JAMA Oncology Research Articles

Immune checkpoint inhibitors: A bibliometric analysis of research trends and hotspots based on the most frequently cited clinical trials (2013 - 2021).

To quantitatively and qualitatively evaluate research trends and hotspots for immune checkpoint inhibitors (ICIs), according to the most frequently cited clinical trials. Numerous clinical trials have been carried out using ICIs for activating anti-tumor immunity in cancer patients. The most frequently cited clinical trials have been used as a database for achieving the objectives of this analysis. The most frequently cited articles on ICIs meeting the inclusion criteria were extracted from the Web of Science database. Citation report information including annual outputs, most relevant journals, and country of origin together with burst references, keywords, information on co-occurrence, citation networks, and cluster topics were analyzed using standard bibliometric procedures. A total of 112 most frequently cited articles on clinical trials of ICIs were retrieved for the period 2013 to 2021 of which the journal JAMA Oncology had the highest number of citations. Most studies originated in the U.S., and therefore studies from this country had a determinant effect of the results of the investigation. Burst reference topics included studies on ipilimumab for melanoma, anti-PD-L1 antibody in advanced cancer, anti-PD-1 antibody in cancer, nivolumab combined with ipilimumab or as monotherapy in untreated melanoma, and pembrolizumab for PD-L1 positive non-small-cell lung cancer. Nine clusters were grouped in the citation network. The topic/keywords "cancer", "immunotherapy", "PD-1 blockade", "PD-L1", "expression", "ipilimumab", "nivolumab", "pembrolizumab", and "safety" were the search priorities, whereas "multicenter", "resistance", "adverse events", and "renal-cell carcinoma" were seen as emerging topics in this specific field. The bibliometric analysis of the most frequently cited clinical trials with ICIs provided information on the characteristics of the studies evaluated as well as hotpots and trends in evolving immunopharmacotherapy research on ICIs.

IMMU-11. CLINICAL EXPERIENCE WITH THE CONCEPT OF MULTIPHASE COMBINED TREATMENT FOR ADULTS WITH GBM

Abstract BACKGROUND We published survival data of 50 adults with GBM treated with individualized multimodal immunotherapy (IMI) as part of a multiphase combined treatment (Van Gool et al, https://doi:org/10.1016/bs.mcb.2023.06.001). Analysis was repeated with new observation data. METHODS Patient definition for retrospective analysis: start IMI between 27/05/2015 and 31/10/2023, >18y, newly diagnosed, IDH1 wild-type, MGMT promoter-methylation status documented, survival known, no second malignancy. RESULTS Forty (14 female, 26 male) GBM patients were MGMT-promoter-unmethylated (unmeth), while 31 (15 female, 16 male) were MGMT-promoter-methylated (meth). Comparing the molecular subgroups, both respective median age; 48 years (range 18-65) and 54 years (range 26-72), and respective Karnofsky performance index; 70 (range 50-100) and 80 (range 60-100), were equal. Patient distribution (< complete resection, complete resection, not documented) was equal: 17/15/8 (unmeth) versus 17/11/3 (meth). Both groups were treated similarly: in median 37 (range 0-147) sessions of modulated electrohyperthermia, in median 37 (range 5-147) bolus injections of Newcastle Disease Virus, in median 2 (range 0-6) IO-Vac® vaccines with a median total number of 30.7x10e6 DCs (range 0-158x10e6). The median overall survival (mOS) for the total group was 27 months. The 2-year overall survival (OS) was 57.9 % and the 3-year OS 37.1 %. The mOS for unmeth patients was 22.1 month, with a 2-year OS of 42.7%. The mOS for meth patients was 37.7 months, with a 2-year OS of 75.5%. Sampling five control arms of contemporary RCTs as external control arm (Liau et al, JAMA Oncol 2023) showed for unmeth and meth patients a mOS of 14.6 resp. 21.3 months with a 2-year OS of 21% resp. 42%, which reflects the current prognosis for these patients. CONCLUSIONS Our analysis confirms that the integration of IMI during and after standard of care improves the OS. Similar multiphase combined treatment strategy, including IMI, should be considered to treat childhood GBM.

Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms. To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications. All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting. Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01). In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.

Oral cancer drug repositories: Challenges and solutions.

11063 Background: Frequent drug shortages and high out-of-pocket costs due to inadequate and unaffordable insurance coverage hinder access to oral chemotherapy. Amidst this, oral cancer drugs estimated a mean of $4290/patient are wasted due to dose modification, discontinuation or death[Lam M. et al, JAMA Oncol. 2023;9(9):1238-1244]. To combat this discrepancy, multiple states have passed laws establishing drug repositories that collect unused oral cancer medications and redistribute them to patients in need. ASCO has also endorsed these programs, even advocating for open distribution systems allowing donations from individuals. Methods: We analysed statewise cancer drug repositories(source:National Conference of State Legislatures) and communicated with representatives from programs including SIRUM, RemediChain and I-DROP Coalition. We used a mixed methods approach to examine the breadth and functioning of these programs. Results: 28 out of the 44 states with laws establishing prescription drug repositories operate state-run drug recycling programs (Updated September 2023). However, only 14 states (California, Florida, Iowa, Michigan, Minnesota, Montana, Nebraska, Nevada, Ohio, Pennsylvania, Tennessee, Utah, Washington and Wisconsin) have provisions for donation of cancer medications, or for creation of separate cancer drug repositories. Other nonprofits like RemediChain and SIRUM function at a national level, covering 47 states and Washington D.C. between them. Conversations with 3 such programs revealed multiple obstacles that limit the effectiveness of drug recycling. All 3 programs reported inadequate donations, ranging from 2-3 donations/month in a state level program (I-DROP) to 1-10 donations/day in a larger national level program (RemediChain). 3/3 programs received more donations of unused pills from patients or their families than from pharmacies/health facilities. All 3 surveyed programs reported limited and inconsistent supply of donated drugs; expiration of drugs before redistribution; lack of demand for specialty drugs and unavailability of common oncology drugs that patients request since these drugs are less likely to go unused. All surveyed programs mentioned struggling with funding and staffing. Notably, all 3 repositories stressed that informing patients about recycling options right at the beginning of treatment was crucial to improve donation rates; and that expanding repository donor and recipient coverage could increase the chances of successfully redistributing drugs. Conclusions: Improving awareness amongst providers and patients, campaigning for federal funding and increasing the scale of coverage by expanding repository programs to all states and allowing interstate transfer of drugs could address current challenges to drug recycling. This would limit wastage of expensive medication while reducing financial burden on patients and improving access to life saving treatment.

