Partial Radiographic Response Research Articles

CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA

Abstract Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.

Personalized Medicine in Histiocytic Disorders: Novel Targets in Patients Without MAPK Alterations.

BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective. We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations. Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months. We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.

177Lu]Lu-PSMA-617 as first-line systemic therapy in patients with metastatic castration-resistant prostate cancer: a real-world study.

The use of [177Lu]Lu-PSMA-617 radioligand therapy has become increasingly recognized as a viable therapeutic approach for patients in the advanced stages of metastatic castration-resistant prostate cancer (mCRPC). However, there is limited data regarding its effectiveness and safety in earlier lines. This study aims to present our institution's experience with [177Lu]Lu-PSMA-617 as a first-line systemic therapy for mCRPC. We collected and analyzed data from consecutive mCRPC patients who underwent first-line treatment with [177Lu]Lu-PSMA-617 at our center from 2015 to 2023. The various outcome measures included best prostate-specific antigen-response rate (PSA-RR) (proportion of patients achieving a ≥ 50% decline in PSA); objective radiographic response rate (ORR) (proportion of patients achieving complete or partial radiographic responses); radiographic progression-free survival (rPFS) (measured from treatment initiation until radiographic progression or death from any cause); overall survival (OS) (measured from treatment initiation until death from any cause); and adverse events. Forty treatment-naïve mCRPC patients with PSMA-positive disease on [68Ga]Ga-PSMA-11 PET/CT were included (median age: 68.5 years, range: 45-78; median PSA: 41 ng/mL, range: 1-3028). These patients received a median cumulative activity of 22.2 GBq (range: 5.55-44.4) [177Lu]Lu-PSMA-617 over 1-6 cycles at 8-12 week intervals. A ≥ 50% decline in PSA was observed in 25/40 (62.5%) patients (best PSA-RR). Radiographic responses were evaluated for thirty-eight patients, with thirteen showing partial responses (ORR 34.2%). Over a median follow-up of 36 months, the median rPFS was 12 months (95% confidence interval, CI: 9-15), and the median OS was 17 months (95% CI: 12-22). Treatment-emergent grade ≥ 3 anemia, leucopenia, and thrombocytopenia were noted in 4/40 (10%), 1/40 (2.5%), and 3/40 (7.5%) patients, respectively. The findings suggest that [177Lu]Lu-PSMA-617 is a safe and effective option as a first-line treatment in mCRPC. Further trials are needed to definitively establish its role as an upfront treatment modality in this setting.

A phase II trial of induction systemic mFOLFIRINOX followed by hepatic arterial infusion of floxuridine and dexamethasone given concurrently with systemic mFOLFIRI as a first-line therapy in patients with unresectable liver-dominant intrahepatic cholangiocarcinoma (HELIX-1).

511 Background: Most patients with intrahepatic cholangiocarcinoma (ICC) have unresectable or multifocal liver-dominant disease. Survival after first-line systemic therapy remains poor, with median progression-free (mPFS) and overall survival of 7.2 and 12.8 months, respectively. Hepatic arterial infusion (HAI) therapy with floxuridine maximizes liver-specific treatment with minimal systemic toxicity and potentially offers improved disease control when combined with systemic therapy. Methods: HELIX-1 (NCT04251715) is an investigator-initiated, first-line, single-center, single-arm phase II clinical trial for patients with liver-dominant unresectable or multifocal ICC. The trial was designed with a patient safety run-in evaluating toxicity from the combined therapy. Pre-trial screening included laparoscopy, biopsies, and PET/CT. Eligible patients were treated with systemic mFOLFIRINOX for 4 cycles in order to select those likely to benefit from HAI. Patients with disease control on restaging proceeded to HAI pump placement and treatment with HAI floxuridine for 14 days followed by systemic mFOLFIRI on a 28-day cycle. The co-primary objectives were to assess safety of the combined therapeutic strategy and the disease control rate (DCR) at 6 months (RECIST v1.1) at end of trial (EOT). Results: A total of n=5 patients with liver-only ICC enrolled in the trial and completed the entire study protocol. The median age was 60 years (range 42-69) with a dominant lesion size of 9.8cm (range 8.4-14.5). All patients had both right and left hemiliver involvement with a median of 9 intrahepatic tumors (range 1-15). No patients experienced grade 3 or 4 adverse events, or hepatic dysfunction leading to cessation of HAI therapy. The DCR at 6 months was 100%, with a mPFS of 18.2 months. All five patients achieved partial radiographic response (PR) while receiving HAI therapy, and remain alive with liver-only disease at a median of 18.4 months (range 12.7-20) after study enrollment. After continuing treatment with HAI and systemic mFOLFIRI beyond the EOT, two patients transitioned to HAI treatment only and then to biochemical and radiographic surveillance without therapy after demonstrating PR and CA19-9 normalization. Conclusions: Integration of HAI floxuridine with mFOLFIRI following mFOLFIRINOX induction for patients with liver-only advanced ICC is well-tolerated and demonstrates longer DCR in comparison to historical controls. The combined regimen minimized systemic toxicity and allowed a large proportion of patients to transition to liver-only HAI treatment with maintained disease control. Future directions include combining HAI with new first-line systemic regimens for patients with advanced ICC. Clinical trial information: NCT04251715 .

