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CD19 is an important target for novel anti-lymphoma treatments as it is broadly and homogenously expressed across many B-cell malignancies [1,2]. Approximately 30–50% of patients with diffuse large...

MARC‐2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR‐TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR‐TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6‐month progression‐free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3‐81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0‐51.3) overall, 54.4% (95% CI, 35.2‐70.1) vs 23.7% (95% CI, 10.5‐39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26‐0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18‐0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2‐6.2) and 16.8 months (95% CI, 14.3‐24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment‐related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR‐TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most.

Background Infection with SARS‐CoV‐2 leads to COVID‐19, the course of which is highly variable and depends on numerous patient‐specific risk factors. Patients with tumor diseases are considered to be more susceptible to severe COVID‐19; however, they also represent a heterogeneous group of individuals with variable risk. Identifying specific risk factors for a severe course of COVID‐19 in patients with cancer is of great importance. Methods Patients diagnosed with solid tumors or hematological malignancies and PCR‐confirmed SARS‐CoV‐2 infection were included into the multicentric ADHOK (Arbeitsgemeinschaft der Hämatologen und Onkologen im Krankenhaus e.V.) coronavirus tumor registry. Detailed information about the patients’ cancer disease, treatment, and laboratory parameters prior to infection, was collected retrospectively. The outcome of the SARS‐CoV‐2 infection was graded according to the WHO. Results A total of 195 patients (68% with solid neoplasms and 32% with hematological malignancies) were included in the registry. Overall, the course of the SARS‐CoV‐2 infection varied greatly, as 69% of all patients were either asymptomatic or encountered a mild to moderate course, while 23% of the cohort died from COVID‐19. In multivariable analysis, preinfection laboratory parameters (determined at least 10 days and a median of 21 days before the first documentation of SARS‐CoV‐2 infection) significantly correlated with severe course of the disease. Out of these, the absolute neutrophil count prior to infection showed the strongest association with COVID‐19‐related death. Conclusion The course of COVID‐19 in patients with tumor diseases is highly variable. Preinfection laboratory parameters may aid to identify patients at risk for severe COVID‐19 at an early stage prior to infection with the virus. German Clinical Trials Register identification: DRKS00023012., The course of SARS‐CoV‐2 infection in tumor patients is highly variable. Subgroups at risk for severe COVID‐19 are yet imprecisely defined. Laboratory parameters prior to infection, particularly pre‐infection neutrophils, may identify patients at risk for death.

Background: Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G, et al. Lancet Oncol 2020, Duell J, et al. Haematologica 2021). Here, we report the final, 5-year follow-up of L-MIND. Data cut-off was Nov 14, 2022. Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, 1-3 prior systemic therapies (including a CD20-targeting regimen), and ECOG PS 0-2. Tafasitamab (12 mg/kg) was given for up to 12 cycles in combination with LEN (25 mg), then as monotherapy until disease progression (PD) or unacceptable toxicity. The primary endpoint was best objective response rate (ORR; complete response [CR] or partial response [PR], by independent radiology committee). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and incidence and severity of adverse events (AEs). Exploratory analyses evaluated efficacy endpoints by prior lines of therapy (pLoT). Results: Of 81 pts enrolled, 80 were treated (full analysis set [FAS]). The ORR (FAS) of 57.5% [95% CI: 45.9-68.5], with CR of 41.2% [30.4-51.6] (n=33) and PR of 16.2% [8.9-26.2] (n=13), was generally consistent with the primary and 3-year analyses. Median DoR was not reached (NR) with median follow up (mFU) of 44.0 months [29.9-57.0]. Median PFS was 11.6 months [5.7-45.7] (mFU 45.6 [22.9-57.6]) and median OS was 33.5 months [18.3-NR] (mFU 65.6 [59.9-70.3]). At data cut-off, OS was >60 months in 21 pts (18 with best response of CR, 1 PR, 1 stable disease and 1 PD), including 14 with 1 pLoT and 7 with ≥2 pLoT. Pts with 1 pLoT (n=40) in the FAS had higher ORR (67.5%; 52.5% CR [n=21] and 15% PR [n=6]) compared to pts with ≥2 pLoT (n=40; 47.5%; 30% CR [n=12] and 17.5% PR [n=7]). However, median DoR was not reached for both subgroups, indicating similar long-term efficacy for responders. AEs were consistent with previous reports and manageable; incidence declined after transition from combination to tafasitamab monotherapy and again with monotherapy >2 years. Conclusion: The final, 5-year analysis of L-MIND showed prolonged durable responses with tafasitamab + LEN combination therapy, followed by long-term tafasitamab monotherapy, in pts with R/R DLBCL ineligible for ASCT, with median DoR not reached after 44 months mFU. No new safety signals were identified, confirming the tolerability profile observed with earlier data cuts. These long-term data suggest that this immunotherapy may have curative potential that is being explored in further studies. Citation Format: Johannes Duell, Pau Abrisqueta, Marc Andre, Marinela Augustin, Gianluca Gaidano, Eva González Barca, Wojciech Jurczak, Nagesh Kalakonda, Anna Marina Liberati, Kami J. Maddocks, Tobias Menne, Zsolt Nagy, Olivier Tournilhac, Abhishek Bakuli, Aasim Amin, Konstantin Gurbanov, Gilles Salles. Five-year efficacy and safety of tafasitamab in patients with relapsed or refractory DLBCL: Final results from the phase II L-MIND study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT022.