Pathological complete response to predict long term outcomes in the I-SPY2 TRIAL.

597 Background: The I-SPY2 platform trial uses pathologic complete response (pCR) to identify active agents in patients with stage 2/3 breast cancer. Only patients with HR+ HER2- tumors, and low risk 70-gene assay results are excluded. 2118 patients were enrolled from March 2010 through June 2022 with follow-up data from 2005 patients as of January 2024. We have reported the improved event-free (EFS) and distant-recurrence free (DRFS) survival for 950 patients (1) who achieved a pathological complete response (pCR). Here we report the outcomes for the additional 1055 patients not included in our initial report. Methods: Patients have been randomized to one of 25 arms. Residual Cancer Burden (RCB) assessment was performed by site pathologists who were trained to ensure uniform response classification; RCB 0 = pCR. EFS is defined as time to local or distant recurrence or death. DRFS is defined as time to distant recurrence or death. Patients without events were censored at time to last follow-up. Association between pCR and EFS/DRFS was assessed using Cox proportional hazard modeling with significance assessment using the log rank test. EFS and DRFS at 3 years are estimated using the Kaplan Meier method. Results: Median follow up was 3.3 years (0.05-10.2 y). There were 144 EFS and 123 DRFS events. pCR rates varied by subtype, but achieving pCR was associated with an EFS of 96% and DRFS of 96%. For patients without pCR the EFS was 82% and DRFS was 84% at 3 years. The relationship between pCR and EFS was significant and clinically impactful within each subtype. Conclusions: pCR continues to have a strong positive association with EFS and DRFS as in our initial report. It is notable that EFS for non-pCR patients improved to 82% from our initial report of 78%. Initially few patients received additional adjuvant therapy except for standard of care endocrine and HER2-targeted therapy. Increased adoption of post neoadjuvant therapy with the approval of several agents for patients with non-pCR likely contributed to this improvement. I-SPY also reported a shift in residual cancer burden for patients receiving investigational therapies, which also may improve outcome for non-pCR patients. Taken together, these data demonstrate the value of pCR as an early endpoint regardless of tumor type or drugs delivered. These findings emphasize the need for new agents that will allow all patients to achieve pCR and potentially avoid the need for additional therapy after surgery. 1. Yee, et al. JAMA Oncol 2020. 2. Symmans, et al. JAMA Oncol 2021. Clinical trial information: NCT01042379 . [Table: see text]

A comprehensive analysis of patient demographics and disparities in contemporary oncology clinical trials (2022-2023).

e13748 Background: Overcoming disparities in cancer research is a major challenge that needs to be prioritized in clinical trials in oncology. In this study, we aimed to assess the current representation of patient demographics in phase 2 and 3 clinical trials in oncology to illuminate healthcare inequities during clinical trial recruitment. Methods: We identified published phase 2 and phase 3 oncology studies in five medical journals (New England Journal of Medicine, Journal of Clinical Oncology, Lancet, Lancet Oncology, and JAMA Oncology). We extracted data on patient demographics including sex, age, race, and ethnicity. We also extracted information on trial sponsorship (industry vs investigator initiated). Results: We included 381 articles published between 2022 and 2023 (108 investigator-initiated; 273 industry-sponsored). Details on age groups (&lt;65 vs &gt;65) were available in 149 studies (n=78,523 patients) including 47,192 (60.1%) &lt; 65; and 31,331 (39.9%) &gt;65. Data on gender were available in 373 studies (n=159,836 patients) including 73,308 (45.9%) males and 86,526 (54.1%) females (2 patients were listed as other). Race was reported in 214 studies (n=92,562) including 65,876 Caucasian (71.2%), 3,428 (3.7%) Black, 18,235 (19.7%) Asian, and 5,023 (5.4%) other/missing. Ethnicity data were available in 52 studies including 2,570 Hispanics (12.4%) and 18,234 non-Hispanics or unknown (87.6%). Conclusions: While there are efforts being made to diversify the recruitment of clinical trials, inequities in trial recruitment remains a major issue. Caucasian and younger patients represented the majority of patients, which may not be reflective of real-world practice. There is an important need to focus on increasing enrollment of underrepresented populations and understanding barriers to enrollment.

Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (&lt;65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (&lt;5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .

Safety of pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in patients (pts) with biliary tract cancer with peritoneal metastases.

