Abstract
Purpose
EGFR amplification has been reported to occur in ~50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world.
Methods
EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography.
Results
EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia vs the rest of the world (35% vs 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases).
Conclusions
EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.
Keywords: EGFR, biomarker, screening, depatux-m, GBM
Introduction
Glioblastoma (GBM) is an aggressive brain malignancy characterized by poor prognosis. Alterations, such as amplification or mutation of the Epidermal Growth Factor Receptor (EGFR) gene, are common. Previous work by us and others analyzing relatively small cohorts of up to a few hundred patients reported that EGFR amplification is observed in approximately 50% of GBMs,[1–3] and is highly stable over the disease trajectory (~80% retained in those sampled at recurrence) [4, 5].
The presence of EGFR amplification as determined by fluorescence in situ hybridization (FISH) in a central laboratory is an eligibility criterion in several ongoing therapeutic clinical trials of an antibody-drug conjugate targeting activated EGFR, depatuxizumab mafodotin (depatux-m, formerly ABT-414) [6], in patients with GBM (Phase 3 INTELLANCE-1, NCT02573324; Phase 2 INTELLANCE-2, NCT02343406; Phase 1/2 INTELLANCE-J, NCT02590263). We analyzed molecular screening data from these 3 trials, involving 3303 patients, to confirm the frequency of EGFR amplification reported in smaller cohorts, and to explore differences by region of world, results of which are presented here.
Materials and Methods
Study design
INTELLANCE-1 (RTOG 3508/AbbVie M13–813, NCT02573324) is an ongoing Phase 3, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of depatux-m in combination with radiotherapy/temozolomide (RT/TMZ) vs RT/TMZ alone in patients with EGFR-amplified, primary GBM as a collaboration between the Radiation Therapy Oncology Group Foundation and AbbVie; ABL is the overall study chair (Supplementary Fig. S1). Briefly, eligible adult patients have histologically confirmed de novo (clinically defined) GBM (or gliosarcoma subtype); centrally confirmed EGFR amplification; chemoradiation therapy start within 7 weeks of diagnosis; and Karnofsky performance score (KPS) ≥ 70. Patients were randomized 1:1 and stratified according to recursive partitioning analysis (RPA) class [7]; region of the world; O6-methylguanine-DNA-methyltransferase (MGMT) methylation status; and EGFRvIII mutation status.
INTELLANCE-2 (EORTC 1410 BTG/AbbVie M14–483/, NCT02343406) is a Phase 2, randomized, open-label trial evaluating the efficacy and safety of depatux-m alone or in combination with TMZ compared to lomustine or TMZ in patients with EGFR-amplified, recurrent GBM as a collaboration between the European Organisation for the Research and Treatment of Cancer and AbbVie; MJvdB is the overall study chair (Supplementary Fig. S2) [8, 9]. Briefly, eligible adult patients have a first recurrence of histologically confirmed, de novo (clinically defined) GBM; centrally confirmed EGFR amplification; World Health Organization (WHO) performance score 0–2; and are naïve to EGFR-directed therapy. Patients were randomized 1:1:1 and stratified according to WHO performance score (0 vs > 0); timing of relapse (< vs ≥ 16 weeks from last TMZ treatment); and region of the world [8, 9].
INTELLANCE-J (M13–714, NCT02590263) is an ongoing AbbVie-led Phase 1/2, non-randomized, open-label trial evaluating the safety, pharmacokinetics, and efficacy of depatux-m in Japanese patients with malignant glioma (Supplementary Fig. S3) [10]. Eligible adult patients in the Phase 1, Arm A portion have histologically confirmed, recurrent WHO grade III or IV glioma per Response Assessment in Neuro-Oncology (RANO) criteria, with KPS ≥ 70; in Arm B and Arm C have histologically confirmed, newly diagnosed WHO grade III or IV glioma with surgical resection of tumor occurring > 1 week and ≤ 6 weeks prior to study start, with KPS ≥ 80; in the Phase 2 portion have recurrent GBM per RANO criteria; centrally confirmed EGFR amplification; completed RT/TMZ at time of initial diagnosis; KPS ≥ 70; and are naïve to EGFR-directed therapy.
For a complete listing of all countries included in each region of the world for each trial, see Table 1.
Table 1.
