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

Gadgeel, Shirish M.; Gandhi, Leena; Riely, Gregory J.; Chiappori, Alberto; West, Howard; Azada, Michele C.; Morcos, Peter N.; Lee, Ruey Min; Garcia, Linta; Yu, Li; Boisserie, Frédéric; Laurenzio, Laura Di; Golding, Sophie; Sato, Jotaro; Yokoyama, Shumpei; Tanaka, Tomohiro; Ou, Sai Hong Ignatius

doi:10.1016/s1470-2045(14)70362-6

Cited by 641 publications

(515 citation statements)

References 21 publications

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“…Alectinib (Alecensa, CH5424802, Roche/Chugai) is an anaplastic lymphoma kinase (ALK) inhibitor, approved for the treatment of advanced NSCLC refractory to crizotinib (Gadgeel et al 2014). It was subsequently shown to be an effective RET inhibitor in vitro and in vivo (Kodama et al 2014).…”

Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

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Section: Investigational Drugsmentioning

confidence: 99%

Novel targeted therapeutics for MEN2

Plaza-Menacho

Mologni

2018

Endocrine-Related Cancer

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“…A phase I/II study of alectinib in previously crizotinib-treated patients showed a response rate of 55% with an intracranial response rate of 52%, which included a patient with leptomeningeal carcinomatosis [30]. In a single-group, multicenter phase II study conducted in the USA and Canada, the ORR was 52% with a median duration of 13.5 months [25].…”

Section: Therapeutic Optionsmentioning

confidence: 99%

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Qin

Gadgeel

2017

Targ Oncol

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Tumorigenic rearrangements in anaplastic lymphoma kinase (ALK) account for 3–7% of all non-small cell lung cancers (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superiority to chemotherapy in response rate, duration of response, and progression-free survival. However, eventually all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site, which served as the impetus for the development of more potent next-generation ALK inhibitors. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Investigations into whether the initiation of a second-generation ALK inhibitor as first-line therapy is the superior treatment paradigm has resulted in the approval of ceritinib as initial therapy. Alectinib has also shown impressive results as front-line therapy, as recently reported in two large randomized studies that compared it to crizotinib. There is a significant need to better understand the drivers of and mechanisms underlying resistance to ALK inhibitors. While specific mutations have been identified, there is currently only limited evidence that the identification of specific mutations should impact selection of the next ALK inhibitor. The best treatment option for patients who become TKI refractory is also unclear, though there is some evidence to suggests that these patients are not responsive to checkpoint inhibitors and may respond better to chemotherapy. Combination therapy with other classes of agents may help to overcome resistance mechanisms and should be investigated further.

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“…In the dose-finding portion of the AF-002JG trial, a phase I/II study performed in the United States in ALK-positive NSCLC patients previously treated with crizotinib, alectinib allowed a RR of 55% (74). In a global phase II study testing alectinib in crizotinibrefractory ALK-rearranged NSCLC (NP28673), the RR was 50% in the whole study population (including both patients pretreated with chemotherapy and chemotherapynaive) and 45% in the subgroup of patients pretreated with chemotherapy (76).…”

Section: Alectinibmentioning

confidence: 99%

“…Initial data concerning intracranial activity of alectinib derived from a phase I/II trial enrolling patients who progressed on or were intolerant to crizotinib (74). Among the 21 patients with CNS metastases at baseline treated in the dose-escalation portion of the study, 11 (52%) achieved a brain objective response (6 complete and 5 partial responses) and eight (38%) patients had stable disease; brain responses were observed at different drug doses.…”

Section: Efficacy Of Alk Inhibitors On Brain Metastasesmentioning

confidence: 99%

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

Facchinetti¹,

Tiseo²,

Maïo³

et al. 2016

Transl. Lung Cancer Res.

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Abstract:Crizotinib is an oral inhibitor of anaplastic lymphoma kinase (ALK) with remarkable clinical activity in patients suffering from ALK-rearranged non-small cell lung cancer (NSCLC), accounting to its superiority compared to chemotherapy. Unfortunately, virtually all ALK-rearranged tumors acquire resistance to crizotinib, frequently within one year since the treatment initiation. To date, therapeutic strategies to overcome crizotinib resistance have focused on the use of more potent and structurally different compounds. Second-generation ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802/ RO5424802) and brigatinib (AP26113) have shown relevant clinical activity, consequently fostering their rapid clinical development and their approval by health agencies. The third-generation inhibitor lorlatinib (PF-06463922), selectively active against ALK and ROS1, harbors impressive biological potency; its efficacy in reversing resistance to crizotinib and to other ALK inhibitors is being proven by early clinical trials. The NTRK1-3 and ROS1 inhibitor entrectinib (RXDX-101) has been reported to act against NSCLC harboring ALK fusion proteins too. Despite the quick development of these novel agents, several issues remain to be discussed in the treatment of patients suffering from ALK-rearranged NSCLC. This position paper will discuss the development, the current evidence and approvals, as long as the future perspectives of new ALK inhibitors beyond crizotinib. Clinical behaviors of ALK-rearranged NSCLC vary significantly among patients and differential molecular events responsible of crizotinib resistance account for the most important quote of this heterogeneity. The precious availability of a wide range of active anti-ALK compounds should be approached in a critical and careful perspective, in order to develop treatment strategies tailored on the disease evolution of every single patient.

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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

Cited by 641 publications

References 21 publications

Novel targeted therapeutics for MEN2

Novel targeted therapeutics for MEN2

The Current Landscape of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer: Emerging Treatment Paradigms and Future Directions

Tackling ALK in non-small cell lung cancer: the role of novel inhibitors

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