Molecular Markers and Targeted Therapies in the Management of Non-Small Cell Lung Cancer
Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.71 Its indication will soon be broadened to the first-line setting based on the ALEX trial.72 Alectinib is a potent and highly selective TKI of ALK73 with activity against known resistant mutations to crizotinib.74,75 It also inhibits RET but not ROS1 or c-MET.76 ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).72 Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.77
Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).78 Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.
Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.79 Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.81
,ROS1 REARRANGEMENTS
CASE PRESENTATION 3
A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.
What treatment plan should be put in place for this patient?
FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS
Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.82 This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.8 It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.83 As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.84 Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.85 The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).86 During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.85
