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Chromosomal rearrangements involving rearranged during transfection gene (RET) occur in 1% to 2% of NSCLCs and may confer sensitivity to rearranged during transfection (RET) inhibitors. Alectinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor (TKI) that also has anti-RET activity in vitro. The clinical activity of alectinib in patients with RET-rearranged NSCLC has not yet been reported.
Methods
We have described four patients with advanced RET-rearranged NSCLC who were treated with alectinib (600 mg twice daily [n = 3] or 900 mg twice daily [n = 1]) as part of single-patient compassionate use protocols or off-label use of the commercially available drug.
Results
Four patients with metastatic RET-rearranged NSCLC were identified. Three of the four had received prior RET TKIs, including cabozantinib and experimental RET inhibitors. In total, we observed two (50%) objective radiographic responses after treatment with alectinib (one confirmed and one unconfirmed), with durations of therapy of 6 months and more than 5 months (treatment ongoing), respectively. Notably, one of these two patients had his dose of alectinib escalated to 900 mg twice daily and had clinical improvement in central nervous system metastases. In addition, one patient (25%) experienced a best response of stable disease lasting approximately 6 weeks (the drug discontinued for toxicity). A fourth patient who was RET TKI–naive had primary progression while receiving alectinib.
Conclusions
Alectinib demonstrated preliminary antitumor activity in patients with advanced RET-rearranged NSCLC, most of whom had received prior RET inhibitors. Larger prospective studies with longer follow-up are needed to assess the efficacy of alectinib in RET-rearranged NSCLC and other RET-driven malignancies. In parallel, development of more selective, potent RET TKIs is warranted.
Fusion kinases resulting from chromosomal rearrangements have emerged as important oncogenic drivers in NSCLC. Anaplastic lymphoma kinase gene (ALK) and ROS1 rearrangements are identified in 3% to 5% and 1% to 2% of patients with NSCLC, respectively, and confer sensitivity to treatment with targeted tyrosine kinase inhibitors (TKIs), such as crizotinib.
These findings have spurred ongoing efforts to uncover novel recurrent fusions in lung cancer.
Rearranged during transfection gene (RET) rearrangements were first identified in NSCLC in 2011 and have since been found in 1% to 2% of patients with NSCLC. As with ALK- and ROS1-rearranged NSCLC, RET-rearranged NSCLC has been associated with characteristic features such as younger age, history of never smoking, and adenocarcinoma histologic type.
Importantly, responses to multitargeted TKIs with anti-RET activity, such as cabozantinib and vandetanib, have been described in patients with RET-rearranged lung cancer,
Drilon AE, Sima CS, Somwar R, et al. Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. Paper presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2015; Chicago, IL.
Seto T, Yoh K, Satouchi M, et al. A phase II open-label single-arm study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC): Luret study. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
Lee SH, Lee JK, Ahn MJ, et al. A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
suggesting that RET rearrangements define a new targetable subset of NSCLC.
Despite the preliminary antitumor activity reported with the aforementioned multitargeted TKIs, the toxicities observed with these agents and the likelihood of acquired resistance emerging on the basis of experiences with other oncogene-driven lung cancers collectively underscore the need to develop more potent and selective RET inhibitors.
Alectinib is an orally active TKI originally developed to target anaplastic lymphoma kinase (ALK). In phase I and II studies, alectinib demonstrated high response rates in patients with advanced ALK-rearranged NSCLC, including those with central nervous system (CNS) disease,
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
leading to accelerated approval by the U.S. Food and Drug Administration (FDA). Recent work has shown that alectinib also inhibits RET with a half maximal inhibitory concentration of 4.8 nM.
These findings, together with alectinib’s favorable toxicity profile, provide a strong rationale for investigating the efficacy of alectinib in patients with RET-rearranged NSCLC. Here, we present a clinical series of four patients with RET-rearranged metastatic NSCLC treated with alectinib.
Methods
Identification of RET Rearrangements
RET rearrangement testing was performed by fluorescence in situ hybridization (FISH) or targeted next-generation sequencing (NGS) using anchored multiplex polymerase chain reaction.
RET FISH was performed on formalin-fixed paraffin-embedded tissue using break-apart probes (Kreatech RET (10q11) Dual Color, Break Apart Rearrangement Probe [Leica Biosystems, Nussloch, Germany]). Samples with more than 15% of cells showing split signals were defined as RET rearranged. The rearrangement NGS panel targets validated oncogenes, including ALK exons 19 to 22, ROS1 exons 31 to 37, and RET exons 8 to 13.
