Alectinib in Combination With Bevacizumab in ALK Positive NSCLC

Description

BACKGROUND The burden of Lung Cancer Lung cancer remains the most lethal malignancy worldwide, claiming more lives compared to any other malignant disease in both developed and developing countries, as well as globally. Although some countries have accomplished a decrease in incidence rates, most regions, particularly those in the developing world, face the challenge of an epidemic of paramount importance, which is likely to take hundreds of thousands of lives in the coming years. In Latin America, regional trends show that lung cancer incidence and mortality are on the rise, in Mxico, for example, trends from the Global Cancer Statistics group (GLOBOCAN) show that it is likely that incident lung cancer cases will double by 2030, compared to those reported in 2010.

The management of lung cancer, therefore, requires a surge in our efforts. For many decades, lung cancer treatment was based on the use, alone or in combination, of radiotherapy, surgery and chemotherapy. The scarce therapeutic options were further limited by their lack of long-term efficacy, with a 5-year survival rate for lung cancer patients which ranged from 5-16%, and which remained unchanged from the 1970s to the dawn of this new century. Nowadays, the therapeutic outlook for lung cancer patients is changing dramatically. Novel data regarding the molecular mechanisms of the disease led to the development of targeted treatments, including Tyrosine Kinase Inhibitors (TKIs) which can dramatically improve outcomes in specific subgroups of lung cancer patients.

Anaplastic Lymphoma Kinase Translocation (ALK) Between 6-8% of Non-Small Cell Lung Cancer cases have been shown to harbor the fusion gene of echinoderm microtubule based protein-like4 (EML4) and the anaplastic lymphoma Kinase (ALK) because of a chromosomal inversion in 2p21 and 2p23.

The formation of ALK fusion proteins results in the activation and deregulation of gene expression and signaling, which contributes to increased cell proliferation and survival in tumors expressing these genes. This is supported by reports which state that the TRK-fused gene (TFG) and kinesin family member 5B (KIF5B) genes may also serve as ALK fusion partners in some patients with NSCLC. Expression of these ALK fusion genes causes their transformation and enhanced proliferation. Tumors that contain the EML4-ALK fusion oncogene or its variants are associated with specific clinical features, including never or light smoking history, younger age, and adenocarcinoma with signet ring or acinar histology. Alterations of the ALK gene are generally found in a mutually exclusive relationship with mutations in epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma (KRAS). Nonetheless, EGFR mutations may develop as a resistance mechanism after treatment with ALK inhibitors.

Wild-type ALK is hardly expressed in most normal human tissues, but is expressed at higher levels in a few limited types of tissues such as developing and mature tissue of the nervous system (glial cells, neurons, endothelial cells and pericytes. In contrast, an aberrant ALK with constitutively active kinase results from the formation of the EML4-ALK fusion gene by chromosomal translocation and will likely be expressed in cells with this genotype.

Patients with advanced NSCLC who have this genetic abnormality are preferably treated with an ALK inhibitor. This observation is based on a previous phase III study which compared treatment with standard chemotherapy vs. crizotinib (ALK-TKI) in treatment-nave patients with ALK-rearrangement. Results from this trial demonstrated a prolonged progression-free survival (PFS) along with an improved response rate and quality of life in patients treated with crizotinib. Due to a potentially confounding crossover effect, differences in overall survival (OS) did not reach statistical significance. In spite of these encouraging results, patients treated with crizotinib have short-lived responses, with an average of 10 months of therapy before discontinuation. Other shortcomings of first-generation ALK-inhibitors include their ineffectiveness in the context of the central nervous system as well as the development of resistance mechanisms.

• Alectinib Alectinib is a second-generation ALK inhibitor that has activity in crizotinib-resistant disease. Additionally, Alectinib has been shown to provide adequate CNS activity and has a more complete blockade of ALK. It received FDA approval for first-line treatment of ALK-positive metastatic NSCLC, as well as for patients who have progressed on or are intolerant to crizotinib.

Initial approval of Alectinib for ALK-rearranged NSCLC previously treated with crizotinib came in 2015. Bases for approval were derived from an initial study, in which 122 patients with evaluable, ALK-rearranged, crizotinib-resistant disease were included. Eighty percent had progressed after prior platinum-based chemotherapy. With a median follow-up of 47 weeks, Alectinib was associated with an overall objective response rate (ORR) of 50%, a disease control rate (DCR: objective response plus stable disease) of 79%, and a median duration of response of 11 months. The median progression-free survival (PFS) was 8.9 months.

A second phase II study including 69 patients with measurable advanced ALK-rearranged NSCLC who had progressed on crizotinib found that Alectinib was associated with an ORR of 48% at a follow-up of 4.8 months.

Further, Alectinib received approval in 2017 and is now recommended as a first-line therapeutic option in ALK-rearranged NSCLC. Approval was based on results from the trial comparing alectinib (Alecensa) with crizotinib (Xalkori) as first-line treatment against ALK-positive non-small cell lung cancer (ALEX) trial, a global study including 303 patients which compared treatment with Alectinib vs. crizotinib for ALK-rearranged metastatic NSCLC patients who had not received previous systemic therapy. Study results reported an improved PFS, with a hazard ratio (HR) of 0.53. Additionally, patients receiving Alectinib had a significantly lower incidence of CNS progression (12% vs. 45%) and a higher proportion of patients with response duration of 12 months (64% vs. 36%). Further, grade 3 to 5 toxicities were less frequent with Alectinib (41% vs. 50%).

