Radiographic Disease Progression Research Articles

Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.

e17022 Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate >90% and 5-year survival rate >95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in <30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.

Longitudinal circulating tumor DNA monitoring for detection of molecular residual disease in patients with advanced germ cell tumors.

e17022 Background: Germ cell malignancies, commonly manifesting as testicular cancer, is one of the most common malignancies in men 15 to 45 years of age, with the incidence doubling over the past 40 years. When identified promptly and treated with a multidisciplinary approach, germ cell tumors have an excellent prognosis with cure rate >90% and 5-year survival rate >95%. Treatment involves radical orchiectomy for diagnostic and therapeutic purposes. Further management includes active surveillance, adjuvant chemotherapy, retroperitoneal lymph node dissection (RLND), and radiation therapy. While AFP, B-HCG, and LDH are good biomarkers, they are not sensitive or specific for detecting molecular residual disease (MRD). B-HCG is detected in <30% of individuals with seminoma and B-HCG and AFP are detected in 50–60% of patients with non-seminomatous tumors. We describe the use of circulating tumor DNA (ctDNA) for detection of MRD in advanced germ cell malignancy, especially when baseline biomarkers are negative. Methods: This is a retrospective analysis of 20 patients with testicular cancer treated at Rush University Medical Center who monitored closely for MRD. Signatera (Natera Inc.), a personalized tumor-informed ctDNA assay, was utilized for detection and quantification of ctDNA in patients’ plasma samples, measured at MRD (1-12 weeks post-orchiectomy) and regular intervals thereafter, regardless of treatment modality. Event free survival (EFS) was determined, defined as the period from radical orchiectomy to date of radiographic progression of disease. Results: There was a total of 20 patients (35% seminoma, 65% non-seminoma) with 2 of the patients having extragonadal disease. The mean age was 32.2 years old with IQR (28-36). Post operatively, 20% underwent RLND, 10% were on surveillance, 53% received post-orchiectomy chemotherapy, 6.7% of patients underwent autologous stem cell transplant. The median follow up time is 1.14 years. Two patients had positive ctDNA despite negative baseline traditional biomarkers. There were 23.3% (7/30) of patients that had evidence of radiographic progression. Of the patients with progression, serial ctDNA monitoring had high rates of concordance (85%, 6/7) of ctDNA positivity with biomarker positivity and radiographic progression. Conclusions: Overall, ctDNA correlated with, and sometimes even preceded, traditional biomarkers and radiographic findings of disease progression. The ctDNA positivity of 2 patients in this cohort despite negative baseline AFP, B-HCG, and LDH, highlights the sensitivity and specificity of ctDNA for MRD compared to more traditional biomarkers. Serial monitoring of ctDNA offers valuable insights into germ cell tumor disease status, including presence of MRD, and there is a need for prospective studies to guide treatment escalation and de-escalation in germ cell tumors.

Repeat Peptide Receptor Radionuclide Therapy in Neuroendocrine Tumors: A NET Center of Excellence Experience.

The available data for the safety and efficacy of repeat peptide receptor radionuclide therapy (PRRT) are almost exclusively from European centers. We present an updated experience with repeat PRRT in a cohort of US patients with neuroendocrine tumors (NETs) at our NET center of excellence. We used our single-center longitudinal NET registry to identify patients who had been previously treated with at least one dose of PRRT (PRRT 1, either 177Lu DOTATATE or 90Y DOTATOC) and following radiographic disease progression were re-treated with a second course of PRRT (PRRT 2). We reviewed patient, tumor and treatment characteristics, objective response rates, and toxicities after PRRT 1 and PRRT 2. A total of 11 patients were included in the analysis. 45.5% (5/11) of patients received 177Lu DOTATATE PRRT only, both for PRRT1 and PRRT 2, while 54.5% (6/11) of patients received 90Y DOTATOC PRRT for PRRT1. At first restaging scan after PRRT2 (3-6months), 18.2% (2/11), 36.4% (4/11), and 27.3% (3/11) of patients had PR, SD, and PD, respectively; 2/11 patients (18.2%) died before the first restaging scan. Therefore, 5/11 (45.5%) patients were noted to have disease progression. Median PFS for PRRT1 was 25.4months and median PFS for PRRT2 was 13.1months (p = 0.0001). We did not find a statistically significant difference between the occurrence of short and long-term hematological toxicities as well as renal toxicity after PRRT1 and PRRT2. We show that repeat PRRT may benefit select patients and have an acceptable safety profile. In our cohort, PFS was significantly lower after PRRT2 as compared to PRRT1.

Development and validation of a prognostic prediction model for cervical cancer patients treated with radical radiotherapy: a study based on TCGA database.

