Prospective and clinical validation of ALK immunohistochemistry: results from the phase I/II study of alectinib for ALK-positive lung cancer (AF-001JP study).
BACKGROUND
Anaplastic lymphoma kinase (ALK) fusions need to be accurately and efficiently detected for ALK inhibitor therapy. Fluorescence in situ hybridization (FISH) remains the reference test. Although increasing data are supporting that ALK immunohistochemistry (IHC) is highly concordant with FISH, IHC screening needed to be clinically and prospectively validated.


METHODS
In the AF-001JP trial for alectinib, 436 patients were screened for ALK fusions through IHC (n = 384) confirmed with FISH (n = 181), multiplex RT-PCR (n = 68), or both (n = 16). IHC results were scored with iScore.


RESULTS
ALK fusion was positive in 137 patients and negative in 250 patients. Since the presence of cancer cells in the samples for RT-PCR was not confirmed, ALK fusion negativity could not be ascertained in 49 patients. IHC interpreted with iScore showed a 99.4% (173/174) concordance with FISH. All 41 patients who had iScore 3 and were enrolled in phase II showed at least 30% tumor reduction with 92.7% overall response rate. Two IHC-positive patients with an atypical FISH pattern responded to ALK inhibitor therapy. The reduction rate was not correlated with IHC staining intensity.


CONCLUSIONS
Our study showed (i) that when sufficiently sensitive and appropriately interpreted, IHC can be a stand-alone diagnostic for ALK inhibitor therapies; (ii) that when atypical FISH patterns are accompanied by IHC positivity, the patients should be considered as candidates for ALK inhibitor therapies, and (iii) that the expression level of ALK fusion is not related to the level of response to ALK inhibitors and is thus not required for patient selection.


BACKGROUND
JapicCTI-101264 (This study is registered with the Japan Pharmaceutical Information Center).
Pathology Project for Molecular Targets Division of Pathology, the Cancer Institute, Japanese Foundation for Cancer Research, Tokyo kentakeuchi-tky@umin.net.
K
K
Takeuchi
Pathology Project for Molecular Targets Division of Pathology, the Cancer Institute, Japanese Foundation for Cancer Research, Tokyo.
Y
Y
Togashi
Chugai Pharmaceutical Co. Ltd, Tokyo.
Y
Y
Kamihara
Chugai Pharmaceutical Co. Ltd, Tokyo.
T
T
Fukuyama
Kurashiki Central Hospital, Okayama.
H
H
Yoshioka
Tohoku University Hospital, Miyagi.
A
A
Inoue
Chugai Pharmaceutical Co. Ltd, Tokyo.
H
H
Katsuki
Okayama University Hospital, Okayama.
K
K
Kiura
Kinki University Hospital Faculty of Medicine, Osaka.
K
K
Nakagawa
National Kyushu Cancer Center, Fukuoka.
T
T
Seto
Miyagi Cancer Center, Miyagi.
M
M
Maemondo
Aichi Cancer Center, Aichi.
T
T
Hida
National Hospital Organization Hokkaido Cancer Center, Hokkaido.
M
M
Harada
National Cancer Center Hospital, Tokyo.
Y
Y
Ohe
Shikoku Cancer Center, Ehime.
N
N
Nogami
Shizuoka Cancer Center, Shizuoka.
N
N
Yamamoto
The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo.
M
M
Nishio
St Luke's International Hospital, Tokyo, Japan.
T
T
Tamura
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002227:Carbazoles / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010880:Piperidines / Q000627:therapeutic use*; D011446:Prospective Studies; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D002227:Carbazoles; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C582670:alectinib
ALK; FISH; alectinib; companion diagnostics; iScore; immunohistochemistry