Countries in each region of the world for INTELLANCE-1, -2, and -J.
| Region | INTELLANCE-1 | INTELLANCE-2 | INTELLANCE-J |
|---|---|---|---|
| Africa | South Africa | NA | NA |
| Americas | Argentina, Brazil, Canada, Columbia, United States | Canada, United States | NA |
| Asia | China, Hong Kong, Singapore, South Korea, Taiwan | Singapore, South Korea, Taiwan | Japan |
| Europe | Austria, Belgium, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Portugal, Russian Federation, Spain, Switzerland, United Kingdom | Austria, Belgium, Czech Republic, Finland, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Spain, Switzerland, United Kingdom | NA |
| Middle East | Israel | NA | NA |
| Oceania | Australia, New Zealand | Australia | NA |
NA, not applicable.
Fluorescence in situ hybridization (FISH)
Before accrual to any of the 3 clinical trials above, FISH was performed by a central laboratory on all archival, formalin-fixed, paraffin-embedded (FFPE) GBM tumor samples as described [11]. A cell was considered EGFR-amplified if the EGFR/CEP 7 ratio was ≥ 2. The tumor was considered positive for EGFR amplification if ≥ 15% cells were amplified. We determined the rate of centrally determined EGFR amplification among submitted tumors and tabulated the frequency by region of the world.
Statistical analysis
Fisher’s exact test was used to determine statistical significance when comparing populations.
Results
In INTELLANCE-1, valid FISH results were obtained from 2074 patients screened across 27 countries and 183 study sites (Table 2). Of those, 1111 patients (54%) had EGFR-amplified tumors. However, among 215 patients screened from Asia (China, Hong Kong, Singapore, South Korea, Taiwan), the EGFR amplification rate was only 32%. Comparison of the rate of EGFR amplification in Asia vs the rest of the world excluding Asia (ROTW; 1043/1859 patients, 56%) was highly statistically significant (P < 0.0001).
Table 2.
INTELLANCE-1 EGFR screening results
| Region | Amplified, n | Nonamplified, n | Total, n | Positive, % |
|---|---|---|---|---|
| Africa | 6 | 6 | 12 | 50% |
| Americas | 433 | 398 | 831 | 52% |
| Asia | 68 | 147 | 215 | 32% |
| Europe | 497 | 309 | 806 | 62% |
| Middle East | 35 | 28 | 63 | 56% |
| Oceania | 72 | 75 | 147 | 49% |
| Total | 1111 | 963 | 2074 | 54% |
In INTELLANCE-2, valid FISH results were obtained from 1076 patients screened across 20 countries and 93 study sites; 577 patients (54%) had EGFR-amplified tumors (Table 3). However, among 116 patients screened from Asia, (South Korea, Singapore, Taiwan), the EGFR amplification rate was 41% vs the ROTW (530/860 patients, 62%), a significant difference (P < 0.0030).
Table 3.
INTELLANCE-2 EGFR screening results
| Region | Amplified, n | Nonamplified, n | Total, n | Positive, % |
|---|---|---|---|---|
| Africa | NA | NA | NA | NA |
| Americas | 53 | 33 | 86 | 62% |
| Asia | 47 | 69 | 116 | 41% |
| Europe | 437 | 332 | 769 | 57% |
| Middle East | NA | NA | NA | NA |
| Oceania | 40 | 65 | 105 | 38% |
| Total | 577 | 499 | 1076 | 54% |
NA, not applicable.
Pooling FISH results from INTELLANCE-1 and -2, we found that EGFR amplification was detected in 35% of patients from Asia (115/331) vs 56% (1573/2819) among patients from the ROTW. This difference was highly statistically significant (P < 0.0030, Table 4).
Table 4.
Pooled INTELLANCE-1/2 EGFR screening results
| Region | Amplified, n | Nonamplified, n | Total, n | Positive, % |
|---|---|---|---|---|
| Africa | 6 | 6 | 12 | 50% |
| Americas | 486 | 431 | 917 | 53% |
| Asia | 115 | 216 | 331 | 35% |
| Europe | 934 | 641 | 1575 | 59% |
| Middle East | 35 | 28 | 63 | 56% |
| Oceania | 112 | 140 | 252 | 44% |
| Total | 1688 | 1462 | 3150 | 54% |
To confirm these findings, we used INTELLANCE-J as a validation dataset in which 153 Japanese patients were screened with confirmed FISH results. Fifty-one patients (33%) had an EGFR-amplified GBM, similar to rates observed in Asia in both INTELLANCE-1 and -2. Across all 3 studies, < 1% of patients screened for EGFR amplification by FISH had uninformative data.
