Siegel, Barry A.

Abstract BACKGROUND Differentiating radiation necrosis from tumour progression after radiation therapy (RT) for brain metastases (BM) remains clinically challenging, and accurate imaging is crucial to prevent unnecessary surgery or unwarranted changes in therapy. 18F-Fluciclovine is a PET radiopharmaceutical with low background uptake in the brain and increased uptake in BM. The PURSUE study (NCT04410367) aimed to establish image interpretation criteria (IIC) for detecting suspected recurrent BM after RT using 18F-fluciclovine PET, based on several measures of lesion uptake. MATERIAL AND METHODS Across 7 US sites, 23 patients with solid tumour BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Three independent, blinded readers qualitatively rated lesion 18F-fluciclovine uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland). The primary endpoint was the diagnostic performance of different thresholds of lesion uptake on qualitative (visual) reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]), and dynamic measures. A committee, including two independent imaging physicians, reviewed all data to establish the IIC, which were subsequently used to evaluate the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions underwent histopathological analysis, with 10 (43%) being pathologically confirmed BM recurrence. The highest performing qualitative measure of 18F-fluciclovine lesion uptake was ‘marked’, rendering 92-100% and variable (40-80%) across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, the committee established IIC as: "Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely." Application of these IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% positive predictive value, and 83-85% negative predictive value across readers. CONCLUSION PURSUE is the first prospective, multicentre study to define IIC for 18F-fluciclovine PET for accurate identification of suspected recurrent BM after RT, verified by histopathology. In this initial cohort, the IIC convey excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine PET in future studies. This study was sponsored by Blue Earth Diagnostics Ltd.

Abstract BACKGROUND After radiation therapy (RT) for brain metastases (BM), differentiating radiation necrosis from tumor recurrence remains challenging. PURSUE (NCT04410367) evaluated various measures of lesion 18F-fluciclovine uptake to establish image interpretation criteria (IIC) for 18F-fluciclovine-PET to accurately diagnose recurrent BM. METHODS Patients with solid tumor BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine-PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Lesion 18F-fluciclovine uptake was qualitatively rated as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland) by three independent blinded readers. The primary endpoint was diagnostic performance of different uptake thresholds on qualitative reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]) and dynamic measures. IIC were determined by committee and subsequently used to assess the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions from 23 enrolled patients underwent histopathological analysis; 10 (43%) were pathologically-confirmed BM recurrence. The highest performing qualitative measure was ‘marked’, rendering 92-100% sensitivity and 40-80% specificity across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, IIC was established as: “Lesions with 18F-fluciclovine uptake of SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely.” Application of the IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% PPV, and 83-85% NPV across the readers. CONCLUSIONS PURSUE is the first prospective, multicenter trial to establish IIC for 18F-fluciclovine-PET for suspected recurrent BM after RT, verified by histopathology. Finalized IIC demonstrated excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine-PET in future studies.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

Abstract Purpose: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. Experimental Design: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. Results: SUVmax &lt;11.4 was most prognostic for FFP (P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect. Conclusions: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism. See related commentary by Williamson et al., p. 4136