Treatment with Alectinib
All patients were treated at Massachusetts General Hospital. Patients 1 and 2 were treated with alectinib as part of single-patient compassionate use protocols. Patients 3 and 4 received commercial alectinib off label.
Results
Case 1
Case 1 involves a 50-year-old male former light smoker with stage IIIB lung adenocarcinoma who was treated with definitive chemoradiation (Table 1). He experienced a relapse with lung and brain metastases 11 months later and underwent a craniotomy with tumor resection followed by stereotactic radiosurgery. The results of EGFR, ALK, and ROS1 testing were negative; RET FISH identified a RET fusion. He therefore began receiving an experimental RET inhibitor. After an initial improvement in systemic disease, he was found to have worsening symptomatic brain metastases. He underwent whole brain radiotherapy followed by resumption of the drug, but continued CNS progression prompted a change in therapy. He began receiving alectinib, 600 mg twice daily, 2 months after completing whole brain radiotherapy. The dose was increased to 900 mg twice daily to augment CNS penetration on the basis of pharmacokinetic and safety data from a phase I dose-finding study of alectinib.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib.
Patient 1 had no reported toxicities while receiving alectinib. Repeat imaging 6 weeks later showed improvement in both intracranial (Fig. 1A) and extracranial disease, including decreased bilateral septal thickening, nodularity, and pleural effusion. According to the Response Evaluation Criteria in Solid Tumors (RECIST), version (v) 1.1, patient 1 achieved a confirmed partial response (PR) (–38.9%). After 3.5 months, an enlarging right frontal brain lesion developed and required resection 3 months later followed by fractionated radiation to the surgical resection cavity. Ultimately, alectinib was discontinued after a total of 8 months of therapy for both intracranial and extracranial disease progression. He has since been treated with stereotactic radiosurgery for a progressive CNS metastasis, followed by platinum-based doublet chemotherapy (duration of therapy 1 month) and subsequently paclitaxel and bevacizumab (duration of therapy more than 5 months).
Table 1Baseline Characteristics of RET-Positive Patients Treated with Alectinib
Figure 1Responses to alectinib. (A) Axial, T1 post–gadolinium magnetic resonance images before alectinib (A1) and after 6 weeks of therapy (A2) in patient 1 with rearranged during transfection gene (RET)-rearranged NSCLC, demonstrating a decrease in size of the intracranial metastases. (B) Axial chest computed tomography (CT) images at baseline (B1) and after 8 weeks of therapy (B2) in patient 2 with kinesin family member 5B gene (KIF5B)-RET, showing a decrease in the number and size of liver lesions. Her hepatic disease had progressed while she was receiving cabozantinib followed by an experimental rearranged during transfection (RET) inhibitor in the context of dose reductions on account of toxicities. (C) Axial chest CT images at baseline (C1) and after 6 weeks of therapy (C2) in patient 3 with coiled coil domain containing 6 gene (CCDC6)-RET, which reveals a decrease in size of the dominant right upper lobe lung mass and an adjacent small peripheral right upper lobe nodule. Postradiation changes are seen. (D) Axial chest CT images at baseline (D1) and after 6 weeks of therapy (D2) in patient 4 with KIF5B-RET, demonstrating disease progression with an increase in bilateral nodularity, septal thickening, and mediastinal mass/lymphadenopathy. The post alectinib scans (D2) were performed without contrast because of the patient’s renal dysfunction.
Case 2 involves a 62-year-old female never-smoker with a history of surgically resected lung adenocarcinoma (see Table 1) in whom liver and lung metastases developed and progressed despite four lines of chemotherapy. Her original lung resection specimen revealed a RET rearrangement by FISH. A liver biopsy specimen also tested positive for a kinesin family member 5B gene (KIF5B)-RET fusion by NGS. Cabozantinib therapy was initiated with stable disease on the first restaging scans, but it was discontinued within a month on account of grade 3 hyperbilirubinemia. She then received stereotactic body radiation therapy to the liver lesions. Given no other evidence of disease, she was monitored closely until she began receiving an experimental RET inhibitor in December 2014. This was complicated by toxicities requiring two dose reductions, and the drug was ultimately discontinued for disease progression. Given fairly indolent growth, the patient then remained off therapy for 3 months. Subsequent imaging revealed new, enlarging lung and liver lesions. With limited alternative options, she began receiving alectinib, 600 mg twice daily. A repeat computed tomography scan 8 weeks later revealed moderate regression (–27.8%) in the number and size of liver lesions, although this was classified as stable disease by RECIST v1.1 (Fig. 1B). Unfortunately, she experienced grade 3 toxicities of hyperbilirubinemia and an increase in creatinine kinase level (Common Terminology Criteria for Adverse Events, v. 4.03), requiring discontinuation of alectinib after 10 weeks. She went on to receive platinum-doublet chemotherapy (duration of therapy 2.5 months), followed by nivolumab (initiated in February 2016 and ongoing).
