Resensitization to Crizotinib by the Lorlatinib<i>ALK</i>Resistance Mutation L1198F

At, Shaw; Friboulet, Luc; Leshchiner, Ignaty; Jf, Gainor; Bergqvist, Simon; Brooun, Alexei; Bj, Burke; Yl, Deng; W, Liu; Dardaei, Leila; Rl, Frias; Schultz, Kirk R.; Logan, Jennifer; Lp, James; Smeal, Tod; Timofeevski, Sergei; Katayama, Ryohei; Aj, Iafrate; Liang, Le; McTigue, Michele; Getz, Gaddy; Tw, Johnson; Ja, Engelman

doi:10.1056/nejmoa1508887

Cited by 431 publications

(370 citation statements)

References 23 publications

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“…This was first presented by Shaw et al, who described a patient with metastatic ALK -rearranged NSCLC who received lorlatinib through a clinical trial after progression of disease on crizotinib, ceritinib, and carboplatin–pemetrexed chemotherapy [48]. At time of progression on lorlatinib, she underwent biopsy of a resistant liver lesion which demonstrated the presence of C1156Y (previously detected) and L1198F mutations.…”

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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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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“…As described for EGFR-mutated NSCLC, progressing to the third-generation inhibitor AZD9291 because of the emergence of C797S mutation, sensible to first-generation compounds (94), ALK substitution L1198F drives resistance to ceritinib, alectinib, brigatinib and lorlatinib, while resensitizing tumor cells to crizotinib (95).…”

Section: Lorlatinibmentioning

confidence: 99%

“…If crizotinib treatment can be usefully followed by next-generation molecules, the inverse therapeutic sequence cannot be envisaged, with the exception of only one case reported worldwide so far (95). Novel molecules administered as upfront ALK inhibitors should therefore allow disease control periods at least comparable to experienced crizotinib-based sequences.…”

Section: Positioning In Clinical Practicementioning

confidence: 99%

“…Novel molecules administered as upfront ALK inhibitors should therefore allow disease control periods at least comparable to experienced crizotinib-based sequences. Moreover, mechanisms of resistance to the second-and third-generation ALK inhibitor are up to now clearly defined and seem to differ from events leading to crizotinib exhaustion (95,125). From this point of view, the administration of the novel compounds as the first ALKdirected approach could leave physicians "molecularly unarmed" at the moment of disease progression.…”

Section: Positioning In Clinical Practicementioning

confidence: 99%

See 1 more Smart Citation

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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“…Although further studies are needed in order to address whether the type of resistance mutation will guide the decision on which ALK-TKI should be offered to crizotinib-resistant NSCLCs, it is important to pinpoint that, similarly to crizotinib, also next-generation ALK-TKIs are subject to the development of resistance under the selective pressure of treatment. With regard to this, Shaw et al reported a case of crizotinib-resistant tumor with an ALK C1156Y secondary mutation which did not respond to ceritinib, consistently with the fact that ceritinib is not active against the C1156Y resistance mutation, but responded to lorlatinib instead [14]. Upon the development of resistance to lorlatinib, re-biopsy of the tumor showed the gain of the additional L1198F mutation, which resensitized the tumor to crizotinib treatment.…”

mentioning

confidence: 91%