TPS4186 Background: Biliary tract cancers are rare with the majority of pts diagnosed with metastatic disease at initial presentation. Up to 20% of pts will have peritoneal metastases, resulting in symptoms of ascites, abdominal pain, and potential bowel obstruction. Despite advances in standard of care systemic treatments such as combination gemcitabine, cisplatin, and durvalumab (gem/cis/durva), penetration to peritoneal metastases may be poor. While addition of nab-paclitaxel to gem/cis increased objective response in a phase 2 study (1), SWOG 1815 did not demonstrate a significant improvement in survival with the triplet combination compared to gem/cis (2), possibly due to added toxicity. PIPAC directly delivers treatment to the peritoneal space, which could potentially reduce toxicity and improve efficacy. We aim to investigate the safety of PIPAC nab-paclitaxel plus systemic gem/cis/durva in biliary tract cancer pts with peritoneal metastases. Methods: This is an investigator-initiated, non-randomized phase 1 trial enrolling up to 12 evaluable pts using a modified phase 1 queue 3+3 design. Eligible pts must have treatment-naïve histologically or cytologically confirmed intra/extra-hepatic cholangiocarcinoma or gallbladder cancer with documented metastatic disease and visible peritoneal disease on imaging or laparoscopy. Gem/cis (800/25 mg/m2) will be administered on Days 1 and 8 of 3-week cycles; durva (1500 mg) will be administered on Day 1. Pts will receive PIPAC nab-paclitaxel (90 mg/m2) on Day 3 of Cycles 1, 3, and 5. If dose-limiting toxicities (DLTs) occur, nab-paclitaxel may be reduced to 70 mg/m2; the DLT window for each pt is 42 days after the first PIPAC. After eight 3-week cycles, durva (1500 mg) will be continued on Day 1 of 4-week cycles until disease progression or unacceptable toxicity. The primary endpoint is treatment-related adverse events (AEs) graded by NCI Common Terminology Criteria for Adverse Events version (v) 5.0. AEs will be monitored during treatment and for 4 weeks after the last dose of treatment with any agent. Secondary endpoints include objective response per Response Evaluation Criteria in Solid Tumors v1.1, peritoneal regression grading score at each PIPAC, peritoneal carcinomatosis index at time of laparoscopy, post-operative surgical complications, progression-free/overall survival, PIPAC technical failure rate, EQ-5D-5L and MD Anderson Symptom Inventory responses before/during treatment, and number of daily steps taken before/during treatment. Exploratory endpoints include characterization of sub-clonal tumor evolution/tumor microenvironment changes and PIPAC nab-paclitaxel pharmacokinetics/pharmacodynamics. Enrollment began 6/2023 and is ongoing. 1. Shroff et al, JAMA Oncol 2019. 2. Shroff et al, JCO 2023 LBA490. Clinical trial information: NCT05285358 .

Health-related quality of life (HRQoL) with tepotinib in patients with MET exon 14 (METex14) skipping non-small cell lung cancer (NSCLC) with brain, liver, adrenal, or bone metastases in the phase II VISION trial.

8575 Background: Tepotinib, a highly selective MET inhibitor, showed robust and durable activity in patients with METex14 skipping NSCLC in the VISION trial (NCT02864992) (1). Systemic and intracranial activity was seen in patients with brain metastases. Secondary endpoints in the overall population showed stability in overall HRQoL, dyspnea and chest pain, with clinically meaningful improvement in cough. We analyzed HRQoL in patients with brain, liver, adrenal or bone metastases. Methods: Eligible patients (including patients with brain metastases if asymptomatic or neurologically stable on a stable steroid dose) received oral tepotinib 500 mg (450 mg active moiety) once daily. HRQoL was assessed at baseline and during follow-up using the EORTC QLQ-C30 Global Health Score (GHS), EQ-5D-5L visual analog scale (VAS), and EORTC QLQ-LC13 cough, dyspnea, and chest pain scores. Subgroup analyses evaluated patients with brain, liver, adrenal or bone metastases at baseline per independent review (data cut-off: November 20, 2022). Mean change from baseline across all visits was evaluated by linear mixed model regression in patients with baseline and ≥1 post-baseline score. Results: Of 313 enrolled patients, change from baseline in HRQoL was evaluable in 52 patients with brain (16.6%), 56 with liver (17.9%), 54 with adrenal (17.3%), and 86 with bone metastases (27.5%). At baseline, mean ± standard error (SE) EORTC QLQ-C30 GHS was worst in patients with bone metastases (49.90 ± 2.03), followed by patients with adrenal (51.85 ± 2.51), liver (58.33 ± 2.77), or brain metastases (59.94 ± 2.53). A similar pattern was observed for baseline EQ-5D-5L VAS (bone: 60.42 ± 1.94; adrenal: 63.06 ± 2.45; liver: 65.30 ± 2.46; brain: 66.75 ± 2.57). During tepotinib treatment, overall HRQoL (i.e. EORTC QLQ-C30 GHS and EQ-5D-5L VAS) remained stable in patients with brain, liver, adrenal or bone metastases (Table). Symptom scores in these patients showed trends for improvement in cough, with stability in dyspnea and chest pain. Conclusions: In the VISION trial in METex14 skipping NSCLC, patients with brain, liver, adrenal or bone metastases maintained overall HRQoL during tepotinib treatment, with trends for improvement in cough, consistent with results for the overall population. 1. Mazieres et al. JAMA Oncol 2023;9:1260–66. Clinical trial information: NCT02864992 . [Table: see text]

Molecular profiling of serial liquid biopsy specimens utilizing cell free DNA (cfDNA) and circulating tumor cells (CTCs) in TBCRC041: A phase II study of alisertib in endocrine resistant metastatic breast cancer (MBC).