Radiotherapy or concurrent chemoradiotherapy is the standard treatment for patients with locally advanced or inoperable cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, treatment failure for CESC patients treated with radical radiotherapy still occurs due to local recurrence and distant metastasis. The previous prediction models were focused on all CESC patients, neglecting the prognostic differences under different treatment modalities. Therefore, there is a pressing demand to explore novel biomarkers for the prognosis and sensitivity of radiotherapy in CESC patients treated with radical radiotherapy. As a single biomarker has limited effect in stratifying these patients, our objective was to identify radioresponse-related mRNAs to ameliorate forecast of the prognosis for CESC patients treated with radical radiotherapy. Sample data on CESC patients treated with radical radiotherapy were obtained from The Cancer Genome Atlas (TCGA) database. We randomly separated these patients into a training and test cohorts using a 1:1 ratio. Differential expression analysis was carried out to identify radioresponse-related mRNA sets that were significantly dysregulated between complete response (CR) and radiographic progressive disease (RPD) groups, and univariate Cox regression analyses, least absolute shrinkage and selection operator (LASSO) method and multivariate Cox regression were performed to identify the radioresponse-related signature in the training cohort. we adopted survival analysis to measure the predictive value of the radioresponse-related signature both in the test and entire cohorts. Moreover, we developed a novel nomogram to predict the overall survival (OS) of CESC patients treated with radical radiotherapy. In addition, immune infiltration analysis and Gene Set Enrichment Analysis (GSEA) were conducted to preliminarily explore possible mechanisms. This study included a total of 92 CESC patients subjected to radical radiotherapy. We developed and verified a risk score model based on radioresponse-related mRNA. The radioresponse-related mRNA signature and International Federation of Gynecology and Obstetrics (FIGO) stage were served as independent prognostic factors for CESC patients treated with radical radiotherapy. Moreover, a nomogram integrating radioresponse-related mRNA signature with FIGO stage was established to perform better for predicting 1-, 3-, and 5-year survival rates. Mechanically, the low-risk group under the risk score of this model had a better survival status, and the distribution of CD4 T cells was potentially involved in the regulation of radiotherapy response in CESC, leading to a better survival outcome in the low-risk group. This study presents a new radioresponse-related mRNA signature that shows promising clinical efficacy in predicting the prognosis of CESC patients treated with radical radiotherapy.

A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Radiographic Progression at Castration-Resistant Prostate Cancer Diagnosis: A Prognostic Indicator of Metastatic Hormone-Sensitive Prostate Cancer

BackgroundThe critical role of radiographic assessment at the time of castration-resistant prostate cancer (CRPC) diagnosis is underscored by this study. We performed a retrospective analysis of radiographic changes in metastasis from the time of diagnosis of metastatic hormone-sensitive prostate cancer (mHSPC) to CRPC diagnosis. We also explored its impact on prognosis post-CRPC. Materials and MethodsWe retrospectively analyzed 98 men who underwent radiographic examinations (bone scans and computed tomography [CT]) at the time of CRPC diagnosis. When radiographic studies demonstrated progression at CRPC diagnosis, patients were assigned to the radiographic progressive disease (rPD) group. The remaining patients were placed in the "non-rPD" group. The overall survival (OS) post-CRPC was compared between the 2 groups. ResultsThe median OS post-CRPC was significantly shorter in the rPD group (n = 50) compared to the non-rPD group (n = 48) (32 months vs. not reached, P = .0124). Multivariate analysis showed that radiographic progression and shorter time to CRPC were associated with a shorter OS post-CRPC (hazard ratio [HR] = 3.14; 95% confidence interval [CI], 1.21-8.12, P = .019). ConclusionRadiographic progression at the point of CRPC diagnosis independently predicts a shorter OS post-CRPC in patients with mHSPC. Therefore, assessing radiographic changes at the time of CRPC diagnosis could be instrumental in managing CRPC in patients with mHSPC.

Pharmacokinetics/pharmacodynamics of ivosidenib in advanced IDH1-mutant cholangiocarcinoma: findings from the phase III ClarIDHy study

PurposeReport pharmacokinetic (PK)/pharmacodynamic (PD) findings from the phase III ClarIDHy study and any association between PK/PD parameters and treatment outcomes in this population.MethodsPatients with mutant isocitrate dehydrogenase 1 (mIDH1) advanced cholangiocarcinoma were randomized at a 2:1 ratio to receive ivosidenib or matched placebo. Crossover from placebo to ivosidenib was permitted at radiographic disease progression. Blood samples for PK/PD analyses, a secondary endpoint, were collected pre-dose and up to 4 h post-dose on day (D) 1 of cycles (C) 1 − 2, pre-dose and 2 h post-dose on D15 of C1 − 2, and pre-dose on D1 from C3 onwards. Plasma ivosidenib and D-2-hydroxyglutarate (2-HG) were measured using liquid chromatography-tandem mass spectrometry. All clinical responses were centrally reviewed previously.ResultsPK/PD analysis was available for samples from 156 ivosidenib-treated patients. Ivosidenib was absorbed rapidly following single and multiple oral doses (time of maximum observed plasma concentration [Tmax] of 2.63 and 2.07 h, respectively). Ivosidenib exposure was higher at C2D1 than after a single dose, with low accumulation. In ivosidenib-treated patients, mean plasma 2-HG concentration was reduced from 1108 ng/mL at baseline to 97.7 ng/mL at C2D1, close to levels previously observed in healthy individuals. An average 2-HG inhibition of 75.0% was observed at steady state. No plasma 2-HG decreases were seen with placebo. Plasma 2-HG reductions were observed in ivosidenib-treated patients irrespective of best overall response (progressive disease, or partial response and stable disease).ConclusionOnce-daily ivosidenib 500 mg has a favorable PK/PD profile, attesting the 2-HG reduction mechanism of action and, thus, positive outcomes in treated patients with advanced mIDH1 cholangiocarcinoma.Clinical trial registrationNCT02989857 Registered February 20, 2017.

FOENIX-CCA4: A phase 2 study of futibatinib 20 mg and 16 mg in patients with advanced cholangiocarcinoma (CCA) and fibroblast growth factor receptor 2 (FGFR2) fusions/rearrangements.