Druggable genomic landscapes of high-grade gliomas.

Despite the putatively targetable genomic landscape of high-grade gliomas, the long-term survival benefit of genomically-tailored targeted therapies remains discouraging. Using glioblastoma (GBM) as a representative example of high-grade gliomas, we evaluated the clonal architecture and distribution of hotspot mutations in 388 GBMs from the Cancer Genome Atlas (TCGA). Mutations were matched with 54 targeted therapies, followed by a comprehensive evaluation of drug biochemical properties in reference to the drug's clinical efficacy in high-grade gliomas. We then assessed clinical outcomes of a cohort of patients with high-grade gliomas with targetable mutations reviewed at the Johns Hopkins Molecular Tumor Board (JH MTB; n = 50). Among 1,156 sequence alterations evaluated, 28.6% represented hotspots. While the frequency of hotspot mutations in GBM was comparable to cancer types with actionable hotspot alterations, GBMs harbored a higher fraction of subclonal mutations that affected hotspots (7.0%), compared to breast cancer (4.9%), lung cancer (4.4%), and melanoma (1.4%). In investigating the biochemical features of targeted therapies paired with recurring alterations, we identified a trend toward higher lipid solubility and lower IC50 in GBM cell lines among drugs with clinical efficacy. The drugs' half-life, molecular weight, surface area and binding to efflux transporters were not associated with clinical efficacy. Among the JH MTB cohort of patients with IDH1 wild-type high-grade gliomas who received targeted therapies, trametinib monotherapy or in combination with dabrafenib conferred radiographic partial response in 75% of patients harboring BRAF or NF1 actionable mutations. Cabozantinib conferred radiographic partial response in two patients harboring a MET and a PDGFRA/KDR amplification. Patients with IDH1 wild-type gliomas that harbored actionable alterations who received genotype-matched targeted therapy had longer progression-free (PFS) and overall survival (OS; 7.37 and 14.72 respectively) than patients whose actionable alterations were not targeted (2.83 and 4.2 months respectively). While multiple host, tumor and drug-related features may limit the delivery and efficacy of targeted therapies for patients with high-grade gliomas, genotype-matched targeted therapies confer favorable clinical outcomes. Further studies are needed to generate more data on the impact of biochemical features of targeted therapies on their clinical efficacy for high-grade gliomas.

DDDR-29. TARGETING FGFR FUSIONS: A CASE OF CATEQUENTINIB (AL3818) AND TEMOZOLOMIDE COMBINATION THERAPY FOR RECURRENT MGMT METHYLATED TACC-FGFR FUSION POSITIVE GLIOBLASTOMA

Abstract BACKGROUND There is no gold-standard for the management of recurrent glioblastoma (GBM). However, advances at the interface of molecular testing and rational drug design have opened avenues for personalized medicine. Here we describe the case of a 52-year-old patient with recurrent GBM (WHO grade 4) with known FGFR3-TACC3 fusion and MGMT promoter methylation by Caris molecular profiling. Initial treatment included radiotherapy with concomitant and adjuvant temozolomide. However, after 18 months off therapy, the patient became clinically and radiographically progressive with multifocal disease. Herein, we describe our experience with temozolomide and catequentinib (AL3818) in a single patient. METHODS We reviewed the available literature on targeting FGFR3-TACC3 fusion positive glioblastoma with catequentinib (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-Yl] oxy] methyl] cyclopropanamine dihydrochloride). Catequentinib is an oral small-molecule pan-kinase inhibitor with selective VEGFR2 inhibition, it is under investigation in multiple phase 2 and 3 clinical trials and can safely be administered concomitantly with temozolomide. We obtained single-patient Investigational New Drug (IND) approval and free drug was shipped directly from the manufacturer (Advenchen Laboratories; Jiangsu Chia-Tai Tianqing Pharmaceutical) to our institution’s investigational chemotherapy pharmacy. We administered catequentinib 12 mg by mouth for 14 days on and 7 days off of a 21-day cycle along with temozolomide 50mg/m2/day of a 28-day cycle with routine monitoring of laboratory parameters. RESULTS The combination of temozolomide and catequentinib was well-tolerated, resulted in clinical stability, and partial radiographic response at 3-month follow-up. CONCLUSION Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.

