ALK REARRANGEMENTS
CASE 2 PRESENTATION
A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.
How would you respond to this patient’s inquiry?
FIRST-LINE TKIS FOR ALK REARRANGEMENTS
ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.61 The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.62 ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.
Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.63 PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).64 Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).65 PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).66 In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.
Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.67 It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.68 In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).69 Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.70