TPS572 Background: In 2022, the U.S. FDA approved futibatinib, a covalently binding inhibitor of FGFR1–4, for previously treated patients with advanced intrahepatic CCA and FGFR2 fusions/rearrangements. In the pivotal phase 2 FOENIX-CCA2 study, futibatinib 20 mg once daily (QD) resulted in an objective response rate (ORR) of 42% by independent review and a median duration of response (DOR) of 9.7 months. Futibatinib was tolerable and had a manageable safety profile.1 Limited phase 1 data suggest futibatinib may also have antitumor activity at a lower dose (16 mg QD), with fewer dose modifications required for adverse events.2 The aim of FOENIX-CCA4is to confirm the clinical benefit of futibatinib 20 mg QD and explore the safety and efficacy of futibatinib 16 mg QD in previously treated patients with advanced CCA and FGFR2 fusions/rearrangements. Methods: In this global, phase 2, randomized, open-label study (NCT05727176), patients with CCA harboring FGFR2 fusions/rearrangements who have received ≥1 line of gemcitabine/platinum-based therapy for advanced/metastatic disease will be randomized 1:1 to futibatinib at a starting dose of 20 mg or 16 mg QD continuously on a 21-day cycle. Randomization will be stratified by the number of prior lines of systemic therapy for advanced disease (1 vs ≥2). Futibatinib will be continued until progressive disease or unacceptable toxicity. Tumor response will be assessed at baseline, every 6 weeks for the first 12 weeks, and every 9 weeks thereafter until radiographic progressive disease or initiation of new anticancer therapy. The primary endpoint is ORR according to Response Evaluation Criteria in Solid Tumors version 1.1, as assessed by blinded independent central review (analyzed when all patients responding to futibatinib have ≥6 months’ follow-up from the first onset of response). DOR is a key secondary endpoint. Other secondary endpoints are progression-free survival, overall survival, safety, and quality of life. Sample size (120 patients) was estimated on the assumption that if the lower ORR between futibatinib 16 mg and 20 mg is 32% (with ≥60 patients per arm), the probability of correctly selecting the treatment arm with a true ORR of 42% is 0.87. Enrollment is ongoing in Europe, the US, and Asia-Pacific. 1. Goyal L et al. N Engl J Med. 2023;388:228–39. 2. Meric-Bernstam F et al. Cancer Discov. 2022;12:402–15. Clinical trial information: NCT05727176 .

Evaluating novel therapies and circulating tumor DNA (ctDNA) as a marker of response in curatively treated gastrointestinal cancers with microscopic residual disease.

TPS765 Background: ctDNA has emerged as a novel tool that can identify the earliest sign of relapse (MRD) after curative therapies with specificities of 93-100%, positive predictive values over 98%, and median lead times of 8-9 months before radiographic relapse. ctDNA has allowed us to identify a "new stage" of high-risk patients (pts) with no evidence of disease radiographically (rNED) and MRD who lack guideline-directed treatment (tx) strategies as, traditionally, they wait for radiographic progression of disease (POD) before starting therapies. Treating MRD is a promising strategy supported by observational studies where ctDNA clearance is linked with improved survival and on-tx ctDNA kinetics predict drug efficacy. We designed a pilot investigator-initiated trial to 1) determine the feasibility of using a surrogate marker, ctDNA, as a rapid signal for positive therapeutic activity and 2) obtain pilot data on the efficacy of a novel combination therapy (atezolizumab [A] + bevacizumab [B]) in eradicating MRD in previously curatively treated pts with GI cancers. Methods: We will enroll 20 pts with any-stage GI cancers divided over 4 cohorts (n=5 colorectal [CRC], n=5 hepatocellular/biliary tract carcinoma, n=5 gastric, n=5 pancreatic adenocarcinoma) who have a positive Signatera ctDNA test and rNED any time after completing standard curative-intent therapies. Pts are treated with A 1200 mg IV + B 15 mg/kg IV on day 1 of a 21-day cycle for up to 1 year with imaging every 12 weeks and serial ctDNA testing every 3 weeks. Co-primary endpoints are rates of pt enrollment in 12 months and rates of ctDNA responses at a 12-week landmark after tx initiation. Pts with ctDNA POD (ctDNA doubling on each of 2 sequential tests, any rate of rise in 3 sequential tests, or radiographic relapse) will stop while those with ctDNA complete response (CR; clearance on 2 sequential tests + ongoing rNED) or ctDNA partial/stable response (PR; not ctDNA CR or POD + ongoing rNED) will continue tx. Each cohort's Bayesian predictive probability of positive therapeutic activity will be calculated. If at least 60% of a cohort experiences ctDNA CR, it will be expanded by 5 pts. This scenario is equivalent to Simon's 2-stage Minimax design testing a null hypothesis of 20% CR vs. an alternative hypothesis of at least 60% CR at 5% alpha with 80% power. If at least 5/10 pts in an expanded cohort experience ctDNA CR, this will generate interest in developing a larger confirmatory trial to evaluate pt survival outcomes with A+B and ctDNA as a surrogate for survival. Secondary endpoints are toxicity and reasons for enrollment failure. Exploratory endpoints are associations between ctDNA conversion and disease-free survival, tumor whole exome sequencing data, and peripheral blood immune profiles collected at baseline and on tx. Enrollment began in Q1 2023. 4 pts are enrolled in the CRC cohort. Clinical trial information: NCT05482516 .