Case 3
Case 3 involves a 48-year-old male former light smoker in whom metastatic NSCLC was diagnosed in 2013 (see Table 1). Targeted NGS of a supraclavicular lymph node specimen revealed a coiled coil domain containing 6 gene (CCDC6)-RET fusion confirmed by FISH. He was treated with carboplatin and pemetrexed followed by cabozantinib, achieving stable disease. Treatment with cabozantinib (60 mg daily) was complicated by grade 2 hand-foot syndrome, requiring a dose reduction (40 mg daily) and eventual discontinuation of the drug. Thereafter, he received pemetrexed (18 months of therapy) followed by nivolumab. After receiving nivolumab for 2 months, patient 3 experienced hemoptysis and exhibited radiographic evidence of disease progression. He received a course of palliative chest radiation. In March 2016, he began receiving alectinib, 600 mg twice daily. Within 3 days, he reported dramatic improvement in energy and respiratory symptoms. Adverse events were notable for only grade 1 fatigue and grade 1 rash. Restaging scans 6 weeks later demonstrated postradiation changes and decreases in the dominant right upper lobe mass and right pleural effusion, which improved further on repeat imaging after he had been receiving alectinib for 14 weeks. By RECIST v. 1.1, patient 3 achieved an unconfirmed PR (–35.5%) (Fig. 1C). The patient continues to receive alectinib.
Case 4
Case 4 involves a 58-year-old female never-smoker in whom stage IV lung adenocarcinoma was diagnosed in April 2014 (see Table 1). She was treated with carboplatin and pemetrexed followed by pemetrexed maintenance therapy for 18 months. In the interim, targeted NGS of a malignant gastrohepatic lymph node revealed a KIF5B-RET fusion. In March 2016, her disease progressed with a worsening right hilar mass, lymphangitic carcinomatosis, and retroperitoneal lymphadenopathy. She thus began receiving alectinib, 600 mg twice daily. Clinically, she experienced worsening dyspnea and cough. Repeat computed tomography scans 6 weeks later showed progressive disease (+30.8% by RECIST v. 1.1) (Fig. 1D), prompting discontinuation of the drug. She went on to receive nivolumab before transitioning to hospice care in the setting of rapid clinical deterioration.
Discussion
Genetic alterations in RET have been identified in a number of malignancies and include gain-of-function point mutations (medullary thyroid cancer) and chromosomal rearrangements (papillary thyroid carcinomas, chronic myelomonocytic leukemia, and NSCLC).
In addition, more recently, preliminary findings from several prospective clinical trials focused on RET-rearranged NSCLC have been presented. For example, in a phase II study of 20 patients with RET-rearranged lung cancer treated with cabozantinib (of whom 18 were evaluable for response), the objective response rate (ORR) was 38%, with stable disease in 56% of patients.
Drilon AE, Sima CS, Somwar R, et al. Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. Paper presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2015; Chicago, IL.
Seto T, Yoh K, Satouchi M, et al. A phase II open-label single-arm study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC): Luret study. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
Lee SH, Lee JK, Ahn MJ, et al. A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
Alectinib is a U.S. Food and Drug Administration–approved ALK inhibitor that has demonstrated significant efficacy in patients with ALK-rearranged NSCLC.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
but its clinical activity in patients with RET-rearranged NSCLC has not yet been determined. Here, we have described a series of four patients with RET-rearranged NSCLC who were treated with alectinib. Importantly, three of the four patients were previously treated with other RET inhibitors, including cabozantinib. In total, objective radiographic responses were observed in two of four cases, with one additional patient achieving a best response of stable disease. Alectinib notably demonstrated evidence of CNS activity in one patient whose disease progressed during administration of an experimental RET inhibitor, which is consistent with prior reports of effective CNS penetration by alectinib.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib.