CTIM-23. SAFETY RUN-IN RESULTS OF A PHASE I/II STUDY TO EVALUATE ATEZOLIZUMAB IN COMBINATION WITH CABOZANTINIB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of glioblastoma (GBM) in both newly diagnosed and recurrent disease which underscores the need for rational combinatorial strategies. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and has been shown to enhance the magnitude of tumor-specific T cell responses. Combining PD-L1/PD-1 axis inhibition with targeted therapy like cabozantinib which has both anti-tumoral and immunomodulatory properties may result in synergistic effects. Cabozantinib may modulate the myeloid cell population to overcome resistance to anti-PD-1/PD-L1 therapy. METHODS Eligibility criteria were those with recurrent GBM, age >18 yrs with 1st or 2nd recurrence who were naïve to antiangiogenic and receptor tyrosine kinase inhibitor treatment. The primary objective of the phase I run-in was to evaluate the safety of atezolizumab in combination with cabozantinib. RESULTS 1 dose-limiting toxicity (DLT) of a grade 3 ALT elevation was observed in the first 6 DLT evaluable patients treated during the safety run-in phase. Regarding immune related adverse events, 1 of 6 patients developed atezolizumab-related grade 1 hypothyroidism. 1 of 6 patients developed study treatment-related grade 2 diarrhea. 2 patients after completion of 2 cycles of treatment had evidence of a partial radiographic response ( > 50% decrease). 1 patient had a near partial radiographic response (45% decrease). 2 patients had stable disease after completion of 2 cycles of the combinatorial treatment. 1 patient had only completed the first 28-day cycle, DLT period, and had not yet had imaging to reassess disease status. CONCLUSIONS The combination of atezolizumab with cabozantinib was tolerable, and no new safety signals were noted. In this small cohort of recurrent GBM patients, radiographic responses were observed. The phase II component of the trial is recruiting patients (n = 45) to evaluate clinical efficacy. Multi-omic correlative studies and fecal microbiome analyses are planned.

Abstract A053: Epigenomic analyses of circulating tumor DNA in patients with metastatic castration resistant prostate cancer (mCRPC) treated with immune checkpoint blockade and PARP inhibition

Abstract Background: Molecular characterization of mCRPC has revealed disruption of DNA damage repair genes that may improve sensitivity to PARP inhibitors such as olaparib (O), which in turn may further complement the activity of the PD-L1 immune checkpoint inhibitor, durvalumab (D), through mechanisms such as activation of the STING pathway. We hypothesized that (epi)genomic analyses of circulating tumor DNA (ctDNA) would identify mechanisms of treatment response in patients with mCRPC treated with O plus D (NCT02484404). Methods: Eligible patients for this study had mCRPC with prior treatment by abiraterone and/or enzalutamide. Study participants were administered 300 mg of O twice daily and 1500 mg of D every 4 weeks. We obtained blood samples in Streck tubes from 38 (out of 60) study participants. Plasma samples were acquired at baseline and at progression. Buffy coat was isolated from each sample. Genomic DNA and cell-free DNA (cfDNA) were separately isolated and assembled into sequencing libraries. Low-pass whole-genome sequencing (3-4 × coverage) was performed for somatic copy number and fragmentomic analyses. In a subset of samples with the greatest cfDNA content, chromatin immunoprecipitation sequencing (ChIP-seq) with antibodies against H3K4me2 and H3K4me3 was performed directly in additional aliquots of plasma. Results: Amongst the 38 patients with at least one cfDNA sample, 5 patients had a radiographic partial response (PR) per RECIST v1.1, 28 patients had stable disease (SD), and 6 patients had progressive disease (PD) during the first two months of treatment. At baseline, ctDNA content in plasma was significantly lower in patients who went on to have PR or SD versus PD (p=0.02). However, upon progression, ctDNA content in plasma was not significantly different between groups. Losses to PTEN and NKX3-1 were significantly enriched in ctDNA from patients with PD (p=0.041 and p=0.047, respectively). By contrast, biallelic combined losses to BRCA2, RB1, BRCA1 and TP53 were observed in all PRs at baseline but not in any patient with PD (p=0.048). In patients with SD, longitudinal fragmentomic analysis inferred that the activity of the mitogenic KLF4 transcription factor (TF) was the most increased upon progression, while activity of the protective HIF2A TF was the most decreased. However, the TF binding motifs predicted by H3K4me2 and H3K4me3 cfDNA ChIP-seq did not significantly change in patients with PD. Conclusions: Distinctive genomic and epigenomic profiles were observed in plasma from patients with responsive vs. progressive disease, and the profiles may predict responses to combination D+O therapy. Deeper whole-genome sequencing of these samples currently in progress will reveal the contribution of germline and somatic point mutations to clinical response. Ongoing efforts to estimate the phylogenetic architecture of patients’ tumors from these plasma samples will enable the inference of drug response phenotypes as a function of evolutionary potential and potentially identify new opportunities to target treatment-resistant disease. Citation Format: Anna Baj, Clara C. Y. Seo, Nicholas T. Terrigino, John R. Bright, S. Thomas Hennigan, Isaiah M. King, Shana Y. Trostel, William D. Figg, William L. Dahut, Jung-Min Lee, David Y. Takeda, Fatima Karzai, Adam G. Sowalsky. Epigenomic analyses of circulating tumor DNA in patients with metastatic castration resistant prostate cancer (mCRPC) treated with immune checkpoint blockade and PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A053.