Early and Sustained Circulating Tumor DNA Response Dynamics after Loncastuximab Tesirine for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Introduction: Circulating tumor DNA (ctDNA) has emerged as a tool to characterize tumors and track minimal residual disease (MRD) in many malignancies, including diffuse large B-cell lymphoma (DLBCL). ctDNA levels have been shown as prognostic after first-line treatment and CD19-targeted chimeric antigen receptor (CAR19) T cell therapy in DLBCL. Loncastuximab tesirine (loncastuximab tesirine-lpyl [Lonca]), an antibody-drug conjugate comprising an antibody targeting CD19 and a pyrrolobenzodiazepine dimer cytotoxin, is approved for relapsed/refractory (R/R) DLBCL. The ultrasensitive ctDNA-MRD detection method, phased variant enrichment and detection sequencing (PhasED-Seq) was applied to evaluate molecular response and mutational genotypes in patients (pts) undergoing Lonca treatment. Methods: LOTIS-2 study (NCT03589469) evaluated the efficacy of Lonca in R/R DLBCL after ≥ 2 lines of prior systemic therapy. Samples from 33 LOTIS-2 pts were profiled by PhasED-Seq (Foresight Diagnostics), representing a range of best responses to therapy, including 8 complete response (CR), 14 partial response (PR), and 11 progressive disease (PD). Pts received a median of 4 treatment cycles with Lonca (range 2-22). Baseline plasma and peripheral blood mononuclear cells were used to identify tumor-specific phased variants (PVs), which were used to monitor ctDNA-MRD after 1 cycle of treatment (cycle 2, day 1 [C2D1]) and at the end of treatment (EOT). Samples were reported quantitatively with levels of ctDNA-MRD and qualitatively as ctDNA-MRD positive or negative. Absolute ctDNA levels and log-fold change (LFC) in ctDNA were compared with outcomes including best overall response, progression-free survival (PFS), and overall survival (OS), as determined by the independent review committee. The ctDNA mutational profile of each pt was evaluated at baseline and EOT to assess emerging clonal alterations with emphasis on CD19. Results: PVs were successfully genotyped from pretreatment plasma in 31/33 pts (94%) with sufficient material for analysis. The median pretreatment ctDNA level was 141 haploid genome equivalents /mL (hGE/mL) (range 0.4-3608), similar to previous DLBCL studies in first-line and relapsed settings. Interestingly, pretreatment ctDNA levels were not predictive of outcomes to treatment (hazard ratio [HR] 0.99, P=0.96). The prognostic value of ctDNA levels was assessed at C2D1. Absolute ctDNA levels and the change from baseline levels were significantly prognostic for the response to treatment. Pts achieving either a CR or a PR had significantly greater reduction in their ctDNA levels than those failing to respond (CR vs PD, median LFC -1.5 vs 0.1, P=0.001; PR vs PD, median LFC -1.1 vs 0.1, P=0.006) (Fig 1A). Interestingly, pts achieving a CR or a PR did not have significantly different changes in ctDNA at C2D1 ( P=0.15). When dividing pts at the median into those with high vs low ctDNA levels at C2D1, lower levels of ctDNA were significantly associated with superior PFS and OS (PFS: HR 4.4, P=0.009; OS: HR 3.2, P=0.01) (Fig 1B). At the EOT, 5 of 6 CR pts had cleared their ctDNA-MRD to undetectable levels vs 1 of 6 at C2D1. The CR pt who did not show deepening of molecular response was the only CR pt who ended Lonca treatment for radiographic disease progression; all other CR pts ended treatment for other reasons (e.g., toxicity, transplant, or persistent complete remission). To assess for emergent clonal mutations, the mutational profiles of pts were evaluated before Lonca treatment and at EOT. Prior studies in DLBCL after CAR19 T-cell therapy have revealed recurrent, although infrequent, mutations in CD19 as a mechanism of resistance. In this cohort, no emergent alterations in CD19 at the EOT (0/31 pts) were observed. One pt was identified with a baseline mutation in CD19 (R363C); this pt achieved a PR followed by PD after 3 cycles of treatment with persistence of the mutation in CD19. Conclusions: ctDNA molecular response assessment using PhasED-Seq is prognostic for outcomes in pts receiving Lonca monotherapy. ctDNA levels as early as C2D1 can predict outcomes and are indicative of a fast response to Lonca. Furthermore, molecular responses can deepen with additional cycles. CD19 alterations do not appear to be a common emergent mechanism of resistance to Lonca. In this exploratory study, ctDNA-MRD predicts Lonca efficacy and outcomes and should be further considered as a universal biomarker in DLBCL.

Nivolumab in Lymphomatoid Granulomatosis (LYG) and Other Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders (LPDs) and Non-Hodgkin Lymphomas (NHLs) with Systemic and/or CNS Involvement: Preliminary Analysis of Efficacy and Safety from an Ongoing Phase II Study