Moreover, as alectinib has little anti–kinase insert domain receptor effect and rarely causes hypertension and proteinuria (in contrast to the other available RET inhibitors),
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
Although these data are encouraging, this report has several notable limitations. First, we have described a single-institution experience with treating a small number of patients with RET-rearranged NSCLC with alectinib, and follow-up was limited. Larger prospective studies with longer follow-up are warranted to better evaluate the efficacy of alectinib in this setting. Indeed, a phase I/II study investigating the activity of alectinib in patients with advanced RET-rearranged NSCLC (UMIN000020628) is currently enrolling in Japan. Second, patients in this study received different doses of alectinib (ranging from 600 mg to 900 mg twice daily), and the optimal dose to treat RET-rearranged lung cancers remains to be established. One of the two patients who achieved a PR and also had improvement in CNS disease was treated with alectinib 900 mg twice daily—suggesting that perhaps a higher dose may be more appropriate to inhibit this particular driver fusion gene. Moreover, the patients presented herein had generally received prior RET TKIs, and therefore, further studies are needed to assess the potential activity of alectinib in RET TKI-naive patients. In addition, moving forward it will be critically important to identify molecular mechanisms of resistance to RET inhibitors by using repeat biopsies and/or cell-free DNA assays. Of note, among the three patients previously treated with RET inhibitors in this series, post-RET TKI/pre-alectinib biopsies were not performed, except in patient 2, but this specimen was insufficient for molecular testing. In general, mechanisms of resistance to RET inhibitors at the time of progression during administration of these agents, including alectinib, remain uncharacterized. Alectinib appears to have activity against RET gatekeeper mutations in vitro,
but whether this will be validated clinically is unknown. Ultimately, more potent and selective RET inhibitors that have activity against both wild-type and mutant RET will need to be developed, and understanding of resistance mechanisms will be helpful to guide these efforts.
In summary, our series provides the first clinical data demonstrating initial antitumor activity of alectinib in patients with advanced RET-rearranged NSCLC, including in patients with CNS disease. Larger prospective studies are needed to evaluate the efficacy of alectinib in patients with NSCLC and other malignancies driven by recurrent RET fusions. In parallel, development of more potent and selective RET inhibitors is warranted.
Acknowledgments
Alectinib was provided to two patients on a compassionate use basis by Genentech/Roche. We thank the members of the Massachusetts General Hospital Cancer Center Protocol Office for their assistance and the Be a Piece of the Solution and LungStrong advocacy groups for their support.
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First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
Drilon AE, Sima CS, Somwar R, et al. Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers. Paper presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29–June 2, 2015; Chicago, IL.
Seto T, Yoh K, Satouchi M, et al. A phase II open-label single-arm study of vandetanib in patients with advanced RET-rearranged non-small cell lung cancer (NSCLC): Luret study. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
Lee SH, Lee JK, Ahn MJ, et al. A phase II study of vandetanib in patients with non-small cell lung cancer harboring RET rearrangement. Paper presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3–7, 2016; Chicago, IL.
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
Alectinib dose escalation reinduces central nervous system responses in patients with anaplastic lymphoma kinase-positive non-small cell lung cancer relapsing on standard dose alectinib.
Disclosure: Dr. Sequist has served as a compensated consultant for AstraZeneca, Ariad, and Genentech/Roche and an uncompensated consultant for Clovis Oncology, Novartis, Merrimack, and Taiho. Dr. Brastianos has served as a compensated consultant for Genentech/Roche and Angiochem and received honoraria from Genentech/Roche and Merck. Ms. Wanat has served as a consultant for Clovis Oncology. Dr. Engelman has served as a paid consultant for Novartis, Chugai, Genentech/Roche, and Loxo. Dr. Shaw has served as a compensated consultant for or received honoraria from Pfizer, Novartis, Genentech/Roche, Ariad, Ignyta, Daiichi-Sankyo, Taiho, Blueprint Medicines, Loxo, and EMD Serono. Dr. Gainor has served as a compensated consultant or received honoraria from Novartis, Bristol-Myers Squibb, Merck, Ariad, Loxo, Genentech, Boehringer-Ingelheim, Jounce Therapeutics, Clovis, and Kyowa Hakko Kirin. The remaining authors declare no conflict of interest.
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