Circulating tumor DNA (ctDNA) dynamics in response to checkpoint inhibitor immunotherapy in colorectal cancer.

e15540 Background: Circulating tumor DNA (ctDNA) is emerging as a sensitive and specific non-invasive marker of active disease in patients (pts) with colorectal cancer (CRC) and may be used for monitoring response to immunotherapy (IO) in all solid tumors. However, the dynamics of ctDNA changes in response to IO and their correlation to radiographic response has not been well-established. Methods: We searched for all pts in our institution who received IO for a solid tumor diagnosis and who also received quantitative ctDNA testing using Signatera. We retrospectively evaluated radiographic treatment response using RECIST v1.1 and correlated radiographic response to time-matched changes in quantitative ctDNA. Objective response rate (ORR) was defined as the percentage of pts achieving radiographic partial response (PR) plus complete response (CR). Results: We identified 6 pts with advanced CRC who underwent serial ctDNA testing while receiving IO; all patients had loss of mismatch repair protein expressions. Median age was 70 years (range 35-90), and 50% of patients were female. All pts were actively receiving IO at the time of data cutoff. Two pts were receiving ipilimumab plus nivolumab, the other 4 pts were receiving pembrolizumab; 1 pt had only received 1 cycle of IO at time of cutoff, thus did not have on-treatment imaging and was excluded from further analysis. For the response evaluable patients, ORR was 100%, with all pts (5/5) achieving PR after median of 3 cycles (range 1-3 cycles) of treatment. Quantitative ctDNA decreased by 83-100% in all pts analyzed. 1 pt had radiographic (pseudo-)progression at time of first radiographic assessment, however at this timepoint, ctDNA had decreased by 60%; this pt continued on immunotherapy based on clinical benefit including ctDNA data. Subsequent radiographic assessment of this pt confirmed partial response and ctDNA response decreased by total of 95% after a total of 3 cycles of IO. Conclusions: In this small patient population, we show that quantitative ctDNA directly corresponds to radiographic response to IO, and may guide treatment decisions by differentiating pseudoprogression from true progression. Further longitudinal studies will show if ctDNA changes correlate to duration of response, early identification of treatment resistance, and ultimately survival.

Immune checkpoint inhibition in locally advanced rectal adenocarcinoma at Mayo Clinic.

e15626 Background: Studies have shown the effectiveness of immune checkpoint inhibition (ICI) in patients with tumors demonstrating microsatellite instability (MSI-H) and an associated defect in DNA mismatch repair (dMMR). In particular, KEYNOTE-177 demonstrated significant survival benefit for patients with unresectable or metastatic colorectal cancer with MSI-H or dMMR. Recently published case reports and series have demonstrated similar outcomes for patients with locally advanced and resectable rectal cancer. We report on the experience of patients with locally advanced, resectable rectal adenocarcinoma treated across the Mayo Clinic Health System. Methods: We conducted a retrospective analysis of patients treated at Mayo Clinic since 2015 A search of the Mayo Clinic database was done to include parameters for confirmed rectal adenocarcinoma, dMMR in pathology reports. Patients receiving ICI treatment including pembrolizumab, nivolumab/ipilimumab and durvalumab in any combination with chemotherapy and/or radiation were included. Patients with metastatic disease at the time of surgical intervention or ICI were excluded. Clinical data was assimilated. Results: Twenty-one patients met criteria for inclusion in our analysis. Fifteen patients had de novo disease. Six patients had local recurrence and had been treated previously with chemotherapy, radiation (RT) and surgery. None of the patients included had prior ICI therapy. Fifteen patients had Lynch syndrome. The median age of diagnosis was 41.5 years. Seven patients underwent surgical intervention. of the seven patients received surgery upfront followed by immunotherapy. The remaining six had neoadjuvant immunotherapy alone or in combination with chemotherapy and/or radiation. Prior to surgery, all patients demonstrated radiographic partial response (rPR). 67% of these demonstrated a pathologic complete response (pCR) while 33% had residual disease. The patient who received surgery upfront and adjuvant ICI continues to have radiographic stable disease after 1 year of treatment. For patients who did not have surgery, 50% had radiographic “complete or near complete” response (rCR), 43% had rPR and 7% had radiographic stable disease. Ten patients received RT and ICI with 70% demonstrating rCR and 30% rPR. Overall, the objective response rate was 90 Response to treatment was observed upwards of 75 months. Only 1 person in the study had progression of disease that occurred after 14 months of therapy. Conclusions: Similar to KEYNOTE-177, patients with locally advanced MSI-H/dMMR rectal cancer have significant and durable response to immunotherapy alone or in combination with chemotherapy, radiation and surgery. Further large prospective trials are needed to validate these findings and determine a standardized approach.