Background: Programmed cell death protein-1 (PD-1) is a signaling molecule on the surface of T-cells that suppresses the cytotoxic effects of T-cells on tumor cells. We previously demonstrated increased PD-1 expression on CD8+ T-cells compared to healthy controls in pts with LYG, which could be reversed with immunotherapy using interferon alpha-2b (Melani et al. Lancet Haematol. 2023). Additionally, elevated expression of programmed death-ligand 1 (PD-L1) has been observed in other EBV-LPDs and NHLs as well as in chronic viral infections, such as EBV. Given this likely shared disease pathobiology, we hypothesized that treatment with the anti-PD-1 antibody, nivolumab, may reverse T-cell exhaustion and result in anti-tumor responses in pts with LYG and other EBV-LPDs and NHLs, including those with systemic and/or CNS involvement. Methods: Relapsed/refractory (R/R) EBV-LPD and NHL pts age ≥ 12y with adequate organ function were eligible. Untreated pts were eligible if EBV-LPD. Exclusions included prior use of PD-1/PD-L1/PD-L2/CD137/CTLA-4 antibodies, solid organ transplant, and HIV infection. Pts with a known immunodeficiency or autoimmune illness were eligible if not requiring steroids or immunosuppression within 14d of study. CNS involvement was permitted if no seizure activity within 4w of study. Nivolumab 480 mg IV was given q4w for up to 2y. Pts who achieved CR discontinued nivolumab after 1y of treatment. Responding patients with relapse or progression within 1y of discontinuing treatment were eligible for retreatment. Baseline evaluation included CT, PET, MRI brain, flow cytometry of peripheral blood and CSF, BM biopsy, and optional tumor biopsy. Restaging CT scans were performed after cycles 3, 6, 13, and 19, and end of treatment (EoT). PET was performed after cycles 1, 3, and EoT. Surveillance CT was performed q3m for 1y, q6m for yrs 2-5, and annually thereafter. Results: 11 pts were enrolled and treated; 6 (55%) with EBV-LPD and 5 (45%) with EBV-NHL (all DLBCL). EBV-LPD subtypes included 4 pts with G1-2 LYG and 1 pt each with EBV B-LPD of the CNS and CAEBV. Median age was 48y (range 20-67), and all pts had stage III/IV disease with extranodal involvement of the lung most common in 64% (7/11) and CNS disease in 18% (2/11). Median baseline absolute CD8 count (cells/mcL) was 86 (range 9-1237; normal: 178-853), CD4 count (cells/mcL) was 255 (range 99-1304; normal: 359-1565), and EBV VL in plasma (Log10 IU/mL) was undetected (range undetected-6.78; normal: <2.3). Median prior therapies were 1 (range 0-6) with 3 previously untreated LPD pts and 50% of previously tx pts were refractory to last tx. In 10 pts evaluable for response(1 came off tx prior to restaging), ORR and CR rate were both 60% (6/10). CR rate was 67% (4/6) in EBV-LPD, including 75% (3/4) with LYG, and 50% (2/4) in EBV-NHL (Fig 1A). One (50%) of 2 EBV-LPD pts with CNS involvement achieved CR after 3C of therapy and remains in ongoing response. Median TTR was 3.0m with 50% (3/6) responses ongoing from 3-56m after first response (Fig 1B). With a median follow up of 32m, 2y PFS and OS was 33% and 72% overall. By cohort, median PFS was 36m in EBV-LPD and 1m in EBV-NHL (p=0.003), with a 2y OS of 100% in EBV-LPD and 40% in EBV-NHL (p=0.04). Three EBV-NHL pts died, all of disease progression. One EBV-NHL pt stopped therapy after 2C due to radiographic disease progression in the kidney, but later developed CR without further therapy and remains in remission 56m after stopping therapy consistent with initial pseudoprogression. Adverse events (AEs) were as expected for nivolumab therapy with the most common AEs (% pts) including maculopapular rash (27%), diarrhea (18%), hypothyroidism (18%), and fatigue (18%). One pt developed an immune-mediated G2 myositis and G3 hepatitis following 3C of therapy which resolved after drug discontinuation and corticosteroids. Conclusion: Nivolumab is well tolerated in pts with LYG and other EBV-LPDs and NHLs without unexpected toxicities. Preliminary activity, including durable CRs, is noted across all pt cohorts, including 1 EBV-LPD pt with CNS involvement. With small numbers, statistically longer PFS and OS was observed with nivolumab in LYG and EBV-LPD compared to EBV-NHL, indicating that monotherapy may be sufficient for LYG and other EBV-LPDs, but combination therapy is likely needed for pts with EBV-NHL. Study enrollment continues to better assess the activity and durability of nivolumab in LYG and other EBV-LPDs and NHLs.

Rationale and design of the prognostic transcriptomic signature in fibrotic hypersensitivity pneumonitis (PREDICT) study.

Hypersensitivity pneumonitis is an immunologically mediated form of lung disease, resulting from inhalational exposure to a large variety of antigens. A subgroup of patients with fibrotic hypersensitivity pneumonitis (FHP) develop symptomatic, functional and radiographic disease progression. Mortality occurs primarily from respiratory failure as a result of progressive and self-sustaining lung injury that often occurs despite immunosuppression and removal of the inciting antigen. The development and validation of a prognostic transcriptomic signature for FHP (PREDICT-HP) is an observational multicentre cohort study designed to explore a transcriptomic signature from peripheral blood mononuclear cells in patients with FHP that is predictive of disease progression. This article describes the design and rationale of the PREDICT-HP study. This study will enrol ∼135 patients with FHP at approximately seven academic medical sites. Participants with a confirmed diagnosis of FHP are followed over 24 months and undergo physical examinations, self-administered questionnaires, chest computed tomography, pulmonary function tests, a 6-min walk test and blood testing for transcriptomic analyses. At each 6-month follow-up visit the study will assess the participants' clinical course and clinical events including hospitalisations and respiratory exacerbations. The PREDICT study has the potential to enhance our ability to predict disease progression and fundamentally advance our understanding of the pathobiology of FHP disease progression.

Low PSA radiographic disease progression on C11-choline PET.