INTRODUCTION AND OBJECTIVE:The phase 1/2 KEYNOTE-365 study (NCT02861573) previously showed that pembro+olaparib was associated with antitumor activity and acceptable safety in molecularly unselecte...

This non-interventional, prospective phase IV trial evaluated trabectedin in patients with soft tissue sarcoma (STS) in real-life clinical practice across Germany. The primary endpoints were progression-free survival (PFS) rates at 3 and 6 months, as defined by investigators. Overall, 128 patients from 19 German sites were evaluated for efficacy and 130 for safety. Median age was 58.5 years (range: 23–84) and leiomyosarcoma was the most frequent histotype (n = 45; 35.2%). Trabectedin was mostly used as second/third-line treatment (n = 91; 71.1%). Median PFS was 5.2 months (95% CI: 3.3–6.7), with 60.7% and 44.5% of patients free from progression at 3 and 6 months, respectively. Median overall survival was 15.2 months (95% CI: 9.6–21.4). One patient achieved a complete and 14 patients a partial response, conferring an objective response rate of 11.7%. Decreases in white blood cells (27.0% of patients), platelets (16.2%) and neutrophils (13.1%) and increased alanine aminotransferase (10.8%) were the most common trabectedin-related grade 3/4 adverse drug reactions. Two deaths due to pneumonia and sepsis were considered trabectedin-related. Trabectedin confers clinically meaningful activity in patients with multiple STS histotypes, comparable to that previously observed in clinical trials and other non-interventional studies, and with a manageable safety profile.

Simple Summary: Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection. Abstract: There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC.

The clinical relevance of comprehensive molecular analysis in rare cancers is not established. We analyzed the molecular profiles and clinical outcomes of 1,310 patients (rare cancers, 75.5%) enrolled in a prospective observational study by the German Cancer Consortium that applies whole-genome/exome and RNA sequencing to inform the care of adults with incurable cancers. On the basis of 472 single and six composite biomarkers, a cross-institutional molecular tumor board provided evidence-based management recommendations, including diagnostic reevaluation, genetic counseling, and experimental treatment, in 88% of cases. Recommended therapies were administered in 362 of 1,138 patients (31.8%) and resulted in significantly improved overall response and disease control rates (23.9% and 55.3%) compared with previous therapies, translating into a progression-free survival ratio >1.3 in 35.7% of patients. These data demonstrate the benefit of molecular stratification in rare cancers and represent a resource that may promote clinical trial access and drug approvals in this underserved patient population. Significance: Rare cancers are difficult to treat; in particular, molecular pathogenesis–oriented medical therapies are often lacking. This study shows that whole-genome/exome and RNA sequencing enables molecularly informed treatments that lead to clinical benefit in a substantial proportion of patients with advanced rare cancers and paves the way for future clinical trials. See related commentary by Eggermont et al., p. 2677. This article is highlighted in the In This Issue feature, p. 2659