In another study published in 2017, the J-ALEX trial, 207 Japanese ALK-rearranged, crizotinib-nave NSCLC patients were randomly assigned to Alectinib vs. crizotinib. At a planned interim analysis, results demonstrated improved PFS with Alectinib; median PFS was not reached in the Alectinib arm compared to 10.2 months in the crizotinib arm (hazard ratio [HR] 0.34, 99.7% Confidence Interval [CI] 0.17-0.70). Alectinib was also better tolerated, with the most frequent adverse event being constipation (36%). Patients receiving crizotinib experienced nausea (74%), diarrhea (73%), visual disturbances (55%), and alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) elevations (>30%), among other toxicities.

Data to support the FDA approval for those who have progressed on or are intolerant to crizotinib comes from two phase II studies, both demonstrating response rates to Alectinib of approximately 50 percent in patients with ALK-rearranged locally advanced or metastatic NSCLC who had progressed on crizotinib.

• Brain Metastases Alectinib appears to have important clinical activity in patients with brain metastases, including patients with symptomatic brain metastases, patients with leptomeningeal disease, and patients who have CNS relapse on ceritinib.

Alectinib has also demonstrated improved outcomes relative to crizotinib among patients with brain metastases in 2 phase III trials. In the J-ALEX study, among 43 patients with ALK-positive NSCLC with brain metastases, Alectinib demonstrated improved PFS relative to crizotinib (HR 0.08, CI 0.01-0.61). Similarly, in ALEX, among those with CNS metastases, Alectinib improved PFS relative to crizotinib (HR 0.40, 95% CI 0.25-0.64) and intracranial response rate (81% versus 50%).

Evidence of the activity of Alectinib among patients with brain metastases who have crizotinib-resistant disease comes from phase II studies. In a pooled analysis of two phase II studies, among 136 patients with baseline CNS metastases (70% of whom had prior CNS radiotherapy) the CNS ORR, DCR, and duration of response for Alectinib were 43%, 85%, and 11.1 months, respectively.

• Vascular endothelial growth factor (VEGF) Vascular endothelial growth factor (VEGF) is a potent endothelial-specific angiogenic factor that is expressed in a wide array of tumors. In NSCLC, high levels of VEGF expression are associated with a poor prognosis, suggesting that treatment targeted toward this pathway might be useful.

One approach to blocking the VEGF pathway is the administration of bevacizumab, a recombinant humanized monoclonal antibody (MoAb) that binds VEGF, thereby preventing its interaction with the VEGF receptor.

For good performance status patients with non-squamous NSCLC, the addition of bevacizumab to a platinum based doublet offers a higher response rate, a longer PFS, and improved OS compared with chemotherapy alone.

The effect of adding bevacizumab to platinum-based doublets is illustrated by the two largest trials, in which bevacizumab was continued as maintenance after completion of the planned chemotherapy In the Eastern Cooperative Oncology Group trial E4599, 878 previously untreated patients with advanced, non-squamous NSCLC were randomly assigned to paclitaxel plus carboplatin or the same chemotherapy plus bevacizumab (15 mg/kg) on day 1 of each cycle. Bevacizumab was continued as monotherapy on the same schedule after completion of six cycles of chemotherapy until there was evidence of progressive disease.

Patients receiving chemotherapy plus bevacizumab had statistically significant increases in the ORR (35% vs. 15% with paclitaxel plus carboplatin alone), OS (median 12.3 vs. 10.3 months), one-year and two-year survival rates (51% vs. 44% and 23% vs. 15%, respectively), and PFS (6.2 vs. 4.5 months).

In the AVAiL trial, 1043 patients were randomly assigned to cisplatin plus gemcitabine every three weeks with either low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo on day 1 every three weeks. The cisplatin plus gemcitabine was continued for a maximum of six cycles, while the bevacizumab or placebo was continued as maintenance until there was evidence of progressive disease. PFS was significantly improved with both low-dose and high-dose bevacizumab (median 6.7, 6.5, and 6.1 months, for the 7.5 mg/kg, 15 mg/kg, and placebo groups, respectively). With a median follow-up of 13 months, the benefit in terms of PFS was maintained, as was the improvement in response rate (38%, 35%, and 22%, respectively). However, there were no significant differences in OS when comparing the three treatment arms (median survival 13.6, 13.4, and 13.1 months respectively; HR for death 0.93 and 1.03 vs. placebo).

In a meta-analysis based upon four trials (2194 patients), the addition of bevacizumab significantly increased both OS and PFS compared to chemotherapy alone (hazard ratios for death or progression 0.90, 95% CI 0.81-0.99 and 0.72, 95% CI 0.66-0.79, respectively). The effect on OS was significantly greater in patients with adenocarcinoma compared to other histology subtypes. The addition of bevacizumab increased the risk of grade 3 toxicity.

• Bevacizumab and TKI (Anti EGFR) The combination therapy of bevacizumab plus a TKI has been previously explored in a phase II trial. The study included 154 previously untreated patients who were randomly assigned to erlotinib plus bevacizumab or erlotinib alone. All patients tumors contained either an exon 19 deletion or the amino acid substitution at position 858 in EGFR, from a leucine (L) to an arginine (R) (L858R) mutation. PFS, the primary endpoint of the trial, was significantly increased with the combination regimen (median 16 versus 9.7 months, HR 0.54, 95% CI 0.36-0.79). A similar magnitude of benefit was seen with both types of mutation. OS data are pending.
• Alectinib and Bevacizumab To this date there is no published data of interaction and clinical efficacy of a combination therapy with Alectinib plus bevacizumab in patients with advanced NSCLC.

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