For men with prostate cancer, radiographic progression may occur without a concordant rise in prostate-specific antigen (PSA). Our study aimed to assess the prevalence of radiographic progression using C-11 choline positron emission tomography (PET) imaging in patients achieving ultra-low PSA values and to evaluate clinical outcomes in this patient population. In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET metastatic prostate cancer registry to identify patients experiencing radiographic disease progression (rDP) on C-11 choline PET scan while the PSA value was less than 0.5ng/mL. Disease progression was confirmed by tissue biopsy or response to subsequent therapy. Clinicopathologic variables were abstracted by trained research personnel. Overall survival was estimated using the Kaplan-Meier method. Intergroup differences were assessed using the log-rank test. A univariate and multivariate Cox regression model was performed to investigate variables associated with poor survival after rDP. A total of 1323 patients within the registry experienced rDP between 2011 and 2021, including 220 (16.6%) men with rDP occurring at low PSA level. A median (interquartile range [IQR]) of 54.7 (19.7-106.9) months elapsed between the time of prostate cancer diagnosis and low PSA rDP, during which 173 patients (78%) developed castration-resistant prostate cancer (CRPC). Sites of low PSA rDP included local recurrence (n = 17, 8%), lymph node (n = 90, 41%), bone (n = 94, 43%) and visceral metastases (n = 19, 9%). Biopsy at the time of rDP demonstrated small-cell or neuroendocrine features in 21% of patients with available tissue. Over a median (IQR) follow-up of 49.4 (21.3-95.1) months from the time of low PSA rDP, 46% (n = 102) of patients died. Factors associated with poorer survival outcomes include advanced age at rDP, CRPC status, bone and visceral metastasis (p value <0.05). Visceral metastases were associated with decreased overall survival (p = 0.009 by log-rank) as compared with other sites of rDP. Men with prostate cancer commonly experience metastatic progression at very low or even undetectable PSA levels. Periodic imaging, even at low absolute PSA values, may result in more timely identification of disease progression.

DIPG-52. EXTRAPONTINE PROGRESSION WITH STABLE PONTINE DISEASE POST-RADIOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) ON A CONNECT TRIAL: IMPLICATIONS FOR RADIATION TREATMENT VOLUMES

Abstract Radiotherapy remains the only treatment modality proven to prolong survival and alleviate symptom burden for patients with DIPG. Upfront focal photon radiation to 54 Gy with 1-1.5cm margins is standard. Subventricular, leptomeningeal, and/or spinal dissemination is observed in up to 50% of cases at autopsy, with activation of metastasis-related pathways (eg, epithelial-mesenchymal transition) in a subset of tumors. Given potential for metastatic spread and critical implications for radiation field volumes, we analyzed the frequency of extrapontine disease progression with pontine tumor stability within a prospective cohort with standardized longitudinal imaging. In a CONNECT consortium-sponsored phase Ib trial with a radiosensitizing agent administered concurrently with focal radiation and adjuvantly, among 10 patients with DIPG who experienced progressive disease with available serial imaging, four (40%) had evidence of disease extension and/or non-contiguous dissemination with stable pontine tumor size at a median of 9 months (range: 5-15 months) from diagnosis. Specifically, extrapontine progression was observed in the spinal cord (n=3), cerebellum (n=2), basal ganglia (n=1), temporal lobe (n=1) and/or leptomeninges and ependymal surfaces (n=1), without radiographic pontine disease progression. Five of the remaining six patients (who came off treatment due to pontine progression) subsequently had radiographic evidence of extrapontine extension (cerebellar, spinal, thalamic, supratentorial). Comprehensive molecular profiling is underway on biopsy or autopsy specimens for three patients, focusing on metastasis pathways. In summary, within a small prospective cohort with longitudinal imaging, we observed extrapontine progression despite local pontine disease control following focal radiotherapy in 40% of patients with DIPG at a median of 9 months after diagnosis. Further research will be essential to identify biological predictors of dissemination and corroborate findings in a larger cohort, but results suggest at least a subset of patients with DIPG may benefit from larger radiation volume expansion into contiguous structures and white matter tracts.

Impact of pre-treatment hemoglobin (Hgb) on outcomes in metastatic castration resistant prostate cancer (mCRPC) with lutetium-177-PSMA-617 (Lu-177).

e17065 Background: The Phase 3 VISION and TheraP trials excluded men with Hgb≤ 9 g/dL or blood transfusion within 30 days of Lu-177. Patients (pts) with mCRPC who are eligible for Lu-177 are often pancytopenic due to marrow infiltration and previous cytotoxic therapy. Clinicians are often faced with the dilemma of packed red blood cell (RBC) transfusion (Tx) to meet “eligibility requirements" of Lu-177. The impact of low Hgb levels on treatment (trt) outcomes is unclear. Methods: We retrospectively identified pts with mCRPC who received at least one cycle of Lu-177 between July 2022 and January 2023 at a single institution. Demographic, disease, laboratory and trt characteristics were recorded. Pts with Hgb level ≤10 g/dL or who received RBC Tx up to 14 days prior to the first Lu-177 dose were compared to pts with a pre-trt Hgb level ≥10 g/dL and no prior PRBC Tx. Data were summarized using descriptive statistics. Time to trt discontinuation was defined as the time from the first Lu-177 cycle until progressive disease per treating physician (clinical, radiographic, PSA progression) or adverse effect necessitating cessation and compared using the Kaplan Meier method. Cox proportional hazard regression analysis were utilized to assess the association of Hgb ≤ or ≥ 10 g/dL on the risk of trt discontinuation. Results: 51 pts were included, median follow up was 5.75 months, median age 70 years, 90% Caucasian. 49% (n = 25) had Gleason 9 /10 disease. Median number of prior trt was 4. 94% (n = 48), received prior docetaxel and 39% (n = 20) received prior cabazitaxel. 27% (n = 14) of pts had either Hgb≤10 or received a RBC Tx prior to trt. Of these, 50% of pts (n = 7) had stopped Lu-177 prior to completion of 6 cycles. Median number of cycles was 3. Reasons for trt cessation included clinical decline (n = 4), PSA or radiographic disease progression (n = 2), cytopenia (n = 1). Of pts who had Hgb ≥10 (n = 37), most (86%) are in ongoing trt, 11% (n = 4) have stopped trt due to progressive disease, 1 pt died. Pts with Hgb≤10 had a shorter time to trt discontinuation, 4.5 months (95% CI: 4.43- NA) vs not reached for those with Hgb≥10, p = 0.004 and an increased risk of trt discontinuation HR = 1.65 (95% CI: 1.53-18.09, p = 0.009). Conclusions: Pre-trt Hgb≤10 g/dL may be associated with worse outcomes in pts with mCRPC undergoing trt with Lu-177 and caution should be exercised. A larger data set and longer follow up is needed to further investigate outcomes in this pt population. Multivariable analysis is planned. [Table: see text]