Belzutifan in a Patient With VHL-Associated Metastatic Pancreatic Neuroendocrine Tumor.

von Hippel-Lindau (VHL) disease is a rare autosomal-dominant hereditary disease characterized by mutation of the VHL gene. This gene encodes for the VHL protein, which regulates the activity of HIF-α, a transcription factor involved in the cellular response to hypoxia. Mutations in VHL lead to the accumulation of HIF-α and, consequently, the engagement of hypoxia-sensitive genes with tumorigenic effects. VHL disease is associated with the development of tumors in multiple organs, including pancreatic neuroendocrine tumors (pNETs). Belzutifan is an HIF-α inhibitor; however, it has not been previously evaluated in patients with metastatic or treatment-refractory pNETs. This report presents a 43-year-old woman with VHL-associated metastatic pNET treated with belzutifan after progression on multiple systemic therapies. She began treatment with belzutifan and experienced partial radiographic response within 1 month of treatment. Other than asymptomatic anemia, no adverse effects developed during 5 months of ongoing therapy. Belzutifan is an inhibitor of HIF-2α that targets the underlying pathophysiology of VHL-associated pNETs. Our case report describes exceptional activity in a metastatic pNET arising from VHL.

A phase 1b adaptive androgen deprivation therapy trial in metastatic castration sensitive prostate cancer.

5075 Background: Despite early utilization of new hormonal agents (NHA, abiraterone, enzalutamide and apalutamide) in metastatic castration sensitive prostate cancer (mCSPC), increasingly more men are dying from prostate cancer. While continued development of new drugs is needed, we propose improved survival of metastatic prostate cancer can be obtained through tumor evolution informed treatment strategies. Compared to the conventional treat until progression paradigm, our previous study (NCT02415621) in metastatic castration resistant prostate cancer reported that on and off abiraterone therapy adapted to individual’s PSA response dynamics can provide better cancer control with less abiraterone usage (Zhang et al, Nat Commun. 2017). Here we present the first interim analysis of our adpative therapy trial in mCSPC with a median follow up of 21 months. Methods: Men with asymptomatic mCSPC and no liver metastasis were enrolled after achieved > 75% PSA decline with 12 - 16 weeks of luteinizing hormone-releasing hormone (LHRH) analog, and 8 - 12 weeks of NHA. Both treatments were stopped after enrollment. PSA and testosterone levels were measured every 6 weeks, CT and bone scan were performed every 18 weeks while on study. Treatment will be restarted if subjects develop PSA or radiographic progression per prostate cancer working group 3 criteria. If the testosterone level (T) is > 100 ng/dl, LHRH analog will be restarted. If the T is between 50 and 100 ng/dl, NHA will be restarted. If the T is below 50, combined therapy with LHRH analog and NHA will be restarted. Treatment will be discontinued after achieving 50% or more PSA decline. For patients who restarted therapy for radiographic progression, partial response or stable disease needs to be documented on the post treatment scans along with PSA response prior to stopping therapy. The primary objective is feasibility, which is measured by percentage of patients who remain on study without on treatment disease progression at 12 months from first dose of LHRH analog for mCSPC. Results: 16 evaluable patients were enrolled between April 2019 and June 2021. Five of the 16 patients had high risk mCSPC based on the LATITUDE trial criteria. The median follow up was 21 months at the data cut off in January 2022. Only one patient was off study due to imaging progression at 27.6 months from first dose of LHRH analog for mCSPC. Three of the 16 patients developed on treatment PSA progression at month 12.3 and 15.2, and 20.5. Given none of the first 14 enrolled patients developed disease progression at 12 months, the study has already met its primary objective of feasibility. Conclusions: It is feasible to use individual’s PSA response and testosterone level to guide intermittent therapy with LHRH analog and NHA in mCSPC. The study is ongoing to collect data on secondary endpoints of median time to PSA progression and median time to radiographic progression. Clinical trial information: NCT 03511196.

