Ceritinib in patients with advanced anaplastic lymphoma kinase–rearranged anaplastic large-cell lymphoma

To the editor:

The anaplastic lymphoma kinase (ALK) gene is expressed in >50% of anaplastic large-cell lymphomas (ALCLs).¹ Although most patients with ALK-positive ALCL respond well to anthracycline-based chemotherapy, relapses do occur (5-year failure-free survival 60%) and require salvage therapy,² generally with poor outcomes.² Autologous stem cell transplant is an option in the salvage setting, but not all patients can tolerate this or achieve a sufficiently good response to high-dose chemotherapy to be candidates.³ Recently, brentuximab vedotin has shown encouraging activity in patients with relapsed or refractory ALCL.^4,5

Ceritinib is a novel, selective ALK inhibitor which has been shown to induce complete tumor regression of crizotinib-resistant xenograft models of ALK+ ALCL.⁶ A phase 1 dose-escalation study of ceritinib (ASCEND-1; this trial was registered at www.clinicaltrials.gov as #NCT01283516) was conducted in patients with advanced or metastatic ALK-positive tumors.⁷ Among a total of 304 patients, 3 had relapsed with ALK+ ALCL. All patients were enrolled during the expansion phase of the study, with 1 included in the analysis reported previously.⁷ Here, we report in detail on the safety and efficacy of ceritinib in these 3 patients.

In the ASCEND-1 study, all anatomical responses were assessed as per Response Evaluation Criteria in Solid Tumors 1.0 criteria, as patients with a variety of ALK+ cancers were enrolled. Responses were confirmed by computerized tomography or positron emission tomography/computerized tomography using fludeoxyglucose tracer. Full details of the trial design have been reported previously.⁷

All 3 patients with ALK-positive ALCL initiated ceritinib treatment at a dose of 750 mg/d. Two patients achieved a complete response (CR) and 1 had a partial response (PR) (Table 1). The patient with a PR achieved a maximal tumor reduction of 94.8% from baseline. As of January 2015, responses were ongoing for all 3 patients, with durations ranging from ≥20 months to ≥26 months (Table 1). Two patients experienced adverse events that required ceritinib dose reductions (Table 1) but continue to receive ceritinib at the reduced dose level. The other patient continues to receive ceritinib at 750 mg/d. Toxicities observed in this subgroup analysis were mainly grade 1 or 2. Overall, the common adverse events observed in ALK-positive ALCL were similar to those observed with ALK-positive non–small cell lung cancer.⁷

Table 1.

Patient demographics and efficacy and safety of ceritinib in patients with relapsed/refractory ALK-positive ALCL

	Patient 1	Patient 2	Patient 3
Age (y)	40	48	24
Sex	Male	Female	Male
Performance status	1	1	1
Disease stage (Ann Arbor)	Stage IV*	Stage III B†	Stage III A‡
ALK testing method§	FISH	IHC and FISH	FISH
ALK fusion partner	NPM	NPM	Unknown
Prior treatment (dates)	Hyper-CVAD chemotherapy (June 2012 to November 2012)	CHOP chemotherapy (November 2011 to March 2012)	CHOP chemotherapy (October 2012 to February 2013)
Best response to prior chemotherapy (duration)	CR (2.3 mo)	CR (3 mo)	CR (1 mo)
Relapsed/refractory	Relapsed and refractory	Relapsed	Relapsed
Ceritinib starting dose	750 mg/d	750 mg/d	750 mg/d
Best response to ceritinib	CR (still ongoing)	CR (still ongoing)	PR (still ongoing)
Duration between initiating ceritinib therapy and achieving best response	2 mo	8.3 mo	3 mo
Duration of best response to ceritinib	≥26 mo	≥24 mo	≥20 mo
Adverse events during ceritinib treatment	Grade 1-2 diarrhea and abdominal discomfort	Grade 2 fatigue and grade 3 increase in transaminase levels (dose reduction)	Acute pericarditis (sharp chest pain, T-wave inversions, and small pericardial effusion on ECG) (dose reduction)
		Grade 1 diarrhea and vomiting
Ceritinib dose modification(s)	Not required	Two dose reductions:	One dose reduction:
		To 600 mg/d (week 16)	To 450 mg/d (week 9)
		To 450 mg/d (week 35)

CHOP, cyclophosphamide/doxorubicin/vincristine/prednisolone; ECG, electrocardiogram; FISH, fluorescence in situ hybridization; hyper-CVAD, cyclophosphamide/vincristine/adriamycin/dexamethasone; IHC, immunohistochemistry; NPM; nucleophosmin.