1037 Background: TBCRC041, a randomized phase 2 trial of alisertib (A) ± fulvestrant (F) in women with HR+/HER2- MBC demonstrated promising clinical activity for alisertib (1). Interrogation of baseline (PreC1) and end of cycle 1 (EOC1) cfDNA and CTCs may identify biomarkers associated with response to A±F. Methods: Plasma cfDNA was sequenced using the Guardant INFINITY platform, which includes genomic and methylated tumor fraction (mTF) analysis. Pathogenic variants were determined using publicly available databases and Mayo Clinic annotation pipelines. CTCs were identified as nucleated, EpCAM+/ cytokeratin+/ CD45- cells and assessed for ER/HER2 staining (RareCyte, Seattle). PFS was defined as the time from randomization to progression or death. EOC1-PFS differs from PFS as time starts at C2D1. Stratified log-rank tests and conditional Cox modeling were used to assess whether PFS or EOC1-PFS differed by mutations in ESR1 or PIK3CA, pre-CTC ≥ 5, or mTF&gt;1%. Results: Of the 91 eligible pts, 84 progressed, and 73 were deceased. In the 86 pts with PreC1-cfDNA results, variants were identified in ESR1 (42; 48.8%), PIK3CA (36; 41.9%), AKT1 (7; 8.1%), PTEN(7; 8.1%), BRCA1 (4; 4.7%), and BRCA2 (7; 8.1%). Pts with a PIK3CAmut had significantly decreased PFS (HR 1.8; 95%CI: 1.1 -2.9, p=0.014) but not by ESR1mut status (p=0.583). PreC1 and EOC1-mTF were determined for 78 and 76 pts, respectively. PreC1-mTF was 0-1% in 21; 1.1-10.0% in 27; and 10.1-100% in 30. mTF levels remained between 0-1% in 17 pts fell to 0-1% in 11 pts, and was 0-1% in 5 pts without a preC1-mTF determination. PFS did not differ with respect to PreC1-mTF (p=0.210), but EOC1-PFS was worse in pts with mTF &gt;1% (HR 3.0; 95%CI: 1.6 -5.2, p&lt;0.001). PreC1 and EOC1-CTC were determined for 78 and 76 pts. 36 (46.2%) pts had a PreC1 CTC count ≥ 5. EOC1-CTC levels remained at (n=17) or increased to (n=1) ≥ 5 and was ≥ 5 in 2 pts without a preC1-CTC determination. EOC1-PFS was not significantly different for EOC1-CTC ≥ 5 (p=0.065), but was significantly decreased in pts with PreC1-CTC≥5 (HR=1.8; 95%CI: 1.1-3.0; p=0.018). Broader cfDNA NGS panel and CTC-derived ER/HER2 staining results will be presented at the meeting. Conclusions: Among patients receiving A±F, PFS varied based on the PIK3CAmutation status. cfDNA and CTC assessment PreC1 and EOC1 provided complementary information. Further validation in larger datasets is needed. 1. JAMA Oncol 2023;9:815. Clinical trial information: NCT02860000 .

Abstract PO4-22-03: Intensity Modulated Proton Therapy (IMPT) for the Definitive Adjuvant Management of Women with Breast Cancer: A Single Institutional Experience of 5-Year Oncologic Outcomes

Abstract Purpose: There is limited data reporting the oncologic outcomes of breast cancer patients treated definitively with adjuvant proton beam therapy. Here we report a single institutional experience of oncologic outcomes, treating a predominantly vulnerable breast cancer patient population and compare these to historical standards primarily utilizing photon therapy. Materials and Methods: Unver IRB approval, we retrospectively reviewed 453 definitively treated breast cancer patients from 2016 – 2023 using adjuvant IMPT as part of their cancer care. Patients with recurrent disease, receiving re-irradiation, and those with less than 1-year of follow up were excluded from this analysis. Patients were treated with surgery and systemic therapies as per standards of care. Radiation therapy was administered using pencil beam scanning IMPT with daily image guidance. χ2 and Mann-Whitney U tests were performed to determine differences between select variables. Kaplan-Meier analysis and Cox proportional hazard models were used to analyze overall survival (OS). Results: With a median follow up of 22 months for the entire cohort, 453 patients were treated at XXXX as part of definitive adjuvant management for their breast cancer. Nearly 30% of patients self-identified as black (n=135), average patient age was 54 and 56% (n=255) self-identified as being married with approximately 25% (n=109) of patients having Medicare/Medicaid insurance. 198 patients (43.8%) had an intact breast and the remainder mastectomy of which 37.4% had reconstruction at the time of their radiation. 229 patients (50.7%) received neoadjuvant chemotherapy while 55 patients (12%) received concurrent chemotherapy which was either her2+ directed or Xeloda. The number of patients (%) corresponding to the AJCC 8th edition anatomical staging is as follows: Stage 0: 12 (2.7%); Stage I: 91 (20.1%); Stage 2: 197 (43.6%); Stage 3: 152 (33.6%). Median RT dose delivered for patients receiving comprehensive treatment was 50.4 Gy with 81% of patients receiving a boost to either scar, lumpectomy cavity and/or LN regions. Median RT dose delivered for patients receiving whole breast radiation was 42.56 Gy with a 10 Gy lumpectomy cavity boost. 5-yr OS by stage was 0: 100%; stage I: 98.8%; stage 2: 93.5%; stage 3: 90.8%. Five-year OS for black, white and other race patients were 85.3%, 95.8% and 96%, respectively (White as Ref: HR 3.176, 95% CI: 1.313-7.681, p=0.010 for black patients). For the entire cohort, patients with triple negative disease had a 5-yr OS of 80.4% (HR: 4.33, 95% CI 1.87-10.04, p&amp;lt; 0.001) and there was no difference in OS when insurance status was considered (p=0.378). Conclusions: To the best of our knowledge this represents the largest series of definitively treated breast cancer patients utilizing adjuvant proton therapy and the 5-year OS rates in our analysis coincide with published standards1. Results from the on-going randomized RADCOMP study will provide further guidance as to which patients benefit the most from proton therapy and will further support equivalent oncological outcomes when compared to photon therapy. 1. Weiss A, Chavez-MacGregor M, Lichtensztajn DY, et al. Validation study of the American Joint Committee on Cancer eighth edition prognostic stage compared with the anatomic stage in breast cancer. JAMA Oncol. 4(2):203-209, 2018. Citation Format: Elizabeth Nichols, Gurbani Singh, Desiree Lejano, Sarah McAvoy, Mark Mishra, Melissa Vyfhuis. Intensity Modulated Proton Therapy (IMPT) for the Definitive Adjuvant Management of Women with Breast Cancer: A Single Institutional Experience of 5-Year Oncologic Outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-03.