Robust Response to Futibatinib in a Patient With Metastatic FGFR-Addicted Cholangiocarcinoma Previously Treated Using Pemigatinib.

Futibatinib is a novel FGFR inhibitor currently under investigation as a second-line treatment for locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusions and rearrangements. As FGFR-targeted therapies move into the frontline setting, sequencing of these drugs remains undetermined. To date, no study has investigated the use of futibatinib in the context of pemigatinib resistance. We describe a 50-year-old woman with metastatic FGFR-aberrant intrahepatic cholangiocarcinoma who showed a robust response to futibatinib for 23.6 months, having previously benefited from pemigatinib. Futibatinib was safely used despite her history of decompensated cirrhosis and significant cytopenias. We observed a reduction in CA 19-9 level and a partial radiographic response on futibatinib. Serial next-generation sequencing and cell-free DNA testing proved crucial to making appropriate treatment decisions.

Plasma ctDNA Response Is an Early Marker of Treatment Effect in Advanced NSCLC.

Patients with advanced EGFR-mutant NSCLC across three phase I NCI osimertinib combination trials were analyzed in this study, and an institutional cohort of patients with KRAS-, EGFR-, and BRAF-mutant advanced NSCLC receiving systemic treatment was used for validation. Plasma was collected before treatment initiation and serially before each cycle of therapy, and key driver mutations in ctDNA were characterized by droplet digital polymerase chain reaction. Timing of plasma versus imaging response was compared in a separate cohort of patients with EGFR-mutant NSCLC treated with osimertinib. Across cohorts, we also studied ctDNA variability before treatment start. In the NCI cohort, 14/16 (87.5%) patients exhibited ≥ 90% decrease in mutation abundance by the first on-treatment timepoint (20-28 days from treatment start) with minimal subsequent change. Similarly, 47/56 (83.9%) patients with any decrease in the institutional cohort demonstrated ≥ 90% decrease in mutation abundance by the first follow-up draw (7-30 days from treatment start). All 16 patients in the imaging cohort with radiographic partial response showed best plasma response within one cycle, preceding best radiographic response by a median of 24 weeks (range: 3-147 weeks). Variability in ctDNA levels before treatment start was observed. Plasma ctDNA response is an early phenomenon, with the majority of change detectable within the first cycle of therapy. These kinetics may offer an opportunity for early insight into treatment effect before standard imaging timepoints.

P26.02 A Phase II Trial of Neoadjuvant Osimertinib for Surgically Resectable EGFR-Mutant Non-Small Cell Lung Cancer: Updated Results

