Bounty of Novel Drugs Ushers In New Era for ALK-Positive NSCLC

During the past decade, ALK inhibitors have followed a rapid trajectory from bench to bedside, taking over from chemotherapy as standard frontline treatment for patients with advanced non— small-cell lung cancer (NSCLC) with ALK gene rearrangements.

The first-to-market advantage went to crizotinib (Xalkori), which was initially approved in 2011. That drug has been joined by 3 more potent ALK inhibitors for use in the secondline setting for patients with locally advanced or metastatic disease: alectinib (Alecensa), ceritinib (Zykadia), and brigatinib (Alunbrig). Now, a new era is shaping up in the treatment of ALK-positive NSCLC. Indications for alectinib and crizotinib have recently been expanded into frontline settings and findings from the ALEX trial have demonstrated alectinib’s superiority over crizotinib.

The main limitation concerning the impact of these drugs is the development of resistance, which typically arises quickly and often involves progression to the central nervous system (CNS). Newer ALK inhibitors continue to be developed to counter resistance mechanisms.

Adopting Orphan ALK

Particularly noteworthy, lorlatinib targets the broadest range of resistance mechanisms to date and, if approved, might add to a therapeutic arsenal that could be deployed sequentially over time as the tumor evolves, with the potential to transform ALK-positive NSCLC into a chronic disease.As its name suggests, the anaplastic lymphoma kinase is a receptor tyrosine kinase that was first identified through its aberrant expression in anaplastic large cell lymphoma.¹

ALK spans the cell membrane, with its tyrosine kinase region located on the inside of the cell and, following ligand binding, it activates a complex network of different proteins involved in a variety of signaling networks, including the Janus kinase/ signal transducer and activator of transcription, phosphatidylinositol-3-kinase/ AKT, and mitogen-activated protein kinase pathways (FIGURE²).

Figure. ALK Signaling Pathways in Lung Cancer²

A Lung Cancer Driver

Beyond this, little is known about the precise biological function of the ALK protein and, until recently, it was considered an “orphan” receptor, with no known activating ligand. Studies have established the augmentor α and β proteins (also known as FAM150B and A, respectively) as the ligands for ALK. Other research suggested that heparin may act as an ALK ligand, but this has not been confirmed in subsequent work, although it may bind to FAM150A and regulate ALK activation in that manner.³In 2007, a chromosomal rearrangement involving the ALK gene, which resulted in the expression of a dysfunctional fusion protein, was identified in a resected tumor specimen from a 62-year old patient with lung cancer.⁴

Although ALK fusions are found in other types of lung cancer,⁵ they are most prevalent and best characterized in NSCLC. Multiple types of ALK fusions now have been identified in patients with NSCLC, but the most common is the EML4-ALK fusion. A small inversion in chromosome 2 results in the fusion of the front end of the echinoderm microtubule-associated protein-like 4 (EML4) gene to the back end of the ALK gene.

More than a dozen variants of the EML4-ALK fusion have been identified in NSCLC to date, but all retain the ALK kinase domain, juxtaposed to EML4’s promoter, which results in unfettered activation of ALK. This drives many of the hallmarks of cancer cells through hyperactivation of downstream pathways that play fundamental roles in cell growth, proliferation, and survival, among other cellular processes.

Bench to Bedside

ALK fusions are estimated to occur in between 3% and 7% of cases of NSCLC and define a distinct clinical and histological subset of the malignancy; patients are typically younger, never or light smokers, and have adenocarcinoma histology.^6-8National Comprehensive Cancer Network (NCCN) and International Association for the Study of Lung Cancer guidelines recommend testing all patients who present with advanced NSCLC for ALK fusions because clinical trials have demonstrated the sensitivity of ALK-positive cancers to ALK inhibition.^9,10

The development of ALK inhibitors has become a shining example of the power of personalized medicine, with a growing number of these agents proceeding from bench to bedside in the span of less than a decade and replacing chemotherapy as the preferred frontline option in the treatment of patients with ALK-positive NSCLC.

It took just 4 years from the identification of ALK fusions in patients with NSCLC for the first ALK inhibitor to hit the market. Pfizer’s crizotinib was granted accelerated approval by the FDA in 2011; this status translated into a full approval in 2013 following confirmatory phase III trials.^11,12

Unfortunately, disease progression on crizotinib is all but inevitable. Most patients experience recurrence within 1 or 2 years, including a large proportion who display progression within the CNS.