Abstract PS07-01: Exemestane and breast cancer prevention: how low can we go? Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative dosing regimen

Abstract Exemestane is an effective drug to reduce breast cancer risk reaching an overall 65% reduction in breast cancer in the placebo–controlled phase III MAP.3 trial. To improve its acceptability in primary prevention programs, we are seeking the minimal effective dose. In a 3-arm presurgical trial of 4-6 weeks before breast surgery in 180 postmenopausal women with ER-positive breast cancer, we investigated the activity of alternative exemestane schedules: 25 mg per day (QD), 25 mg three times/week (TIW) or 25 mg per week (QW) and showed that in adherent participants TIW was not inferior to QD in reducing circulating estradiol (Serrano et al JAMA Oncol. doi:10.1001/jamaoncol.2023.0089). Moreover, Ki67 reduction was seen in all arms with no significant difference among arms. Here, we analyzed the concentration of sex steroids, exemestane, and its main metabolite in the cancer and adjacent non-cancerous breast tissue. Tissues samples were homogenized before liquid-liquid extraction. After reconstitution, samples were analyzed by coupling liquid chromatography with tandem mass spectrometry (Sciex QTRAP 6500, Nexera system, Shimadzu). We obtained breast cancer tissue from 93 and non-cancerous breast tissue from 117 participants to measure exemestane, 17-OH-exemestane, and sex steroids. Exemestane and 17-OH-exemestane concentrations were detectable only in the QD arm, while in TIW and QW arms levels were below the Lower Limit of Detection (&amp;lt; LLD). Median exemestane level was 3807 fmol/g and 17485 fmol/g and median 17-OH-exemestane level was 338 fmol/g and 1343 fmol/g in cancer and non-cancerous tissue, respectively. Interestingly, drug and its metabolite accumulated 4-5-fold in non-cancerous tissue compared to cancer tissue in the QD arm. Despite the between-arm drug concentration difference, estradiol was almost completely suppressed in all arms in the non-cancerous tissue, attaining level &amp;lt; LLD in QD and TIW arms, and barely detectable in QW arm. The median in the QW arm was &amp;lt; LLD (&amp;lt; LLD, interquartile range &amp;lt; LLD, 25.5 fmol/g) showing no differences in QD vs TIW and QD vs QW (p = 0.364 and p = 0.693 respectively). While a dose-response trend was observed in cancer tissue, estradiol level was &amp;lt; LLD (&amp;lt; LLD,52.2 fmol/g) on QD, 17.1 (&amp;lt; LLD, 125.3) on TIW, and 128 (&amp;lt; LLD, 224.8) on QW (p=0.046 QD vs TIW arms). Estrone showed a clear dose response trend among arms, whereas no differences were observed for testosterone and androstenedione for both cancer and non-cancerous tissue in all arms. The Ki-67 change was analyzed in the previous paper; here we report the data for those patients who had drug and hormones tissue concentration measured, where Ki-67 decreased in all arms: median Ki67 change from baseline was QD -8 (-10, -3), TIW -6 (-11, -2), QW -4 (-8, -1). Conclusions: Exemestane 25 mg three times a week maintains comparable activity to the standard dose on tissue estradiol suppression and Ki67 decrease. Considering the estradiol suppression in non-cancerous tissue of the lowest exemestane dose, QW might even be considered for breast cancer risk reduction in primary prevention. Further analyses are ongoing to investigate the correlation with other biomarkers including the role of polymorphic UGT2B17 genotype that could identify candidates to lower exemestane dosage. Citation Format: Davide Serrano, Harriet Johansson, Bjørn-Erik Bertelsen, Gunnar Mellgren, Parijatham Thomas, Katherine Crew, Nagi B Kumar, Debora Macis, Valentina Aristarco, Aliana Guerrieri Gonzaga, Sara Gandini, Mauro D’Amico, Tania Buttiron Webber, Irene Maria Briata, Stefano Spinaci, Viviana Galimberti, Giuseppe Viale, Lana A. Vornik, Eduardo Villar-Sanchez, Powel Brown, Brandy M Heckman-Stoddard, Eva Szabo, Bernardo Bonanni, Andrea De Censi. Exemestane and breast cancer prevention: how low can we go? Drug and biomarker tissue levels in a randomized presurgical trial on exemestane alternative dosing regimen [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-01.