The third generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is well-tolerated and effective for first-line treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Adjuvant osimertinib therapy also significantly decreases the risk of disease recurrence for patients with surgically resected (stage IB-IIIA) EGFR-mutant NSCLC. The benefit of neoadjuvant osimertinib for the treatment of surgically resectable EGFR-mutant NSCLC is unknown. The use of neoadjuvant targeted therapies in oncogene-driven NSCLC may offer the advantages of increased pathologic response rates as well as more favorable toxicity profiles compared to cytotoxic chemotherapy. These trials also offer the opportunity to identify mechanisms underlying cancer cell persistence despite optimal oncogene-targeted therapy. This abstract is an update of https://doi.org/10.1016/j.jtho.2019.08.1209. This is an ongoing multi-institution phase II trial of neoadjuvant osimertinib (NCT03433469), which aims to enroll 27 patients with surgically resectable stage I-IIIA (AJCC V7) EGFR-mutant (exon 19 del or L858R) NSCLC. Eligible patients are treated with one to two 28-day cycles of osimertinib 80 mg orally daily followed by surgical resection. The primary endpoint of the study is major pathological response (mPR) rate. Secondary endpoints include safety, unanticipated delays to surgery, surgical complication rate, pathological response rate (0-49% residual viable tumor), pathological complete response rate (pCR), unconfirmed objective response rate, rate of lymph node downstaging, disease-free survival (DFS), and overall survival (OS). As of April 2021, 13 patients with early-stage (6 stage IA/B, 2 Stage IIA/B, and 5 Stage IIIA) EGFR-mutant (7 exon 19 del, 6 L858R) NSCLC have been enrolled and treated with osimertinib for an average of 59 days prior to surgical resection. The mPR rate was 15% (2 of 13). The pathological response rate was 69% (9 of 13). No pCR’s were observed. Partial radiographic responses (PR) were observed in 46% (6 of 13) of patients and stable disease (SD) in 7 patients (100% DCR). Lymph node downstaging was achieved in 4 of 5 patients (80%) with positive lymph nodes detected prior to treatment. DFS and OS data are immature. Treatment was well-tolerated without SAEs and all patients proceeded to surgical resection without unscheduled delay or surgical complications. One patient developed grade 2 treatment-related pneumonitis that resolved without steroid treatment. Pre-treatment tumor biopsies were available for targeted exome sequencing analysis of ∼ 500 cancer-related genes from 7 patients. Loss of function mutations in RBM10 were identified in 3 of 4 (75%) tumors that showed no evidence of pathological response to osimertinib treatment. Interim analysis of this phase II study indicates that neoadjuvant osimertinib treatment in surgically resectable, EGFR-mutant NSCLC is well-tolerated without unforeseen delays in surgery and can induce pathological responses and lymph node-downstaging of disease. However, major pathological responses are rare and complete pathological responses to neoadjuvant osimertinib are not observed. RBM10 mutations were observed in the majority of tumors that did not exhibit a pathological response to osimertinib. Combination therapy approaches, as are being studied in the NeoADAURA trial (NCT04351555), are likely needed to achieve clinically meaningful major pathological response rates in EGFR-mutant lung cancers.

Abstract 630: Response to nivolumab in a pediatric chordoma with overexpression of brachyury

Abstract Chordomas are neoplasms derived from notochord cells that typically form in the spine or skull base, and affect both adults and children. Poorly differentiated chordomas, associated with particularly poor outcomes, occur predominantly in children and are characterized by expression of the transcription factor brachyury and loss of INI1/SMARCB1. The use of immune checkpoint inhibitors in pediatric cancer is of growing interest, with reported anti-tumour activity in pediatric Hodgkin lymphoma and gliomas with mismatch repair deficiency. However, responses to immune checkpoint inhibitors are infrequent and unpredictable in pediatric solid tumours, and the molecular markers that can distinguish the seemingly indiscriminate response remain to be defined. Understanding which pediatric patient populations may benefit from immune checkpoint inhibitor therapies is essential. Here we describe the molecular profiles of two pediatric poorly differentiated chordomas using whole-genome, transcriptome and whole-genome bisulfite sequencing as part of the Personalized Oncogenomics program at BC Cancer (NCT02155621) that studies the impact of embedding comprehensive genomic profiling into the clinical care of advanced cancer patients. Genomic profiling and multiplex IHC revealed a high level of CD8+ T cells in both chordoma samples, despite low mutation burden. DNA methylation-based clustering revealed similarities with SMARCB1-deficient rhabdoid tumour subtypes that are have been characterized by increased levels of immune cell infiltration. A dominant tumour-associated T cell receptor clone was identified in one patient sample, which was demonstrated to have affinity for reconstituted brachyury-MHC complexes, indicating a potential anti-tumour immune response directed against brachyury-derived antigens. As these collective observations pointed to a potential benefit of immune targeted therapy, the patient was treated with nivolumab and subsequently achieved a partial radiographic response by RANO criteria. These observations provide support for the benefit of immune checkpoint inhibitors in poorly differentiated chordomas with high levels of infiltrating CD8+ T cells. Citation Format: Laura Williamson, Craig Rive, Daniela Di Francesco, Emma Titmuss, Elizabeth Chun, Scott Brown, Katy Milne, Erin Pleasance, Anna F. Lee, Stephen Yip, David Dix, Daniel Renouf, Robert Holt, Brad H. Nelson, Martin Hirst, Steven Jones, Shahrad Rassekh, Rebecca Deyell, Janessa Laskin, Macro A. Marra. Response to nivolumab in a pediatric chordoma with overexpression of brachyury [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 630.

Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial.

Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity. A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion (P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached (P < .0001) and 19 months versus not reached (P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed (P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

Dynamics of circulating tumor DNA in patients with advanced solid tumors treated with cediranib and olaparib.