A substantial amount of research has been invested in trying to understand the mechanisms of crizotinib resistance. The most common mechanisms are secondary mutations in the ALK tyrosine kinase domain, which are believed to occur in approximately one-third of cases. The L1196M “gatekeeper” mutation, which regulates the accessibility of the kinase ATP-binding pocket, is particularly prevalent.

Making Resistance Less Futile

Amplification of the ALK fusion gene has also been reported to occur in crizotinibresistant tumors, either alone or in combination with a secondary ALK mutation. Importantly, evidence suggests that, in most cases, tumors that employ these mechanisms of resistance continue to be dependent upon the ALK protein for growth and survival and are, therefore, still susceptible to ALK inhibition.^6,13,14This continued ALK dependency and the need for inhibitors that can more effectively penetrate the blood-brain barrier (BBB) to target CNS metastases has driven the development of several second-generation drugs. These drugs are distinguished by their enhanced potency as ALK inhibitors and greater activity in the CNS.

Ceritinib was the first of this new generation to be approved by the FDA for the treatment of ALK-positive, advanced NSCLC following progression on crizotinib. It received accelerated approval for this indication in 2014, on the basis of the phase I ASCEND-1 trial, a multicenter, single-arm, open-label clinical study involving 163 patients. The overall response rate (ORR) was 56% among patients previously treated with crizotinib.¹⁵

The efficacy of ceritinib in this setting was confirmed in the phase III ASCEND-5 trial, in which it was compared with second-line chemotherapy and demonstrated improved median progression-free survival (PFS) of 5.4 versus 1.6 months, respectively (HR, 0.49; P <.001).¹⁶ Alectinib was hot on the heels of ceritinib, receiving accelerated approval in the second-line setting in 2015. Its efficacy was established in 2 single-arm, phase II clinical trials, which both demonstrated response rates of more than 40%.^17,18

More recently, the results of the phase III ALUR study were reported, in which alectinib was compared with platinum-based chemotherapy in the second-line setting and beyond. In that study, 107 patients were randomized to receive alectinib at 600 mg twice daily or chemotherapy with pemetrexed or docetaxel. Investigator-assessed median PFS was 9.6 months with alectinib, compared with 1.4 months with chemotherapy (HR, 0.15; P <.001). Among patients with measurable CNS disease at baseline, the ORR in the CNS was 54.2% with alectinib and there was no response with chemotherapy. Alectinib also had a more favorable safety profile, with fewer adverse events (AEs) overall, as well as fewer AEs leading to discontinuation or dose reduction.¹⁹

Evolving Frontline Standard

In April 2017, brigatinib became the latest ALK inhibitor to join the second-line treatment options for patients with the aberration. It received accelerated approval on the basis of the phase II ALTA trial, in which 222 patients were randomized to 1 of 2 doses of brigatinib, 90 mg or 180 mg, the latter following a 7-day lead-in at 90 mg to mitigate the potential risk of pulmonary AEs observed in earlier trials. Patients who were able to tolerate escalation to the higher dose had an improved ORR of 54% versus 45% for the 90 mg dose, and an extended median PFS of 12.9 versus 9.2 months. The most common AEs were nausea, diarrhea, headache, and cough, which were primarily grade 1 or 2. Pulmonary AEs occurred in 6% of patients, but escalation to the higher dose was not associated with increased risk.20During the past year, the indications for both ceritinib and alectinib have been expanded to include previously untreated patients, marking a new chapter in the treatment of ALK-positive, advanced NSCLC. This expansion of therapeutic options comes amid continued exploration of approved and emerging ALK inhibitors (TABLE).

Table. Selected Clinical Trials in ALK-Positive NSCLC

The frontline ceritinib approval was based on data from the ASCEND-4 trial, in which 376 patients were randomly assigned to ceritinib at 750 mg daily or platinum/pemetrexed doublet chemotherapy. Ceritinib improved median PFS (16.6 vs 8.1 months, respectively), ORR (72.5% vs 26.7%), and duration of response (23.9 vs 11.1 months). The most frequent AEs were diarrhea, nausea, and vomiting, but these led to treatment discontinuation in only about 5% of patients.²¹ The ASCEND-8 trial subsequently demonstrated that a 450-mg dose is equivalent in efficacy to the approved 750-mg dose and could offer an alternative dosing strategy.²²

The FDA approval for alectinib in the frontline setting was primarily based on the findings of the global phase III ALEX trial. This study is unique in that it is the first randomized, phase III trial to directly compare 2 ALK inhibitors; alectinib was compared with crizotinib in 303 patients with ALK-positive advanced NSCLC who had not received prior systemic therapy for metastatic disease.