10571 Background: Tumor patients (pts.) are considered susceptible to severe COVID-19 after SARS-CoV-2 infection. However, they represent a heterogeneous group of individuals with variable risk. Identification of vulnerable subgroups is important for prioritization of vaccination strategies and possible early therapeutic intervention after infection. Methods: Tumor pts. with PCR-confirmed SARS-CoV-2 infection were included in the multicentric ADHOK registry by 22 institutions. Detailed information about tumor disease and treatment, as well as routine laboratory parameters determined at least 10 days prior to SARS-CoV-2 infection, was collected retrospectively. The primary endpoint was defined as the outcome of the SARS-CoV-2 infection, graded according to the WHO: asymptomatic, mild, moderate, severe, critical, and COVID-19-related death. Results: Until Feb. 5, 2021, 215 pts. (67% with solid tumors, 33% with hematological neoplasms) were included in the registry. 74% of the pts. had an active malignancy. The course of SARS-CoV-2 infection was rather variable: 66% of the pts. remained asymptomatic or showed a mild-to-moderate course, while the rest developed severe or critical disease. The COVID-19-related mortality rate was 24%. Pre-infection routine laboratory values were available for 104 pts., obtained at a median of 21 days before SARS-CoV-2 infection. Compared to COVID-19 survivors, COVID-19 non-survivors showed significantly higher median levels of absolute neutrophil count (ANC: 3.6 vs. 6.4 /nL; p = 0.006, n = 91), neutrophil-to-lymphocyte ratio (NLR: 2.2 vs. 7.2; p = 0.005, n = 75), C-reactive protein (CRP: 9.9 vs. 42.0 mg/L; p = 0.001, n = 104), and lactate dehydrogenase (LDH: 213.0 vs. 267.0 U/L; p = 0.016, n = 78). When categorized by a median split, COVID-19 mortality was significantly higher in pts. with ANC > 4.4 /nL (4% vs. 55%, p < 0.001), NLR > 4.1 (5% vs. 58%, p < 0.001), CRP > 15.4 mg/L (18% vs. 46%, p = 0.003), LDH > 236 U/L (15% vs. 49%, p = 0.003) and lymphocytes < 1.3 /nL (41% vs. 11% p = 0.002). In multivariable analysis, ANC and CRP showed a strong and significant association with COVID-19-related death (OR 23.0 and 7.7, p = 0.007 and 0.029, respectively). To develop an easy-to-apply pre-infection score, we combined ANC and CRP and were able to separate three groups of pts. with significantly different COVID-19 outcomes (p < 0.001) (Table). Conclusions: Our results unveil subgroups of tumor pts. who may be at increased risk of severe COVID-19 and point to pre-infection routine laboratory parameters with potential prognostic power: ANC and CRP may help identify pts. at risk for severe COVID-19 before SARS-CoV-2 infection.[Table: see text]

Context: Tafasitamab, a humanized anti-CD19 antibody, has demonstrated encouraging activity with durable responses with lenalidomide (LEN) in autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the Phase II L-MIND study ( NCT02399085 ). In the primary analysis (cut-off November 30, 2018), the objective response rate (ORR) was 60.0%, median duration of response (DOR) was 21.7 months and median follow-up was 17.3 months. Objective: To report the long-term clinical efficacy and safety of tafasitamab + LEN in the L-MIND study after one additional year of follow-up (cut-off November 30, 2019). Design & Setting: An open-label, single-arm, Phase II study. Patients: Aged ≥18 years with R/R DLBCL (1–3 prior systemic therapies, including ≥1 CD20-targeting regimen), an ECOG performance status 0–2, and ASCT ineligible. Interventions: Tafasitamab (12 mg/kg intravenously, 28-day cycles) was administered once weekly during Cycles 1–3 with a loading dose on Cycle 1 Day 4, then every 2 weeks during Cycles 4–12. LEN (25 mg orally) was self-administered on Days 1–21 of Cycles 1–12. After Cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. Main Outcome Measure(s): The primary endpoint was ORR (independent review committee). Secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), and safety. Results: In this long-term analysis, 80 of 81 enrolled patients received tafasitamab + LEN and were included in the efficacy analysis. ORR was 58.8% (n=47/80); 41.3% (n=33/80) with complete response; and 17.5% (n=14/80) with partial response. Median DOR was 34.6 months (95% confidence interval [CI]: 26.1–not reached [NR]). Median OS was 31.6 months (95% CI: 18.3–NR) with a median follow-up of 31.8 months. Median PFS was 16.2 months (95% CI: 6.3–NR) with a median follow-up of 22.6 months. No unexpected toxicities were reported. Conclusions: After a minimum of two years' follow-up, outcomes are consistent with the primary analysis and confirm the durability of response and meaningful OS of tafasitamab + LEN followed by tafasitamab in ASCT-ineligible patients with R/R DLBCL. Along with an acceptable safety profile, these data support a clinically relevant benefit with this immunological combination.