3035 Background: Circulating tumor DNA (ctDNA) has emerged as a potential biomarker to monitor treatment response in solid tumors. Our group previously showed that changes in ctDNA levels were predictive of radiographic response and survival in NSCLC patients receiving immunotherapy. Here we evaluated whether ctDNA dynamics could similarly be used to assess response in a PARP inhibitor-based therapy. Methods: A total of 122 patients with NSCLC, TNBC, PDAC or SCLC received cediranib (C) 30mg daily and Olaparib (O) 200mg twice daily in a phase II study NCI9881. Using a multigene NGS assay, ctDNA was measured longitudinally at baseline (T0), after 3 to 7 days of C monotherapy (T1), after 1 week of C+O combination (T2), after 4 weeks of C+O (T3), and every 4 weeks (T4+) thereafter. The first radiographic assessment was done after 8 weeks of C+O and every 8-12 weeks thereafter. CtDNA was quantified by determining the allele fraction of cancer-associated somatic mutations in plasma. We defined an early ctDNA response (e-ctDNA-R) as a &gt;10% decrease in mutant allele fraction from T0 to T2, and an early ctDNA progression (e-ctDNA-P) as a &gt; 10% increase; otherwise, it was stable ctDNA (e-ctDNA-S). Results: In total, 493 samples were analyzed from 94 patients, and 40 unique patients had both T0 and T2 ctDNA measurements, as well as corresponding radiographic assessments. These included 10 NSCLC, 17 TNBC, 3 SCLC and 10 PDAC. Of these patients, 4, 21, and 15 patients had PR, SD, and PD as best overall radiographic response respectively. Twenty-three (57.5%) patients had either e-ctDNA-R (17, 42.5%) or e-ctDNA-S (6, 15.0%), 18 (78.3%) of whom subsequently had either radiographic partial response (PR) or stable disease (SD). Seventeen (42.5%) patients had e-ctDNA-P, 10 (58.8%) of whom then had PD. A fair agreement was observed between e-ctDNA-R/S or e-ctDNA-P and radiographic PR/SD or PD with Cohen’s k 0.38 (70% agreement). The correlation between early ctDNA changes and PFS/OS are summarized in the table. All 25 patients with PR/SD eventually progressed. Of these, 17 (68%) had &gt;10% increase in ctDNA from the nadir prior to disease progression (median 94.6%, 95%CI 38.2%-389.1%). The time between ctDNA progression and ctDNA nadir was significantly shorter (median 21 days, 95%CI 21-28) than the time between radiographic/clinical progression and initial PR/SD (median 107 days, 95%CI 56-204, P=0.0015). Conclusions: Longitudinal ctDNA measurements could enable early assessment of treatment response, resistance, and disease progression in patients treated with PARP inhibitor-based therapy. However, in this study, tumor responses and ctDNA changes were generally not as robust as have been observed with other classes of therapy.[Table: see text]

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PurposeTo describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib.MethodsWe report on six patients with NF‐1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively.ResultsSubjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4–28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life‐threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1–2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy.ConclusionTrametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF‐1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

Robotic Pancreaticoduodenectomy for a Technically Challenging Pancreatic Head Cancer

BackgroundRobotic pancreaticoduodenectomy (RPD) is performed for resectable periampullary lesions with comparable outcomes to the open approach.1 Surgical therapy for borderline-resectable (BR) pancreatic tumors is technically challenging and poses a significant risk of bleeding and positive margins.2 As experience with RPD grows at high-volume centers, case selection can be carefully expanded to include complex vascular resections.3 We demonstrate a RPD performed for BR pancreatic adenocarcinoma with portal vein (PV) involvement and presence of anomalous hepatic arterial anatomy. MethodsA 75-year-old female presented with abdominal pain and obstructive jaundice. She was previously healthy and had a relatively normal body mass index (25.7 kg/m2). Endoscopic ultrasound and computed tomography imaging identified a pancreatic head mass measuring 2.3 cm with evidence of concomitant abutment of the PV (90–180 degree) and abutment of a replaced right hepatic artery (rRHA) originating from the superior mesenteric artery (SMA). Following four cycles of neoadjuvant gemcitabine/nab-paclitaxel, restaging imaging demonstrated partial radiographic response, represented by a lesser degree of PV abutment and resolution of rRHA abutment. RPD was performed with side-bite resection of the PV and preservation of rRHA. The video demonstrates the key steps followed in a robotic pancreaticoduodenectomy performed for a technically challenging pancreatic head cancer and highlights robotic control of bleeding from the PV and SMA obviating the need for conversion. Histopathology revealed a residual moderately differentiated ductal adenocarcinoma with 4-of-40 positive lymph nodes and negative surgical margins. The tumor was staged as ypT1cN2 (AJCC 8th edition). The patient had an uneventful postoperative course and was discharged on hospital day 8. ConclusionIn high-volume centers, the robotic approach can be safely used in selected cases of technically challenging BR pancreatic head cancers.