (90%) of ALCL have an aberrant expression of ALK fusion proteins, of which NPM-ALK is the most common (75%). Chemotherapy is a viable option to treat patients with ALCL as it has remission rates of approximately 80%.2 For patients who don’t respond to chemotherapy and for those who develop resistance to the drugs, there is a need for alternative therapies.

A few studies have evaluated the efficacy and safety of crizotinib for the treatment of ALCL.^{6, 7} The first study (NCT00939770), from the Children’s Oncology group, enrolled patients with ALCL, neuroblastoma, and IMTs. This started as a phase 1 dose-escalation study and showed promising results in 2013 when investigators reported that of the 9 patients with ALK-positive ALCL enrolled in the study, all responded to treatment and 7 showed a complete response.6 “Our lesson learned from that trial, which is now entirely published, [is that] the responses were incredibly robust and sustained,” Mossé said. The efficacy was determined based on the ORR, which was 88% (95% CI, 71%-96%), and a complete remission rate of 81%. Serious adverse events occurred in 35% of patients; the most common were neutropenia and infection.

In January, the FDA approved crizotinib for pediatric patients (12 months and older) and for young adults with ALK-positive relapsed or refractory systemic ALCL based on the results from this study.⁸

A recent paper reported preclinical and clinical experiments with ceritinib, combining in vitro data with ALK-positive and -negative cell lines, in vivo mouse studies, and clinical data from a patient with previously treated ALCL.⁹ “We treated a patient with ALCL who had treatment-refractory [disease]. He was post transplant, post chemotherapy, with multiple relapses and, to date, he is in complete remission 5 years after initiation of therapy,” Subbiah said. “As part of the study, we also looked into a large database of 19,000 patients with hematopoietic diseases and found that 58 patients (0.3%) harbored an ALK fusion. That included tumors [such as] histiocytic disorders, multiple myeloma, Castleman disease, and juvenile xanthogranuloma. We feel that ALK inhibitors can definitely be used in the context of a basket study in these tumor types, and this is a tissue-agnostic indication for ALK inhibitors beyond NSCLC.”

Anaplastic Thyroid Carcinoma

ATC is the most aggressive of the thyroid cancers and one of the most lethal carcinomas in humans.¹⁰ ATC responds very poorly to conventional treatments. Genomic profiling of these tumors allows for the use of targeted therapies. ALK mutations and fusions are present in a small percentage of ATCs (0% to 20% in a review of next-generation sequencing studies) and their role remains unclear. In 2015, a group reported a case of a 71-year-old woman with ATC treated with crizotinib.¹¹ Two years after receiving the initial diagnosis, the patient maintained an excellent performance status and had a response of more than 90% across all lesions. Later, this patient was also treated with ceritinib and brigatinib with a good response.¹²

Others

A recent study evaluated the therapeutic effects of crizotinib and alectinib in 7 patients with rare ALK-positive tumors (IMTs, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1).¹³ The ORR for initial ALK inhibitor therapy was 85.7% (95% CI, 44%-97%), which included 2 patients with a complete response, and the median PFS was 8.1 months (range, 1.7 to not estimable) (TABLE).

Mossé and Subbiah both highlighted the potential role of ALK inhibitors in patients with IMTs. “IMTs are a very rare form of sarcoma that are completely resistant to chemotherapy and radiation,” Mossé said, adding that approximately 60% to 70% of these patients have ALK fusions. “The only known curative therapy is complete resection of the tumor with very wide margins, and oftentimes the tumor presents in a place where that’s impossible or with multiple tumors in both lungs and then it’s really unresectable. IMT is an incurable entity even though it is thought to be a disease that doesn’t spread from where it originates. The responses [we saw with crizotinib] were incredibly robust and sustained, and hopefully it will be approved for IMTs soon.”

An editorial published earlier this year reviewed the preclinical and clinical data for the use of ALK inhibitors in non-NSCLC tumor types.¹⁴ The authors suggest that there are 2 potential options for obtaining more confirmatory data on ALK-targeting strategies. The first is a basket approach where multiple cohorts of patients with potential driven disease receive ALK inhibitors. The second approach is to combine the use of big data with electronic medical records to guide decision-making in the clinic.

Additional Studies Needed

“There are newer therapies coming against the resistant mechanisms for ALK inhibitors,” Salgia said. “[For example,] there is a study combining brigatinib with bevacizumab [Avastin] [to treat patients with locally advanced, metastatic, or recurrent ALK-positive NSCLC (NCT04227028)], and that’s going to be important.” Salgia is also interested in the use of ALK inhibitors as neoadjuvant therapy for early-stage patients with an ALK-positive tumor. He wants to determine whether patients can get the ALK inhibitor to reduce the tumor and then have the surgery.

“We’re also doing a lot of artificial intelligence work. ALK-positive patients tend to have a different pattern of metastasis compared with patients with other NSCLCs,” Salgia explained. Investigators are interested in studying the mechanisms involved to see if they can be inhibited as well.

Mossé identified the following goals: for ALCL, to include ALK inhibitors in front-line therapy while decreasing toxicity; for IMT, to develop a prospective trial with ALK-positive patients; and for neuroblastoma, to develop ALK inhibitors with very good central nervous system penetration.

Conclusion

ALK inhibitors have had a transformative impact for patients with NSCLC. The results from the trials done by the Children’s Oncology Group show that there is a strong rationale for testing ALK inhibitors in patients with any cancer bearing an ALK alteration. Investigators are excited about the prospects for existing and newer drugs.

“We’ve seen some great responses to ALK inhibitors, but…even in the lung cancer world, not everybody responds to ALK inhibitors even though they might have ALK fusions. There [are] more data coming out about the variants that are important, so more studies need to be done to be able to not only identify the ALK fusion but also then to be able to say whether a patient will respond,” Salgia said.

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