RANO 2.0: Proposal for an update to the Response Assessment in Neuro-Oncology (RANO) criteria for high- and low-grade gliomas in adults.

2017 Background: Response Assessment in Neuro-Oncology (RANO) criteria for high-grade and low-grade glioma (HGG and LGG) were developed to improve reliability of response assessment in glioma trials. Several limitations of the original RANO criteria have been reported. Methods: To address limitations of the original RANO criteria, a large cohort of patients with newly diagnosed and recurrent glioblastoma were evaluated comparing RANO-HGG with modified RANO (mRANO) and immunotherapy RANO (iRANO) criteria to inform the following proposed updates (RANO 2.0). Results: Based on the 2021 WHO classification of glioma, we recommend a single common set of criteria for all gliomas regardless of WHO grade and IDH mutational status. These criteria will be used for all trials regardless of the treatment modalities being evaluated. In newly diagnosed glioblastoma, the post-radiotherapy MRI, usually obtained approximately 4 weeks after completion of radiotherapy, rather than the post-surgical MRI as proposed in original RANO criteria, will be used as the baseline for comparison of subsequent scans. Since the incidence of pseudoprogression is high in the first 3 months following radiotherapy, confirmation of progression during this period with a repeat MRI (in 4-8 weeks) will be required for determining radiographic progression of disease (PD) if the patient is clinically stable. However, confirmation scans are not mandatory after this period nor for recurrent tumors since these scans do not appear to improve reliability in determining progression. For agents with a high likelihood of producing pseudoprogression such as viral therapies and some other immunotherapies, mandatory confirmation of progression with a repeat MRI is an option. The primary measurement will remain the 2-dimensional maximum cross-sectional area of tumor as the simplest method, but where resources are available, volumetric measurements are an option. For IDH wild-type tumors with contrast enhancement, non-enhancing tumor will no longer be evaluated with the possible exception of patients receiving antiangiogenic therapies. However, in tumors with a significant non-enhancing component, both the contrast enhancing and non-enhancing components will be evaluated as target lesions. Conclusions: We hope that these and other proposed changes by the RANO working group will improve response assessment in glioma clinical trials and help the development of more effective therapy for patients.

Role of Early Intravenous Immunoglobulins in Halting Clinical and Radiographic Disease Progression in Rasmussen Encephalitis

BackgroundRasmussen encephalitis (RE) is a rare progressive presumed autoimmune disorder characterized by pharmacoresistant epilepsy and progressive motor and cognitive deterioration. Despite immunomodulation, more than half of the patients with RE ultimately require functional hemispherotomy. In this study, we evaluated the potential beneficial effects of early initiation of immunomodulation in slowing disease progression and preventing the need for surgical interventions. MethodsA retrospective chart review over a 10-year period was conducted at the American University of Beirut Medical Center to identify patients with RE. Data were collected on seizure characteristics, neurological deficits, electroencephalography, brain magnetic resonance imaging results (including volumetric analyses for an objective assessment of radiographic progression), and treatment modalities. ResultsSeven patients met the inclusion criteria for RE. All patients received intravenous immunoglobulins (IVIGs) as soon as the diagnosis was entertained. Five patients with only monthly to weekly seizures at the time of IVIG initiation had favorable outcomes without resorting to surgery, along with a relative preservation of the gray matter volumes in the affected cerebral hemispheres. Motor strength was preserved in those patients, and three were seizure free at their last follow-up visit. The two patients who required hemispherotomy were already severely hemiparetic and experiencing daily seizures at the time of IVIG initiation. ConclusionsOur data suggest that the early initiation of IVIG as soon as a diagnosis of RE is suspected, and particularly before the appearance of motor deficits and intractable seizures, can maximize the beneficial effects of immunomodulation in terms of controlling seizures and reducing the rate of cerebral atrophy.

