Impact of FDG PET Imaging for Expanding Patient Eligibility and Measuring Treatment Response in a Genome-Driven Basket Trial of the Pan-HER Kinase Inhibitor, Neratinib

Abstract

Purpose: To determine whether FDG PET can expand eligibility in biomarker-selected clinical trials by providing a means to quantitate response in patients with non-assessable disease by RECIST.

Experimental design: SUMMIT (NCT01953926) is a multicenter phase II "basket" trial of the Pan-HER kinase inhibitor, neratinib. Patients had advanced ERBB2 (HER2)-mutant solid tumors, ≥1 measurable lesion, preferably defined unidimensionally by RECIST v1.1, or alternatively metabolically by PET Response Criteria (PRC). The primary aim was to determine the proportion of additional breast cancer patients accrued using PRC who would have otherwise been ineligible based on RECIST criteria alone. The secondary aim was to determine the concordance of response versus non-response between RECIST and PRC.

Results: Eighty-one patients with HER2-mutant metastatic breast cancer were accrued; 77 were evaluable for response by RECIST and/or PRC. 63 (82%) were RECIST-evaluable and 14 (18%) were accrued using PRC alone. Bone-only disease (n = 11; 79%) was the most common reason for classification as non-measurable by RECIST. Twenty-nine patients were accrued and followed using both criteria, of which 25 (86%; 95% confidence interval, 68%-96%) were concordant for response versus non-response as defined by RECIST and PRC.

Conclusions: PRC allowed patients with non-RECIST measurable disease access to therapy and facilitated more rapid accrual of patients to this trial of a rare biomarker. PRC and RECIST both provided methods of response assessment and were generally concordant. Thus, PRC was useful as a supplement to RECIST criteria. This provides a rationale for including FDG PET measurements in future clinical trials involving rare tumors or rare genomically defined subpopulations of more common cancers.

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

G.A. Ulaner is an employee/paid consultant for Sanofi, and reports receiving commercial research grants from Puma. C. Saura is an advisory board member/unpaid consultant for Puma Biotechnology. S.A. Piha-Paul reports receiving other commercial research support from Abbvie, Aminex Therapeutics, Bio-Marin Pharmaceutical, Boehringer-Ingelheim, Cerulean Pharma, Chugai, Curis, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobi Pharmaceuticals, Medimmune, Medication, Merck Sharp and Dohme, NewLink Genetics Corp/Blue Link Pharmaceuticals, NewLink Genetics/Blue Link, Novartis, Pieris, Pfizer, Principia, Puma, Rapt, Seattle Genetics, Taiho, Tesaro, TransThera Bio, and XuanZhu Biopharma, I. Mayer is an employee/paid consultant for Eli-Lilly, Novartis, GlaxoSmithKline, Immunomedics, Macrogenics, Seattle Genetics, AstraZeneca, and reports receiving commercial research grants from Genentech, Pfizer, and Novartis. D. Quinn is an employee/paid consultant for AstraZeneca, Genentech/Roche, Pfizer, and Novartis. K. Jhaveri is an advisory board member/unpaid consultant for Novartis, Pfizer, AstraZeneca, Genentech, Taiho Oncology, Juno Therapeutics, SpecSpectrum Pharmaceuticals, ADC Therapeutics, and Synthon. M. Dujka and R. Bryce are employee/paid consultants for and hold ownership interest (including patents) in Puma Biotechnology. F. Meric-Bernstam is an employee/paid consultant for Genetech, Pieris Pharmaceuticals, Samsung Bioepis, Aduro, OrigMed, Debiopharm Group, Zencor, Jackson Laboratory, Zymeworks, Inflection Bioscience, Darwin Health, Spectrum, Mersana, and Seattle Genetics, reports receiving commercial research grants from Novartis; AstraZeneca; Taiho Pharmaceutical; Genentech; Calithera Biosciences; Debiopharm Group; Bayer; Aileron, reports receiving speakers bureau honoraria from Chugai, and is an advisory board member/unpaid consultant for Taiho, Genentech, Debiopharm Group, Pfizer. D. Solit is an employee/paid consultant for Pfizer, Loxo Oncology, Illumina, Vivideon Therapeutics, and Lilly Oncology. D.M. Hyman is an employee/paid consultant for Chugai, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Genentech/Roche, Found, reports receiving commercial research grants from AstraZeneca, Puma, LOXO Oncology, and Bayer. No potential conflicts of interest were disclosed by the other authors.

©2019 American Association for Cancer Research.

Figures

Figure 1.

Use of RECIST, PRC, and both sets of criteria in assessing eligibility and measurability in patients in SUMMIT. Venn diagram. PRC, PET Response Criteria; RECIST, Response Evaluation Criteria in Solid Tumors.

Figure 2.

Concordant and discordant best overall response measurements between RECIST and PRC. BOR, best overall response based on tumor measurements per RECIST v1.1 or PRC; CR, complete response; PD, progressive disease; PET, positron-emission tomography; PR, partial response; PRC, PET Response Criteria; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease. Dotted line at −30% change distinguishes stable disease from response in target lesions.*, Change †, 0% change in target lesion measurement.

Figure 3.

Measurable disease by PRC but not RECIST in a 70-year-old woman with HER2-mutant breast cancer. A, PET MIP image at baseline demonstrates FDG-avid lesions in the chest (arrow) and abdomen (arrowhead). B, Corresponding axial contrast-enhanced CT and fused PET/CT images of the chest demonstrate a thoracic FDG focus localized to a left hilar node (arrow) 8 mm in short axis on CT. This node was measurable by PRC but not by RECIST. C, Corresponding axial CT and fused PET/CT images of the abdomen demonstrate an abdominal FDG focus localized to a vertebral body (arrowhead) without clear correlate on CT. This osseous lesion was measurable by PRC but not by RECIST. D, PET MIP at 8-week follow-up demonstrates decrease of all FDG foci to background, representing a complete metabolic response. Corresponding axial images in the chest (E) and abdomen (F) confirm decrease to background FDG avidity. There was a sclerotic lesion at the prior FDG-avid osseous metastasis (curved arrow), which could have been mistaken for a new osseous metastasis without the corresponding PET. CT, computed tomography; FDG, 18F-fluorodeoxyglucose; MIP, maximum intensity projection; PET, positron-emission tomography; PRC, PET Response Criteria; RECIST, Response Evaluation Criteria in Solid Tumors.