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. 2021 May 3:5:PO.20.00383.
doi: 10.1200/PO.20.00383. eCollection 2021.

Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

Yuki Takeyasu  1   2 , Hitomi S Okuma  1   3 , Yuki Kojima  1 , Tadaaki Nishikawa  1 , Maki Tanioka  1 , Kazuki Sudo  1 , Tatsunori Shimoi  1 , Emi Noguchi  1 , Ayumu Arakawa  4 , Taisuke Mori  5 , Kuniko Sunami  6 , Takashi Kubo  7   8 , Takashi Kohno  7   9 , Yoshida Akihiko  4   10 , Noboru Yamamoto  11 , Kan Yonemori  1
Affiliations

Impact of ALK Inhibitors in Patients With ALK-Rearranged Nonlung Solid Tumors

Yuki Takeyasu et al. JCO Precis Oncol. .

Abstract

Purpose: Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene in non-small-cell lung cancer and has also been identified in other types of tumors. However, there is limited evidence on the clinical response to ALK tyrosine kinase inhibitors (TKIs), such as alectinib and crizotinib, in rare tumors with ALK fusion. We evaluated the therapeutic effect of ALK-TKIs in rare ALK-rearranged tumors.

Patients and methods: Between April 2012 and April 2019, clinical outcomes and characteristics of patients with ALK-rearranged nonlung solid tumors who received ALK-TKIs (alectinib and/or crizotinib) outside of clinical trials were reviewed. Expression and/or rearrangement of ALK was evaluated by immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing. The tumor response was assessed according to RECIST (version 1.1). Progression-free survival was estimated from initial ALK-TKI initiation until progression.

Results: We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib.

Conclusion: This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, EisaiKazuki Sudo Honoraria: AstraZeneca, PfizerEmi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai PharmaAyumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: AmgenKuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, LillyTakashi Kubo Consulting or Advisory Role: SysmexTakashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, SysmexNoboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, OtsukaKan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.Tadaaki Nishikawa Honoraria: AstraZeneca, Eisai Consulting or Advisory Role: Eisai Speakers' Bureau: AstraZeneca, Eisai Kazuki Sudo Honoraria: AstraZeneca, Pfizer Emi Noguchi Honoraria: Nippon Kayaku Speakers' Bureau: Sysmex, AstraZeneca, Pfizer, Eisai, Lilly Japan, Taiho Pharmaceutical, Chugai Pharma Ayumu Arakawa Research Funding: Chugai Pharma Travel, Accommodations, Expenses: Amgen Kuniko Sunami Honoraria: Sysmex, Chugai Pharma, AstraZeneca, Novartis, Eisai, Riken Genesis, Lilly Takashi Kubo Consulting or Advisory Role: Sysmex Takashi Kohno Consulting or Advisory Role: LOXO Oncology, Lilly Japan Research Funding: Daiichi Sankyo, Sysmex Noboru Yamamoto Honoraria: AstraZeneca, Pfizer, Chugai Pharma, Bristol Myers Squibb Japan, Ono Pharmaceutical, Lilly Japan, Sysmex Consulting or Advisory Role: Eisai, Takeda, Otsuka, Boehringer Ingelheimm, CMIC, Chugai Pharma Research Funding: Chugai Pharma, Taiho Pharmaceutical, Eisai, Astellas Pharma, Novartis, Daiichi Sankyo, Lilly Japan, Boehringer Ingelheim, Takeda, Kyowa Hakko Kirin, Bayer, Pfizer, Ono Pharmaceutical, Janssen, IQVIA, Merck Sharp & Dohme, Abbvie, Bristol Myers Squibb, Merck Serono, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience, Otsuka Kan Yonemori Honoraria: Eisai, Pfizer, AstraZeneca, Novartis, Taiho Pharmaceutical Consulting or Advisory Role: Chugai Pharma, Ono Pharmaceutical, Novartis, Eisai Research Funding: Ono Pharmaceutical No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Histological features of representative cases. (A) Patient 1: histiocytic sarcoma, CLTC|ALK fusion; (B) patient 3: IMT (epithelioid); (C) patient 4: ALK-positive histiocytosis; (D) patient 5: IMT, CLTC|ALK fusion; (E) patient 6: osteosarcoma, ITSN2|ALK fusion; (F) patient 6: negative staining in ALK IHC; (G) patient 7: parotid adenocarcinoma, CTNNA1|ALK fusion; and (H) patient 7: plasma membrane staining in ALK IHC. ALK, anaplastic lymphoma kinase; IHC, immunohistochemistry; IMT, inflammatory myofibroblastic tumor.
FIG 2.
FIG 2.
Trends with tumor burden (sum of target lesions) and clinical courses for each case. ADM, adriamycin; AI, adriamycin/ifosfamide; ALK, anaplastic lymphoma kinase; CAP, cyclophosphamide/adriamycin/cisplatin; CHOP, cyclophosphamide/adriamycin/oncovin/prednisolone; CR, complete response; DTX, docetaxel; GEM, gemcitabine; IFM, ifosfamide; IHC, immunohistochemistry; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; SD, stable disease; TMZ, temozolomide; VP-16, etoposide.
FIG 3.
FIG 3.
Waterfall plot of best response to initial ALK-TKI. ALK, anaplastic lymphoma kinase; TKI, tyrosine kinase inhibitor.
FIG 4.
FIG 4.
Diagnostic radiographic images of representative cases. (A and B) Patient 1: histiocytic sarcoma showing PR; (C and D) patient 3: IMT (epithelioid) showing CR; (E and F) patient 4: ALK-positive histiocytosis showing CR; (G and H) patient 5: IMT; (I and J) patient 6: osteosarcoma showing PD; and (K and L) patient 7: parotid adenocarcinoma showing PR. ALK, anaplastic lymphoma kinase; CR, complete response; PD, progressive disease; PR, partial response; IMT, inflammatory myofibroblastic tumor.
FIG A1.
FIG A1.
(A) Schematic figures of gene fusions detected by NGS (patients 1 and 5): patient 1: CLTC|ALK fusion chr17:57, 769, 218-chr2:29, 447, 574 (exon 31: exon 20) and patient 5: CLTC|ALK fusion chr 17:57, 768, 627-chr 2:29,446,555 (exon 31: exon 20); (B) NGS sequencing results and schematic figure of patient 7: CTNNA1-ALK fusion. Patient 7: CTNNA1|ALK fusion chr5:138, 259, 019-chr2:29, 446, 464 (exon 10: exon 20); (C) NGS sequencing results and schematic figure of patient 6: ITSN-ALK fusion. Patient 6: ITSN2|ALK fusion chr2:29,462,361-chr2:24,438,831 (exon 14: exon 32); ALK, anaplastic lymphoma kinase; chr2, chromosome 2; DH, Dbl homology domain; EH, Eps15 homology domain; IMT, inflammatory myofibroblastic tumor; ITSN2, intersectin 2; NGS, next-generation sequencing; SH3, Src three homology domain; TM, transmembrane domain; TrD, trimerization domain; VH1, vinculin homology one domain; VH2, vinculin homology two domain.
See this image and copyright information in PMC

Comment in

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