^*Patient 1 was diagnosed with stage IV disease involving cervical/mediastinal/celiac nodal disease plus bone marrow, focal L4 vertebral body, and skin.

^†Patient 2 was diagnosed with stage III B disease with lymphomatous involvement of cervical, axillary, inguinal, retroperitoneal, parailiacal, and paraaortal lymph node regions and splenomegaly.

^‡Patient 3 was diagnosed with stage III A disease involving multiple lymph node enlargements from the axillary to inguinal areas.

^§ALK testing method used for enrolling in the ASCEND-1 trial.

Treatment of patients with chemotherapy-relapsed advanced ALK-rearranged ALCL can be challenging and generally has a poor outcome.^2,3 Here, we have shown that the ALK inhibitor ceritinib is active in patients with ALCL who have relapsed after anthracycline-based chemotherapy. Although the number of patients with ALCL treated in our study is small, it is noteworthy that all 3 patients maintained responses to ceritinib salvage therapy for at least 20 months despite having had early relapses after anthracycline chemotherapy, a characteristic known to be associated with a poorer prognosis than late relapse.³ Crizotinib, another ALK inhibitor, has also shown activity in patients with ALK-positive ALCL who had progressed on 1 or more lines of therapy.^8-10 Interestingly, both ceritinib and crizotinib have shown durable responses of >26 months (still ongoing) and 40 months, respectively.⁸ Additionally, crizotinib showed activity in patients with previous autologous bone marrow transplant, but transplant-related toxicities limited the long-term administration of crizotinib.⁸ These results support our observations that treatment with ALK inhibitor-targeted therapy can be effective in patients with ALK+ ALCL.

Given the high remission rate, long duration of remission, and acceptable tolerability of treatment with ceritinib in the 3 patients with ALK+ ALCL in the ASCEND-1 study, ceritinib may have a role in the treatment of patients with ALK-positive ALCL. Two prospective studies (#NCT02343679 and #CLDK378A2407) are currently planned/enrolling to further evaluate the activity of ceritinib in patients with hematologic malignancies, including ALCL.

Authorship

Acknowledgments: The authors thank Elspeth Stewart, QXV Comms, an Ashfield business, part of UDG Healthcare plc (funded by Novartis Pharmaceuticals Corporation), and Shiva Krishna Rachamadugu, Novartis Healthcare Pvt. Ltd., for providing medical editorial assistance with the manuscript. The ASCEND-1 study was funded by Novartis Pharmaceuticals. The phase 1 unit of the West German Cancer Center was supported by an Oncology Center of Excellence grant of the Deutsche Krebshilfe (110534; to H.R. and M.S.). The sponsor (Novartis Pharmaceuticals) and the study investigators designed the study.

Contribution: S.J.H. and B.S. collected data for patient 1; H.R. and M.S. collected data for patient 2; T.M.K. and D.-W.K. collected data for patient 3; A.T.S. was the primary investigator of the study and together with the other authors analyzed the data in conjunction with the study sponsor; and all authors contributed to the development of the manuscript, approved the final version prior to submission, and had access to primary clinical trial data.

Conflict-of-interest disclosure: Those relationships marked with a “C” were compensated. M.S. (C) is a consultant or maintains an advisory role and has been a speaker at continuing medical education events at Novartis Pharmaceuticals. M.S. and H.R. received research funding to an institution from Novartis Pharmaceuticals. B.S. (C) is a consultant or maintains an advisory role at Novartis Pharmaceuticals. S.J.H. (C) received research funding to institution and honoraria and attended Novartis Pharmaceuticals advisory boards. D.-W.K. (C) is a consultant or maintains an advisory role at Novartis Pharmaceuticals. A.T.S. (C) is a consultant or maintains an advisory role at Novartis Pharmaceuticals. A.L.B. and A.Y. (C) are employees of Novartis Pharmaceuticals and own Novartis Pharmaceuticals stock. T.M.K. declares no competing financial interests.

Correspondence: Heike Richly, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Hufelandstraße 55, 45122 Essen, Germany; e-mail: heike.richly@uk-essen.de.