A further analysis was conducted by pooling all patients from Asia vs those from the ROTW in all 3 trials. In this analysis, 166 of 484 (34%) patients from Asia screened for any of the 3 trials had tumors harboring EGFR amplification, significantly lower than 56% (1573/2819 patients) among cases from the ROTW (P < 0.0001). Interestingly, we also observed a trend toward lower amplification rates in Oceania (Table 1; includes Australia and New Zealand), which has a considerable population of Asian descent, but for this analysis, the Oceania region is included with the ROTW.
Discussion
Overall, 54% of GBMs harbored EGFR amplification, consistent with previous reports of approximately 50% [1–3] in smaller data sets. To our knowledge, ours is the largest cohort of patients with GBM that have been screened for EGFR amplification, as well as the first report of a significantly lower EGFR amplification rate (34%, P < 0.0001) in patients from Asia with GBM, warranting further study. Previous reports have observed a higher rate of isocitrate dehydrogenase (IDH) mutations in patients from Asia with GBM [12–15], which have been shown to be mutually exclusive with EGFR amplification [16, 17]. Furthermore, the “classical” TCGA-based subtype, typically associated with a high frequency of EGFR amplification [18], is not prevalent in the Chinese patient population [15]. Although we did not consistently or centrally test or collect IDH mutation status, its relatively increased frequency in Asian populations may be a contributing factor to the lower frequency of EGFR amplification we observed in patients from Asia.
Other cancers are also associated with differences in EGFR abnormalities by population. For example, EGFR mutations are more common in non-small cell lung cancer (NSCLC) in patients of Asian descent, as well as in women never-smokers with adenocarcinoma histology [19, 20]. However, to our knowledge, such demographic differences have not been reported in GBM or other brain tumors. In addition, the mutations observed in NSCLC are typically exon 19–21 deletions or point mutations, which are distinct from the abnormalities typically observed in GBM.
It is possible that patients already tested at locally accruing medical centers and found to have tumors that did not harbor EGFR amplification were not offered to screen for the EGFR-directed therapeutic studies. Accordingly, such pre-screening bias could have falsely elevated the rate of EGFR amplification in patients from some institutions. However, in our experience, EGFR amplification testing in GBM is not commonly performed at most centers, and the large sample size, involving hundreds of sites each with potentially different practice patterns, likely mitigates this potential bias.
Our study design is also limited by the reliance on geographical origin of patients at the time of screening, rather than individual patient ethnicity. We did not collect self-described demography on all screened patients, but we did for patients who then enrolled onto the therapeutic trials following screening, and the data suggests this potential difference between geography and demography does not confound the interpretation. For example, in INTELLANCE-1, only 18 of 148 (12%) enrolled patients of self-described Asian demography were not in Asia geographically; further, no treated patients of self-described non-Asian demography were in Asia geographically. Of note, 100% of patients in INTELLANCE-J were both Japanese geographically and demographically (self-reported); thus, there is no issue of non-Asian patients in that study to confound the EGFR amplification rate by race. Another important consideration is that the amplification rates are slightly lower in Oceania, with its somewhat proportionately larger East Asian population, but the Middle East, with a large Asian but predominantly non-East Asian population, demonstrates rates similar to the ROTW. A possible implication here could be that these amplification differences are not merely regional, but also ethnically-driven. Further ethnicity-based analysis could potentially provide a firmer answer to this question.
In conclusion, this report confirms that approximately 50% of patients have GBMs harboring EGFR amplification. However, this rate is lower, approximately 34%, in patients in Asia (mostly East Asia). Further sub-analyses will be performed to explore if differences by gender, age, or other epidemiological factors exist, and whether other biomarkers (e.g., EGFRvIII mutation) differ by geography.
Supplementary Material
Acknowledgements
The authors and AbbVie would like to thank patients and their families/caregivers; study investigators and staff; Mrinal Y. Shah, PhD for medical writing support, and Yan Sun, PhD for statistical support, both employees of AbbVie, Inc.