Abstract RF01-03: PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study

Abstract Background: The Phase 2 PARSIFAL study assessed whether fulvestrant (FUL) or letrozole (LET) was the optimal endocrine partner for the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) palbociclib (PAL) in patients (pts) with untreated, endocrine-sensitive, hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (ABC) in the first-line setting. This trial failed to demonstrate an improvement in progression-free survival (PFS) of PAL+FUL over PAL+LET (Llombart-Cussac et al. Jama Oncol 2021). Following progression on CDK4/6i-based regimens in the metastatic setting, the EMERALD study (Bardia et al, SABCS 2022 GS3-01) identified early progressions (&amp;lt; 12 months [mo]) as a strong predictor of resistance to subsequent endocrine therapies. Here, we report updated PFS and overall survival (OS) from PARSIFAL, exploring a PFS &amp;lt;12 mo threshold as a prognostic factor for poor outcomes. Methods: This was an observational, international, multicenter study that included pts from the prospective PARSIFAL study, in which pts were randomly assigned (1:1) to receive PAL (oral 125 mg/day, 28-day cycles; 3 weeks on, 1 week off) plus FUL or LET at conventional doses. The primary objective was to extend the assessment of OS of PARSIFAL study with a longer median follow-up. Secondary objectives included extended PFS, other post-progression efficacy data, and the identification of new prognostic and predictive markers. The design had a planned recruitment of at least 388 pts with 195 deaths. The 2-sided stratified log-rank test (α = 0.05) had a 70% power to detect a hazard ratio ≤0.70 in favor of FUL + PAL arm. Results: A total of 389 pts (80.5%) from the PARSIFAL study were included in this analysis, involving 32 of the 47 original sites. Pts signed a new informed consent form according to local regulations. Demographic and baseline disease characteristics were similar between the PARSIFAL-LONG and the overall PARISFAL intention-to-treat populations. At the time of analysis, after a median follow up of 5.0 years (range, 0.1-7.3), 241 and 213 events were reported for PFS and OS, respectively. No differences in efficacy were observed between treatment arms whether for PFS (hazard ratio, 1.0, p=0.985) or OS (hazard ratio, 0.94, p=0.635). In accordance with the protocol for PARSIFAL-LONG, both arms were combined for subsequent analysis. The median PFS (mPFS) for the first-line PAL-based regimen population was 33.2 mo (95%CI, 27.7-39.5), with a median OS (mOS) of 65.4 mo (95%CI, 57.8-72.0). A total of 86 pts (22.1% of the population) had a mPFS time &amp;lt;12 mo (early progressors). mOS and mPFS for this early progressor subgroup were 24.0 mo (95%CI, 17.3-30.1) and 7.0 mo (95%CI, 5.6-8.3), respectively, and only 11 pts (12.8%) were still alive at the time of analysis. The remaining 303 pts (77.9%) were progression-free on PAL-based regimens at 12 mo (PFS≥12). The number of events for PFS and OS at this time were 165 (54.5%) and 138 (45.5%), respectively. mOS from randomization for the PFS≥12 subgroup was 81.5 mo (95%CI, 70.2-not achieved) and the mPFS was 49.8 mo (95%CI, 40.9-59.8). Following progression on PAL-based regimens, the PFS≥12 criteria was a strong predictor for mOS, with 27.0 vs 18.0 mo (hazard ratio, 0.67, 95%CI, 0.51-0.90, p=0.007) for PFS≥12 and early progressors, respectively. These differences may increase in the future, as 54.5% of pts with PFS≥12 are still alive compared to 12.8% of pts with an early progression. Conclusions: Extended follow-up analysis from PARSIFAL study confirms no major differences between LET or FUL when combined with PAL. mPFS and mOS results are consistent with those reported in other first-line trials involving different CDK4/6i. Progression within the first year of first-line CDK4/6i-based regimen for HR+/HER2- ABC pts may be prognostic of less favorable outcomes. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, Meritxell Bellet- Ezquerra, Florence Dalenc, Miguel Gil-Gil, Manuel Ruíz - Borrego, Joaquín Gavilá, Peter Schmid, Pilar Zamora, Duncan Wheatley, Eduardo Martínez-de Dueñas, Kepa Amillano, Antonio Antón, Paul Cottu, Gemma Viñas, Thierry Petit, Petra Tesarová, Juan Cueva, Marco Colleoni, Maria Purificación Martínez del Prado, Raquel Andrés, Marta Díaz Cabo, Susana Victorino, Miguel Sampayo-Cordero, Javier Cortés. PARSIFAL-LONG: Extended follow-up of hormone receptor-positive/HER2-negative advanced breast cancer patients treated with fulvestrant and palbociclib vs. letrozole and palbociclib in the PARSIFAL study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-03.

Abstract 6121: Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer

Abstract Background: Black women have a higher rate of breast cancer mortality compared with their non-Hispanic White (NHW) counterparts, with an 80% higher likelihood of breast cancer death from axillary node-negative, ER-positive (a.k.a. luminal) tumors (Hoskins et al, JAMA Oncol 2021). Black women are 30% more likely to have ER-positive tumors with a high-risk gene expression profile, indicating a role for tumor biology in this disparity (Hoskins et al, JAMA Oncol 2023). The underlying biological mechanisms responsible are unknown. The aim of this study was to investigate the immune cell infiltrate in ER-positive breast tumors as a potential driver of disproportionately aggressive luminal tumor biology among Black women. Methods: Gene expression data from ER-positive tumors diagnosed in women identified as Black or NHW in The Cancer Genome Atlas (TCGA) were deconvoluted with the CIBERSORT tool to estimate the relative intratumoral proportion of 22 immune cell types within each tumor. Differential analysis of imputed immune cell fractions comparing race was conducted with the Mann-Whitney test. P-values were adjusted for multiple comparisons with the false discovery rate (FDR) method. Linear regression of previously reported ancestry estimates for breast cancer patients in TCGA (Huo, et al, JAMA Oncol 2017) was used to test for association between African ancestry and proportion of regulatory T cells (Tregs) in tumors from Black women. Results: CIBERSORT analysis of tumors found a significantly increased proportion of Tregs in tumors from Black (n=86) than NHW (n=534) patients, with log2 fold-change= 0.74 (FDR-corrected p-value= 0.01). Plasma cells, T follicular helper cells and M0 macrophages were increased in tumors from Black women with uncorrected p-values &amp;lt; 0.05, but racial differences in these cell types were not significant after FDR correction (p &amp;gt;0.1). Ancestry analysis among Black women indicated that African ancestry was not associated with the intratumoral proportion of Tregs (1 SD change in proportion African ancestry was associated with 0.06 standard deviation increase in Tregs, p &amp;gt; 0.3). Confirmation of findings with a racially diverse breast tumor TMA from an independent cohort is ongoing and results will be presented. Conclusions: Increased pro-tumorigenic Treg infiltrate in ER-positive breast tumors from Black women may contribute to a disproportionately aggressive tumor phenotype and racial survival disparity. The findings could have therapeutic implications and suggest that immune checkpoint inhibitors may have increased activity against luminal breast cancer in Black patients. Although this study did not show a statistically significant effect for genetic admixture within African Americans, larger studies are needed to distinguish the contribution of ancestry vs. social context, environmental, and behavioral factors as the driver of this racial difference in tumor biology. Citation Format: Neha Hippalgaonkar, George Chlipala, Dezheng Huo, Garth Rauscher, Naiche Adler, Jan Kitajewski, Kent Hoskins. Racial differences in the intratumoral immune cell infiltrate in luminal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6121.