The factors associated with mortality and progressive disease of nontuberculous mycobacterial lung disease: a systematic review and meta-analysis

This systematic review and meta-analysis aimed to comprehensively evaluate the factors associated with mortality and progressive disease in NTM-LD patients. We conducted a literature search to identify the eligible studies, dated between January 1, 2007, and April 12, 2021. Forty-one studies with total 10,452 patients were included. The overall all-cause mortality rate was 20% (95% CI 17–24%). The overall rates of clinical and radiographic progressive disease were 46% (95% CI 39–53%) and 43% (95% CI 31–55%), respectively. Older age, male sex, history of TB, diabetes, chronic heart disease, malignancy, systemic immunosuppression, chronic liver disease, presence of cavity, consolidative radiologic features, acid-fast bacillus (AFB) smear positivity, hypoalbuminemia, anemia, increasing platelet count, high CRP, and high ESR were significantly associated with increased all-cause mortality, whereas increasing body mass index (BMI), hemoptysis, and treatment with rifamycin regimen (in M. xenopi) were significantly associated with decreased all-cause mortality in multivariable analysis. History of TB, Aspergillus co-infection, cough, increased sputum, weight loss, presence of cavity, and AFB smear positivity were significantly associated with increased clinical progression with treatment, while older age and low BMI were significantly associated with decreased clinical progression in multivariable analysis. Older age, interstitial lung disease, presence of cavity, consolidative radiologic feature, anemia, high CRP, and leukocytosis were significantly associated with increased radiographic progression after adjusting for covariates. Older age, history of tuberculosis, presence of cavity, consolidative radiologic features, AFB smear positivity, anemia, and high C-reactive protein were common significant factors associated with the all-cause mortality and clinical or radiographic progressive disease of NTM-LD. These factors are thought to directly affect NTM-LD related mortality. The future prediction models for the prognosis of NTM-LD should be established considering these factors.

Clinical outcomes of immunotherapy continued beyond radiographic disease progression in older adult patients with advanced non‑small cell lung cancer.

Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged ≥70 years) with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond radiographic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined modality therapy. However, prospective research is needed to determine which patients benefit most from the addition of local consolidative radiotherapy, including whether type of disease progression (i.e., sites of progression, pattern of progression) and/or extent of consolidation offered (i.e., complete or incomplete) impact clinical outcomes. Further research is also warranted to determine which patients would most benefit from the continuation of immunotherapy beyond documented radiographic disease progression.

Abstract 4385: Unprecedented tumor: immune interaction–clinical and drug-development implications

Abstract Background: Classic therapeutic (RX) oncology principles demand radiographic response or durable stable disease as surrogates of overall survival (OS) prolongation, the ultimate metric of Rx benefit. Progressive disease (PD), however, is an undisputed indication of treatment failure. Immune Oncology (IO) trials reporting individual patient outcomes using swimmers' plot (SP) suggest substantial OS subsequent to PD, unprecedented pre-IO. Hypothesis: Unrecognized phenomenon of OS benefit in the setting of radiographic PD, is tissue-agnostic and prevalent (&amp;gt;15%). Methods: We conducted a retrospective review of IO monotherapy trials in 3 cancers if SP were reported. Percentage of PD patients (Pts) surviving beyond defined time landmarks is reported (Table). Results: Realizing that 3rd or subsequent Rx lines rarely provide &amp;gt; 6 months OS duration in most cancers, our results indicate that 2/3rd of IO-treated pts, regardless of histology, or line of therapy are performing significantly better than expected; 1/3rd surviving &amp;gt; 1 year beyond PD. Discussion: In IO, radiographic bulk may increase despite undeniable OS benefit (in years). We likely underestimated this phenomenon since pts with PD at 1st assessment aren't included in the SP, and with longer follow up, OS of PD pts is likely to improve with longer time to manifest it. This phenomenon–we term 'Disguised Responders' (DRs)–challenges an oncology principal. DRs needs to be considered by clinicians and future drug developers to accurately identify putative novel drugs. A plausible mechanism of DRs posits that 'virulence' of a given subclone, regardless of size or bulk, dictates Rx outcome. Virulence may operate through cachexia-induction, propensity to metastasize or metabolic adaptability, to name a few. Novel experimental approaches are desperately awaited to probe and measure virulence of different tumor subclones in future drug evaluations. Table 1. Clinical Trials of IO Monotherapy Number and (%) of pts surviving beyond clinical PD (months) Tumor Rx Line 1st Author/Yr N PD (n) &amp;lt;6 6-11 12-23 24-35 36-47 &amp;gt; 48 NSCLC* 2nd + Topalian ''19 22 12 1 2 4 1 4 1st + Fredinandus ''21 45 2 1 1 1st + Kim ''22 139 22 13 5 3 N/A Bilger ''22 18 10 3 4 3 2nd Dart ''21 7 3 2 1 2nd + Tozuka (MR) ''20 11 11 4 6 1 2nd + Tozuka (PD) ''20 51 51 29 12 7 2 1 2nd + Waterhouse ''20 39 38 16 14 4 4 Subtotal 332 149 63 (42%) 44 (30%) 28 (18%) 4 (3%) 5 (3%) 4 (3%) Melanoma 1st + Warburton ''20 70 13 1 4 3 4 1 2nd + Topalian ''19 34 21 1 2 10 4 4 2nd + Weber ''15 38 4 2 1 1 2nd + Dimitriou ''21 125 9 3 4 2 Subtotal 267 47 3 (6%) 8 (17%) 10 (21%) 17 (36%) 5 (11%) 4 (8.5%) RCC** 2nd + Topalian 19'' 10 7 1 1 2 3 7 15% 15% 30% 42% Total 609 203 33% 25% 15% 10% 6% 5.4% *Non-small cell lung cancer. ** Renal Cell Carcinoma Citation Format: Farah Mazahreh, Liyan Mazahreh, Brad Fugere, Ahmad Mazin Safar. Unprecedented tumor: immune interaction–clinical and drug-development implications. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4385.