Objective Measuring the success of molecularly guided therapies is a major challenge in precision oncology trials. A commonly used endpoint is an intra-patient progression-free survival (PFS) ratio, defined as the PFS interval associated with molecularly guided therapy (PFS2) divided by the PFS interval associated with the last prior systemic therapy (PFS1), above 1.3 or, in some studies, above 1.33 or 1.5. Methods To investigate if the concept of PFS ratios is in agreement with actual response evaluations by physicians, we conducted a survey among members of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Programme of the German Cancer Consortium who were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. Results A comparison of classification profiles revealed three distinct clusters of PFS benefit assessments. Only 29% of assessments were consistent with a PFS ratio threshold of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that incorporates the influence of absolute PFS1 intervals on the judgement of clinical benefit by physicians. Application of the modified PFS ratio to outcome data from two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with physician-perceived clinical benefit and identified comparable proportions of patients who benefited from molecularly guided therapies. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials.

5029 Background: Pembro had activity as monotherapy in pretreated advanced mCRPC. Data are presented here from cohort B (pembro + docetaxel/prednisone) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC. Methods: Pts who progressed on or became intolerant to ≥4 wk of abi or enza in the prechemotherapy mCRPC state and progressed within 6 mo before screening were eligible. Pts received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. The primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age, 68 y; visceral disease, 36%; measurable disease, 50%) began pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths from treatment-related AEs (pneumonitis). Most commonly reported immune-mediated AEs were infusion-related reactions (11%) and colitis (10%). Conclusions: Pembro + docetaxel/prednisone has activity in pts with mCRPC who previously progressed on second-generation hormone therapy. AEs were considered mild for the treatment combination. Clinical trial information: NCT02861573. [Table: see text]

5027 Background: Individual activity with pembro or olaparib has been observed in mCRPC pts who progressed on second-generation hormone therapy (HT) and chemotherapy. Data from cohort A (pembro+olaparib) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts with mCRPC who progressed within 6 mo before screening, were docetaxel-pretreated (up to 1 other chemotherapy permitted) for mCRPC and had ≤2 second-generation HTs were eligible. Pts received pembro 200 mg IV Q3W+olaparib 400 mg orally twice daily. Primary end points: safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points: ORR per RECIST v1.1 (investigator review), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, composite response rate, rPFS, and OS. Results: Median (95% CI) follow-up was 11 (6-15) mo. 41 pts initiated treatment (median age, 69 y; visceral disease, 42%; RECIST-measurable, 68%; homologous recombination deficient detected, 0%). Efficacy is outlined in the table. Treatment-related AEs occurred in 39 (95%) pts; most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%). Grade 3-5 treatment-related AEs occurred in 21 (51%) pts. There were 2 deaths; 1 was treatment-related (cause unknown). Conclusions: Pembro+olaparib had activity in pts with mCRPC who were molecularly unselected and were previously treated with docetaxel and second-generation HT. The observed safety profile for the combination is consistent with individual profiles of pembro and olaparib. Clinical trial information: NCT02861573. [Table: see text]