Abstract 4867: Longitudinal latent class analysis to further understand trajectory of density over time and risk of breast cancer

Abstract Background: It is clinically important to refine strategies to manage women with dense breasts as they represent approximately 50% of all women screened. Change in breast density is related to risk of breast cancer.1 We also must understand this change in density over time in women with dense and non-dense breasts. While population level data have been reported to estimate decrease in density with age, this has largely used digitized film images.2 Expanding use of digital mammography and repeated screening generates a large library of images for each woman, offering the potential to use more of the image data. Methods: We use longitudinal latent class analysis to cluster women and estimate their change in density over time. To evaluate the groups of women with different patterns of change in density we fit latent class models to our previously published data.1 This includes 289 pathology confirmed cases of breast cancer and 658 controls among women followed from November 3, 2008 to October 31, 2020. Results: Among women with dense breasts, there are 107 who developed breast cancer during follow-up and 267 control women who remained free from breast cancer. In the women without dense breasts, 173 cases and 383 controls were evaluated and showed similar age and BMI within the controls as seen in women with dense breasts. Prevalence of family history and history of benign breast biopsy did not differ between the two groups. We observe this latent class and trajectory of density phenomenal separately for dense and non-dense groups in our data. We show that the data define 2 classes, those who have decrease in density over time and those who have increase over time. The odds ratio (OR) for cancer comparing decline vs. incline is 4.9 in women with dense breasts (BI-RADS C, D) and 6.17 on women with non-dense breasts (BI-RADS A, B). Discussion: To refine our understanding of patterns of change in breast density over time in relation to breast cancer risk we fit latent class models. Longitudinal change matters as reflected in the 2-class model. This is independent of starting density and confirms that a one-time measure of density is not enough to define level of risk for subsequent breast cancer. Further work is needed to better define the drivers and inhibitors of decline in breast density over time given this change over time as women age is a universal phenomenon.2 1. Jiang S, Bennett DL, Rosner BA, Colditz GA. Longitudinal Analysis of Change in Mammographic Density in Each Breast and Its Association With Breast Cancer Risk. JAMA Oncol 2023;9(6):808-814. (In English). DOI: 10.1001/jamaoncol.2023.0434. 2. Burton A, Maskarinec G, Perez-Gomez B, et al. Mammographic density and ageing: A collaborative pooled analysis of cross-sectional data from 22 countries worldwide. PLoS Med 2017;14(6):e1002335. DOI: 10.1371/journal.pmed.1002335. Citation Format: Graham A. Colditz, Debbie L. Bennett, Shu Jiang. Longitudinal latent class analysis to further understand trajectory of density over time and risk of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4867.

JAMA Oncology—The Year in Review, 2023

JAMA Oncology—The Year in Review, 2023

Paclitaxel protein bound (A) plus gemcitabine (G) plus cisplatin (C) and hydroxychloroquine (HCQ) neoadjuvant therapy for localized pancreatic ductal adenocarcinoma (PDAC).

667 Background: Neoadjuvant therapy has become the consensus treatment for individuals with locally advanced (LA) and borderline resectable (BR) PDAC. Neoadjuvant therapy for resectable (R) PDAC has been in greater use due to concerns over micro metastases at diagnosis. Typical therapies involve the use of multiagent systemic chemotherapy with or without radiation therapy. In retrospective studies, Cancer Antigen 19-9 (CA 19-9) normalization in borderline resectable (BR) and locally advanced (LA) PDAC has been associated with greater OS. The addition of cisplatin (C) to gemcitabine (G) and paclitaxel protein bound (A), has shown promising clinical data in a previously reported study in advanced PDAC [JAMA Oncol. 2020;6(1):125-132]. HCQ has been shown to target autophagy in PDAC and has demonstrated higher response in combination with GA. We conducted a prospective, phase 2 clinical trial of patients with R, BR, and LA PDAC utilizing a regimen combining A + G + C + HCQ with the primary endpoint of CA 19-9 normalization (NCT04669197). Methods: Eligibility criteria include patients with histologically confirmed R, BR, or LA PDAC, elevated CA 19-9, and a KPS ≥ 70% with normal end organ function. Doses are A 125 mg/m2, G 1000 mg/m2, C 25 mg/ m2 on days 1, 8 of a 21-day cycle (IV) along with HCQ 600 mg po bid. Primary objective is to evaluate CA 19-9 normalization with the neoadjuvant chemotherapy. Secondary objectives are to assess R0 rate, pathologic complete response (pCR), safety and tolerability, radiologic response rate (by RECIST 1.1), and 2 year overall survival (OS) from date of study entry. Exploratory objectives include evaluating imaging biomarkers and vascular involvement by tumor in relation to therapy. Results: To date all planned 12 patients have been enrolled, 11 evaluable. 8 male, 4 female; age range 50 to 76 yo. Patient classifications is 3 R; 4 BR; 5 LAPC. Most common drug related grade (gr) 3-4 adverse events (AEs) are: thrombocytopenia gr 3 27%, gr 4 27%, anemia gr 3 36%, and neuropath gr 3 36%. CA 19-9 normalization occurred in 36% (4/11) who have completed at least 1 cycle of treatment. To date, 3 individuals went to surgery, with 3 achieving R0. Overall response rate in measurable patients is 45% (1CR, 4 PR). Median OS and 2-year survival data are not yet matured. Conclusions: In patients with non-metastatic PDAC, the use of A+G+C+HCQ resulted in a CA 19-9 normalization rate in 36% of individuals. Most patients did not go to surgery. The OS data is maturing. Supported by grants from the HonorHealth Foundation and Marley Foundation. Clinical trial information: NCT04669197 .