Funding
AbbVie provided financial support for these studies (NCT02573324, NCT02343406, NCT02590263) and participated in the design, study conduct, analysis and interpretation of the data, as well as the writing, review, and approval of the manuscript. All authors were involved in the data gathering, analysis, review, interpretation, and manuscript preparation and approval. ABL was supported in part by NIH/NCI Cancer Center Support Grants P30CA013696 and 5UG1CA189960. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NIH or NCI.
Funding: AbbVie provided financial support for these studies (NCT02573324, NCT02343406, NCT02590263) and participated in the design, study conduct, analysis and interpretation of the data, as well as the writing, review, and approval of the manuscript. All authors were involved in the data gathering, analysis, review, interpretation and manuscript preparation and approval. A.B. Lassman was supported in part Voices Against Brain Cancer, the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital, and grants P30CA013696 and UG1CA189960 from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute/National Institutes of Health.
Conflict of Interest
Andrew B. Lassman: In the last 36 months, Dr. Lassman reports grants, personal fees and non-financial support from AbbVie, during the conduct of the study; personal fees and non-financial support from Orbus, grants, personal fees and non-financial support from Karyopharm, personal fees and non-financial support from NW Biotherapeutics, grants and non-financial support from Oncoceutics, personal fees and non-financial support from Agios, personal fees and non-financial support from Celgene, personal fees and non-financial support from Novocure, non-financial support from Tocagen, non-financial support from BMS, grants, personal fees and non-financial support from Kadmon, grants, personal fees and non-financial support from Roche/Genentech, grants and non-financial support from Amgen, grants and non-financial support from Millenium, grants and non-financial support from Celldex, grants and non-financial support from Novartis, grants and non-financial support from Pfizer, non-financial support from Keryx/Aeterna Zentaris, grants and non-financial support from VBI Vaccines, grants and non-financial support from Beigene, personal fees from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, personal fees from prIME Oncology, personal fees from Sapience, personal fees from WebMD, personal fees from Physicians’ Education Resource/Chemotherapy Foundation Symposium, personal fees from Astra Zeneca, personal fees from Cortice, outside the submitted work.
Kenneth D. Aldape: Nothing to disclose
Peter J. Ansell, Earle Bain, Jim Looman, Christopher Ocampo, Lisa Roberts-Rapp: Employees of AbbVie and may own stock/options
Walter J. Curran: Consultant for AstraZeneca and BMS; ownership shares of Nanthealth
Marica Eoli: Nothing to disclose
Pim J. French: Research funding from AbbVie
Manabu Kinoshita: Honoraria from Eisai, BrainLab, Nihon Medi-Physics, Canon Medical Systems, Integra Japan, Novocure, Daiichi-Sankyo; research grants from Chugai, Daiichi-Sankyo, Takeda, Ohtsuka
Minesh Mehta: Honoraria from AbbVie, Celgene, AstraZeneca, Tocagen; board of directors with stock options, Oncoceutics; DSMB member, Monteris
Yoshihiro Muragaki: Consulting/advisory role for AbbVie; speakers’ bureau for MSD, Daiichi Sankyo, Chugai Pharma, Otsuka, Eisai, Novartis, Hitachi; research funding to institution from MSD, Daiichi Sankyo, Chugai Pharma, Otsuka, Eisai, Hitachi
Yoshitaka Narita: Honoraria from Chugai, MSD, Eisai, Ohtsuka, Daiichi-Sankyo; consultant for AbbVie, Dainippon-Sumitomo; research grants from Chugai, Eisai, Ono, Daiichi-Sankyo, Stella-Pharma, Meiji
Minghao Song: Employee of Abbott Molecular and may own stock/options
Michael A. Vogelbaum: Indirect equity and royalty interests in Infuseon Therapeutics, Inc.
Annemiek Walenkamp: Research grants from Novartis, Ipsen; honoraria from Novartis, Polyphor
Tony J. C. Wang: Personal fees from AbbVie, AstraZeneca, Doximity, Elekta, Merck, Wolters Kluwer, Novocure; non-financial support from American Cancer Society North Jersey; all outside the submitted work
Peixin Zhang: Nothing to disclose
Martin J. van den Bent: Honoraria from Roche, AbbVie, Celgene, VAXIMM, BMS, Agios, Boehringer Ingelheim; research funding from AbbVie
Footnotes
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