Alectinib more than doubled median PFS compared with crizotinib (26 vs 10 months) and also improved ORR (79% vs 72%). The improved CNS efficacy of alectinib, which has greater penetration of the BBB, was also confirmed; the CNS ORR for alectinib was 81% versus 50% for crizotinib. The most common AEs with alectinib were fatigue, constipation, edema, muscle pain, and anemia.₂₃

Third Generation and Beyond

Based on the results of this trial, the NCCN now recommends alectinib as the preferred frontline option for the treatment of patients with advanced, ALK-positive NSCLC. Similar phase III trials comparing other secondgeneration ALK inhibitors with crizotinib for upfront treatment are ongoing, which could further expand the therapeutic options in this setting in the very near future.Although the development of second-generation drugs has fulfilled the need for more therapeutic options following progression on crizotinib and is now evolving into a new frontline standard of care, resistance also inevitably rears its ugly head following treatment with these drugs. For this reason, researchers continue to unravel the mechanisms of resistance and are developing ever more sophisticated drugs that can counteract them.

The most common mechanism of resistance to the currently approved second-generation inhibitors is the G1202R ALK mutation. Brigatinib is reported to have some activity against this mutation, although its potency may be compromised. A newer drug, lorlatinib, is in development; it is notable for its ability to target this mutation. If approved, lorlatinib could offer a treatment option for patients who progress in the second line.

Lorlatinib has been granted a breakthrough therapy designation on the basis of a phase I/II trial in patients treated with at least 1 prior ALK inhibitor. Results from this ongoing trial were presented at the 2017 World Conference on Lung Cancer (WCLC). As of March 2017, 222 patients were evaluable for efficacy, including 140 patients with CNS progression who could be analyzed for CNS ORR.

There were multiple patient cohorts, including treatment-naïve patients, those treated with prior crizotinib only, and patients who received 1, 2, and 3 prior ALK inhibitors. Lorlatinib demonstrated substantial clinically meaningful efficacy across all cohorts, including in the CNS, even among heavily pretreated patients. The most common AEs were hypercholesterolemia and hypertriglyceridemia.²⁴

Another ALK inhibitor in development is ensartinib, which is designed to target 2 gatekeeper ALK mutations, C1156Y and L1196M. Results from the ongoing phase I/II eXalt2 study were presented at 2017 WCLC, including findings from 19 patients who had been treated with an ALK inhibitor. The ORR was 72% among patients previously treated with crizotinib and 20% after alectinib. The CNS ORR was 33%.

Unanswered Questions

In another presentation on ensartinib, a partial response rate of 87%, including 1 patient with stable disease, was reported among the ALK inhibitor-naïve population. The CNS ORR was 100%, including 1 complete response. The most common AEs with ensartinib were rash, which was predominantly erythematous and maculopapular, as well as nausea, pruritus, vomiting, fatigue, and decreased appetite.^25,26An ALK inhibitor arsenal is being developed for the treatment of NSCLC that could be deployed sequentially over time as resistance develops, with the potential to halt progression for many years and turn ALK-positive NSCLC into a chronic disease. However, several pressing questions remain to be answered.

Most importantly, the optimal sequence of ALK inhibitors is still up in the air. Data about the impact of using second-generation drugs in the frontline setting are currently lacking and there is some concern that they could limit further therapeutic options later in the course of the disease. It is also currently unknown whether the same mechanisms of resistance will surface if a more potent ALK inhibitor is used in an ALK inhibitor-naïve patient.

Several ALK-independent mechanisms of resistance have been identified, including activation of bypass signaling pathways, such as the epidermal growth factor receptor pathway. These mechanisms seem to account for a greater number of cases following use of second-generation drugs than with crizotinib. Combination strategies are being developed to help mitigate these mechanisms of resistance, which could prove increasingly important as the tumor evolves during the course of treatment.

The development of compound resistance mutations has been observed with sequential ALK inhibitor treatment, which adds another layer of complexity. Lorlatinib has been shown to be rendered ineffective by the combination of the C1156Y and L1198F mutations, although it is active against the singular mutations. Interestingly, this particular compound mutation was found to resensitize a tumor to crizotinib, which is normally inactivated by the C1156Y mutation.²⁷

Finally, to date, no ALK inhibitor has demonstrated a statistically significant improvement in overall survival. Researchers believe this is a result of the substantial crossover allowed in clinical trials. Long-term follow-up should help to tease out any possible effects.^13,14