Introduction: Patients with acute myeloid leukemia (AML) are often treated with intensive induction chemotherapy to achieve complete remission (CR). Early response to standard anthracycline plus cytarabine induction (7+3) is assessed by a day 14 nadir bone marrow biopsy. The nadir marrow has limitations, though, including sampling issues and ambiguity as to whether blasts are leukemia cells vs. regenerating marrow. In prior studies, the predictive value for remission of the nadir marrow is only 67-84%. A more accurate predictor of residual disease (RD) would give clinicians an opportunity to modify therapy earlier. Positron emission tomography (PET/CT) with 3'-deoxy-3'-[18F]fluorothymidine (FLT) is a molecular imaging modality that can assess cellular proliferation in the bone marrow compartment. A prior single-institution pilot study showed a significant difference in the marrow FLT uptake between patients with AML who achieved CR and those who had RD after count recovery. Methods: EAI141 was an ECOG-ACRIN-led, prospective, multi-center study designed to assess FLT PET/CT as a predictor of CR after AML induction. The primary objective was to evaluate the predictive value of post-treatment FLT PET/CT imaging for detecting RD, with the secondary objectives of evaluating the predictive value for detecting CR and estimating the sensitivity and specificity. Maximum standardized uptake value (SUVmax) of &gt; 7 g/mL in total bone marrow compartment was chosen prospectively based on data from a pilot study as a marker for presence of leukemia cells at nadir. The predictive values, sensitivity, and specificity of the FLT PET/CT and the nadir bone marrow biopsy were calculated. Eligible subjects were 18 years or older with previously untreated AML who were to receive induction with 7+3. Subjects underwent a nadir marrow biopsy and an FLT PET/CT scan 10-17 days after starting induction, and prior to any re-induction if disease was noted on the nadir marrow. A recovery marrow was performed 28-35 days after initial treatment or re-induction to assess CR or RD. Subjects could undergo an optional pre-treatment scan. Relapse-free survival (RFS) and overall survival (OS) were additional clinical outcomes. Results: 87 subjects from 9 centers were enrolled between 2016-2018, and 61 were considered evaluable. Reasons for being not evaluable included study ineligibility (n=3), no post-treatment scan (n=13), and no remission marrow (n=10). Median age was 58 years (range 21-73); 56% were men and 44% were women. CR was achieved in 56% (34/61). Treatment was a single induction course in 79% (48/61) and re-induction in 21% (13/61). Predictive value based on FLT PET/CT was 60% (9/15, 95% CI 32%-84%) for RD and 61% (28/46, 95% CI 45%-75%) for CR. Of patients who achieved CR, 28/34 had SUVmax ≤ 7 g/mL (sensitivity of 82%) and 9/27 of those who did not had high SUVmax &gt; 7 g/mL (specificity 33%). Predictive value of an aplastic marrow was 59% (26/44) for CR and 56% (9/16) for RD. Of patients who achieved CR, 26/33 had marrow hypoplasia (sensitivity 79%) and 9/27 with RD had disease in the nadir marrow (specificity 33%). Significant heterogeneity of bone marrow compartment post treatment (SUVhetero ranging from 0.24 to 1.07) was observed in FLT-PET/CT scans. Heterogeneity of bone marrow compartment decreased about 50% from pre-treatment to post-treatment FLT PET/CT. OS for all participants, stratified by post-treatment FLT PET/CT response and nadir marrow results, are summarized in the Figure. Conclusions: Although this study did not show significant advantage of FLT PET/CT compared to nadir marrow to predict RD or CR on the average, it did show signal heterogeneity in the study population that may be relevant to disease biology not appreciated by a single sampling site for the nadir or remission marrow. For example, in patients with false negative nadir biopsy, in approximately 20% of patients assessment with FLT PET/CT was correct, likely reflecting bone marrow heterogeneity and limitation of a single point sampling. Similarly, in almost 60% of patients with false positive nadir biopsy, FLT PET/CT assessment was correct. Figure 1 Disclosures Jeraj: AIQ Solutions: Current equity holder in private company. Kostakoglu:F. Hoffmann-La Roche: Consultancy. Strickland:KiTE: Consultancy; Kura: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; ArcherDx: Consultancy; AbbVie: Consultancy. Uy:Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Perlman:GE Healthcare: Research Funding; AIQ: Research Funding.