Analysis of Health-Related Quality of Life Reporting in Phase III RCTs of Advanced Genitourinary Tumors

Background: As recommended in the European Society for Medical Oncology (ESMO) guidelines, assessment of health-related quality of life (HRQoL) should be a relevant endpoint in randomized controlled trials (RCTs) testing new anticancer therapies. However, previous publications by our group and others revealed a frequent underestimation and underreporting of HRQoL results in publication of RCTs in oncology. Herein, we systematically reviewed HRQoL reporting in RCTs testing new treatments in advanced prostate, kidney and urothelial cancers and published between 2010 and 2022. Methods: We searched PubMed RCTs testing novel therapies in genitourinary (GU) cancers and published in fifteen selected journals (Annals of Oncology, BMC Cancer, British Journal of Cancer, Cancer Discovery, Clinical Cancer Research, Clinical Genitourinary cancer, European Journal of Cancer, European Urology, European Urology Oncology, JAMA, JAMA Oncology, Journal of clinical Oncology, Lancet, Lancet Oncology and The New England Journal of Medicine). We excluded trials investigating exclusively best supportive care or behavioral intervention, as well as subgroup or post hoc analyses of previously published trials. For each RCT, we investigated whether HRQoL assessment was performed by protocol and if results were reported in the primary manuscript or in a secondary publication. Results: We found 85 eligible trials published between 2010 and 2022. Only 1/85 RCTs (1.2%) included HRQoL among primary endpoints. Of note, 25/85 (29.4%) RCTs did not include HRQoL among study endpoints. HRQoL results were non-disclosed in 56/85 (65.9%) primary publications. Only 18/85 (21.2%) publications fulfilled at least one item of the CONSORT-PRO checklist. Furthermore, 14/46 (30.4%) RCTs in prostate cancer, 12/25 (48%) in kidney cancer and 3/14 (21.4%) in urothelial cancer reported HRQoL data in primary publications. Next, HRQoL data were disclosed in primary manuscripts of 12/32 (37.5%), 5/13 (38.5%), 5/16 (31.3%) and 5/15 (33.3%) trials evaluating target therapies, chemotherapy, immunotherapy and new hormonal agents, respectively. Next, we found that HRQoL data were reported in 16/42 (38%) and in 13/43 (30.2%) positive and negative trials, respectively. Finally, the rate of RCTs reporting HRQoL results in primary or secondary publications was 55.3% (n = 47/85). Conclusions: Our analysis revealed a relevant underreporting of HRQoL in RCTs in advanced GU cancers. These results highlight the need to dedicate more attention to HRQoL in RCTs to fully assess the value of new anticancer treatments.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

Fertility and Gonadal Function after First-Line Treatment with Nivolumab-AVD in Hodgkin Lymphoma Patients: An Analysis from the Phase II GHSG Nivahl Trial

Background: First-line treatment of patients with classical Hodgkin lymphoma (HL) with anti-PD1 antibodies in combination with AVD chemotherapy is highly effective across risk-groups. Based on encouraging phase II and ongoing phase III trials, anti-PD1 based first-line treatment may hence soon become a first-line treatment option. To date, no data on fertility and gonadal function after anti-PD1 based first-line HL treatment is available. Herein, we present data on pregnancies and gonadal function in patients treated within the randomized GHSG phase II NIVAHL trial. Methods: NIVAHL enrolled 109 patients aged 18-60 years with first diagnosis of early-stage unfavorable HL to receive either fully concomitant (4xN-AVD; group A) or sequential (4xN, 2xN-AVD, 2xAVD; group B) nivolumab-based 1st-line treatment, each followed by 30Gy involved-site radiotherapy (IS-RT). The primary and final analyses showed excellent efficacy and an acceptable safety profile after 1- and 3-years of follow up; details were previously published (Bröckelmann et al. JAMA Oncol 2020 &amp; JCO 2023). Data on pregnancies and births as well as sexual hormones prior, during and after treatment were collected via standardized case report forms. The cohort for this descriptive analysis included women &amp;lt;40 and men &amp;lt;50 years of age. Results: A total of 87 patients (55% female, 51% treatment group A) with a median age of 25 (range 18-49) were eligible for this analysis. Patient characteristics were well balanced between treatment groups and patients presented predominantly with stage IIA disease (75.3%) and presence of the risk factors ≥3 nodal areas (75%), elevated ESR (44%) and bulky mediastinal disease (20.2%). Cryopreservation prior start of treatment was performed in 39.6% of female and 74.4% of male patients. With a median follow-up (FU) of 41 months, a total of 11 pregnancies were documented (12.6%; 9 in female patients, 2 in partners of male patients). These resulted in 8 documented live births (2 abortions, 1 missing info), with none using assisted reproductive techniques. In female patients, median hormone levels remained relatively stable from baseline to 12-24 months of FU for FSH (4.7 -&amp;gt; 4.3 U/l), LH (6 -&amp;gt; 7.2 U/l) and AMH (2.3 -&amp;gt; 2.8 ug/l) while an increase of estradiol was observed (53.6 -&amp;gt; 102 ng/l). Similar trajectories of largely stable hormone levels were observed when stratifying female patients by age groups (i.e. 18-29 and 30-39 years). Women ≥30 years presented higher median FSH (6.1 vs 4.7 U/l) and lower estradiol values (48.8 vs 53.6 ng/l) compared to younger women at baseline, however, presented with similar median FSH levels at 12-24 months of FU (4.2 and 4.4 U/l, respectively). In male patients, hormone levels also remained stable from baseline to 12-24 months of FU for FSH (4.2 -&amp;gt; 4.2 U/l), LH (4.1 -&amp;gt; 3.9 U/l), testosterone (4 -&amp;gt; 5.6 ug/l) and inhibin B (159.4 -&amp;gt; 180 ng/l). More detailed analyses regarding hormonal trajectories of individual patients and stratifications by treatment group are ongoing and will be presented at the meeting. Conclusion: This analysis of pregnancies, births and sex hormones after first-line HL treatment with N-AVD indicates preserved gonadal function in the majority of both female and male patients.