170 Background: Pembro had antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort B combining pembro + docetaxel in mCRPC. Methods: Pts who failed or became intolerant to ≥4 weeks of abi or enza in the pre-chemotherapy mCRPC state received pembro 200 mg IV with docetaxel 75 mg/m2 IV Q3W plus prednisone 5 mg orally twice daily. Pts also progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Response was evaluated by PSA levels Q3W and imaging Q9W for first year and Q12W thereafter. Primary end points: safety and PSA response rate (confirmed PSA decline ≥50%). Key secondary end points: investigator-determined ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 72 pts (median age 68 years; PD-L1+ 29%; visceral disease 36%; measurable disease 50%) initiated pembro + docetaxel. Median (95% CI) follow-up was 10 (8-12) mo. Efficacy is outlined in table below. Treatment-related AEs occurred in 69 (96%) pts; most frequent (≥30%) were alopecia (43%), fatigue (40%), and diarrhea (39%). Grade 3-5 treatment-related AEs occurred in 27 (38%) pts, including 2 deaths due to treatment-related AEs (pneumonitis). Conclusions: Combination of pembro + docetaxel/prednisone has activity in pts with mCRPC previously failing anti-hormonal therapy. Observed safety profile for the combination was consistent with known safety profile of each component. Clinical trial information: NCT02861573. [Table: see text]

5544 Background: Pembro + olaparib has shown antitumor activity and acceptable safety in docetaxel-pretreated pts with mCRPC enrolled in cohort A of the phase I/II KEYNOTE-365 study (NCT02861573). Updated results with new biomarker data are reported. Methods: Pts with docetaxel-pretreated mCRPC who progressed within 6 mo of screening received pembro 200 mg IV Q3W + olaparib 400-mg capsule or 300-mg tablet PO BID. Pts might have received 1 other chemotherapy and ≤2 second-generation androgen-receptor targeted therapies. Primary end points: PSA response rate (decrease ≥50% from baseline, confirmed by a second value ≥3 wks later), ORR per RECIST v1.1, and safety. Key secondary end points: DCR, DOR, rPFS, and OS. Biospecimens (eg, blood, tissue) were collected for biomarker analysis (tissue PD-L1 expression, androgen receptor variant 7 [AR-v7] expression in circulating tumor cells [CTCs], and a T-cell–inflamed gene expression profile [GEP]). ctDNA was analyzed by Guardant Health 360 (GH360) and Omni (GH Omni) assays. FFPE tissue was analyzed by FoundationOne CDx (F1CDx) assay. Results: 84 of 87 enrolled pts were treated; 48/84 (57.1%) had measurable disease. Median (range) time from enrollment to data cutoff was 3.6 mo (0.0-29.2) for all pts and 26.7 mo (21.2-29.2) for 41 pts with ≥27 wks’ follow-up. Confirmed PSA response rate was 9% (95% CI, 3.5-16.8) in 82 pts with a baseline PSA assessment. Median time to PSA progression: 3.8 mo (95% CI, 2.9-4.4). In 24 pts with measurable disease and ≥27 wks’ follow-up, ORR was 8.3% (95% CI, 1.0-27.0; 2 PRs) and DCR ≥6 mo was 20.8% (95% CI, 7.1-42.2). Median (range) DOR was NR (12.0+ to 21.4+ mo); 2 pts had DOR ≥12 mo. In all pts, median rPFS was 4.3 mo (95% CI, 3.4-7.7) and median OS was 14.4 mo (95% CI, 8.1-18.5). Grade ≥3 TRAEs occurred in 29 pts (35%); 2 pts died of TRAEs (1 myocardial infarction, 1 unknown). Overall, 26% had PD-L1+ tumors (combined positive score ≥1). Of 31 pts with CTC data, 12.9% were AR-v7+. No BRCA1/2 mutation was detected by GH360 (n=42). Of 57 pts analyzed by GH Omni, 2 had BRCA2 mutations, 1 had a BRCA1 mutation, 4 had ATM mutations, 1 had a CHEK1 mutation, and 6 had CDK12 mutations. Of 49 pts analyzed by F1CDx, 4 had BRCA mutations; 1 pt had a copy number loss mutation not detected by ctDNA analysis. GEP was not associated with ORR or PSA response. Conclusions: Pembro + olaparib continued to show activity and acceptable safety in pts with docetaxel-pretreated mCRPC. A phase III study of this combination is ongoing (KEYLYNK-010, NCT03834519). Clinical trial information: NCT02861573 .