Abstract Background: Bruton’s tyrosine kinase (BTK) is an essential component of the B-cell receptor signaling pathway, a pathway critical to the survival and proliferation of malignant B cells. Ibrutinib, a small molecule inhibitor of BTK, has shown significant activity in several B-cell malignancies and is currently FDA approved for the treatment of patients (pts) with CLL or mantle cell lymphoma who have received at least one prior treatment.In a Phase 1 dose-escalation study, ibrutinib induced a response in 6 (38%) of 16 patients (pts) with relapsed/refractory FL and 6/11 (54%) of pts treated at doses ≥ 2.5 mg/kg (Advani JCO 2013, Fowler ASH abstr 156:2012). 560 mg daily was identified as a well-tolerated dose in lymphoma resulting in full-target occupancy. On the basis of these results, the Mayo Clinic and Princess Margaret P2Cs conducted a CTEP-sponsored Phase 2 trial of single-agent ibrutinib in relapsed/refractory FL (NCI 9271). Methods: Eligible pts had relapsed or refractory FL (Gr 1, 2, or 3a) that had progressed during or after 1 or more prior chemotherapy regimens. Therapy consisted of ibrutinib, 560 mg daily, until progression or unacceptable toxicity. Response was assessed by CT at 8 weeks and then every 12 weeks. All pts were required to have an on-study biopsy and a second biopsy at progression after response with fresh tissue collected for correlative studies. The primary endpoint was overall response rate (ORR) and secondary endpoints were safety and tolerability, overall survival, time to response, time to treatment failure, duration of response, and progression-free survival (PFS). Planned exploratory correlative studies included C1D8 and C3D1 FDG-PET response evaluation in a subset of 20 patients, and whole-transcriptome sequencing for correlation of mutations with response and resistance. Results: 40 patients (38 evaluable for response) were accrued from April 2013 to April 2014. Median age was 64 years (range 46-82), 70% were men, 55% had FLIPI ≥ 3, median number of prior regimens was 3 (range 1-11), 20% had a prior stem cell transplant, 45% were rituximab refractory, and 36% were refractory to their most recent treatment. At a median follow-up of 6.5 months (mo) (range 1.8-14.6+), the ORR for the 40 intention-to-treat pts is 30% (95% CI: 17-47%) with 1 CR and 11 PRs by CT criteria (4/12 responders had a negative restaging PET/CT). 26 (65%) patients have exhibited tumor size reduction. Only 2/18 (11%) pts with rituximab-refractory disease responded, compared to 8/19 (42%) pts with rituximab-sensitive disease (P=0.06) and 2/3 who were rituximab-naïve. There was no correlation between response and number of prior regimens. Median time to response was 2.4 mo (range 1.8-12.9 mo). Median PFS is 9.9 mo (95% CI: 6 mo, not reached). One of 12 responders has progressed after 9.9 mo on treatment. Median treatment duration was 5 mo (range 1-15+ mo). Dose delays (2 pts) and reductions were infrequent (4 pts). 17 pts have discontinued treatment due to PD (12), refusal (2), AEs (2), and death (1). Gr 3-4 AEs occurred in 30% of pts, including the following AEs in more than 1 pt: anemia (2), neutropenia (3), and infection (2). 3 pts have died (1 PD, 1 pneumonia, 1 gastric hemorrhage). Of the 20 pts with C1D8 PET scans, 19 also had C3D1 PET scans and were evaluable for response. Six of these 19 pts had objective responses by CT criteria at week 8 or beyond. Of the 6 responders, C1D8 PET/CT showed qualitative (visual) improvement in 3 pts, no visual change in 1 pt, and qualitative worsening in 2 pts. On the C3D1 PET/CT, 4 of 6 had qualitative improvement and 2 had no change. Evaluation of quantitative PET data including SUVs and total lesion glycolysis is ongoing and will be presented. Conclusions: Single agent ibrutinib is well tolerated with a modest ORR in relapsed/refractory FL at this early assessment. Continued follow-up is warranted to capture late responders and to establish response duration. Ibrutinib appears less active in FL than in MCL and CLL. Early PET scans (C1D8) do not reliably predict for response. Support by N01-CM-2011-00099 Disclosures Bartlett: Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Research Funding; Janssen: Research Funding; ImaginAb: Research Funding; Genentech: Research Funding; Millennium: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Medimmune: Research Funding; Celgene: Research Funding. Off Label Use: PF-05082566 for B-NHL. Kuruvilla:Janssen: Honoraria. Reeder:Millennium, Celgene, Novartis: Research Funding.

Key Points Ibrutinib has modest activity in FL with low response rates in rituximab-refractory patients. CARD11 mutations predict for lack of response to ibrutinib.