100 Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study evaluating pembro + other agents in mCRPC. Updated results from cohort A (pembro + olaparib) are reported. Methods: Docetaxel-pretreated, molecularly unselected pts with mCRPC with progression within 6 mo of screening per PSA or radiologic bone/soft tissue progression enrolled. Pts may have received 1 other chemotherapy and ≤2 2nd-generation hormone therapy (HT). Pts received pembro 200 mg IV Q3W + olaparib 400 mg PO BID. Primary end points: safety, PSA response rate (confirmed PSA decline ≥50%), and ORR per blinded independent central review. Results: Of 84 treated pts, 42 discontinued, primarily due to progression (n=29). Median age was 71 y (range, 47-83); 26% were PD-L1+, 26% had visceral disease, and 57% had RECIST-measurable disease. Median follow-up was 3 mo for all pts (n=81) and 14 mo for pts with ≥27 wks’ follow-up (n=41). See Table for efficacy outcomes. Treatment-related AEs occurred in 70 (83%) pts. Most frequent (≥30%) were nausea (33%) and anemia (31%). Grade 3-5 treatment-related AEs occurred in 29 (35%) pts. Three pts died of AEs (2 treatment related [l myocardial infarction, 1 unknown cause]). Conclusions: With additional follow-up, pembro + olaparib continued to show activity in docetaxel-pretreated, molecularly unselected pts who previously received HT for mCRPC. Safety of the combination was consistent with individual profiles of each agent. Clinical trial information: NCT02861573. [Table: see text]

e23559 Background: Radiation therapy is an essential backbone of the management of patients (pts.) with soft tissue sarcoma (STS) as part of a multimodal curative or palliative treatment. Concurrent external-beam radiation therapy (EBRT) and chemotherapy with doxorubicin (doxo) and ifosfamide (ifo) may be indicated as well, but is associated with relevant toxicity. Gemcitabine (gem) is a known radiosensitizer and has shown activity in STS. The purpose of this study was to evaluate the efficacy and toxicity of concurrent EBRT and gemcitabine. Methods: A single center, retrospective analysis of 12 patients (pts) with STS treated with concurrent EBRT and gemcitabine from Nov 2017 to Dez 2019 in a neoadjuvant (6 pts) or palliative setting (6 pts). Gemcitabine (gem) was administered with 150-300mg/m2 once weekly for the duration of the EBRT (50 Gy in 25 fractions over 5 weeks). In the neoadjuvant treated group, 4 pts had undifferentiated pleomorphic sarcoma (UPS) G3, 1 leiomyosarcoma (LMS) G2 and 1 retroperitoneal G1 liposarcoma (LPS). The pts. were either not eligible for a neoadjuvant systemic treatment with doxo/ifo or received the EBRT/gem treatment in addition to it. Results: 5/6 pts. with neoadjuvant EBRT/gem had R0 resection and 1/6pt. R1. The IUCC stage was IIIB in 5/6 pts and IB in 1/6 pt. The tumor regression grade (TRG) was > 99% in 3/4 pts. with UPS G3 (75%) and 80% in 1/4 pt. with UPS G3. The TRG for the G2 LMS and for the G1 LPS was 20%. All pts treated in palliative setting had high grade sarcoma and responded to the treatment with partial remission, the 6 months’ local control rate was 83% (5/6 pts) for symptomatic fast growing lesions, 1/6 pt. being in PR at 4 months follow up. The combination treatment was well tolerated with reversible skin toxicity CTCAE grade I. As expected transient thrombocytopenia was observed without limiting effect on the planned EBRT. Conclusions: The combination therapy of EBRT and gemcitabine as sensitizer in pts. with STS is feasible und well tolerated. The treatment is an option for patients not eligible for neoadjuvant systemic treatment with doxo/ifo and in the palliative setting as well. It might be more potent than radiation only in achieving tumor regression and local control for high grade STS.