Median Duration Of Clinical Benefit Research Articles

Abstract PO3-06-10: Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution Study

Abstract Background Sacituzumab govitecan (SG) is approved for treatment of metastatic triple negative breast cancer (mTNBC) in the second line and beyond. Little is known about the real-world outcomes of SG. We aim to evaluate the real-world effectiveness and toxicity outcomes of SG in heterogenous heavily pretreated mTNBC patients (pts) to investigate the consistency of the outcomes in comparison to the clinical trial population. Methods A multi-center retrospective study of pts with mTNBC treated with SG in the US from January 2021 until May 2023 was conducted. Demographics and clinicopathological variables including site of metastases, prior lines of therapy, relative dose intensity (RDI), adverse events (AEs), HER2 immunohistochemistry (IHC) score at time of metastasis, clinical response, clinical benefit rate (CBR) defined as (complete response, partial response (PR) or stable disease (SD) > 6 months) and last follow-up were collected. For continuous variables, Mann-U Whitney and Kruskal Wallis tests were used to compare mean, median, standard deviation, and range. For categorical variables, Fisher's exact tests and Pearson Chi-square tests were used. Univariate and multivariate cox regression models examined RDI and survival outcomes. SAS v9.4 was used to perform statistical analysis at a significance level of 0.05. Results A total of 111 pts were analyzed. The median age was 58 years (range 29-84). The majority of pts were heavily pretreated: 59.1% received >3 prior lines of treatment (Tx) in the metastatic setting, 54.1% received prior immune checkpoint inhibitor (ICI), 8.1% received prior olaparib. 55% of pts had significant disease burden defined by >=3 organs involved by metastatic disease, with 22.5% having brain metastasis at the time of initiation of SG. Of note, 51% had primary refractory disease defined as relapse within 12 months of completion of adjuvant chemotherapy. 98.1% experienced any grade AEs, with the most common being anemia 63.1%. Grade 3 AEs occurred in 51.4% pts with neutropenia being the highest 32.4% followed by anemia 14.4%, diarrhea 7.2% and fatigue 7.2%. Tx interruptions and dose reductions due to AEs occurred in 52.3% of patients and Tx discontinuation rate due to AEs was 11.8%. Elderly pts (defined as >65 years) did not have higher rates of dose reductions due to AEs compared to young pts (< = 65 years) (37.8% vs 59.7 %), p=0.043). The median RDI is 92% (interquartile range (IQR) 33%-100%). The median RDI in elderly pts was 94% (IQR 50%-100%). Among pts in which response was assessed, objective response rate (ORR) was 26.6% (25 pts had PR), and 38.3% had SD. Interestingly, the rate of alopecia was higher in pts who had PR as the best response (28%), compared to 5.6% in pts who had SD, and 3% in progressive disease (PD) p=0.004. The median prior line of therapy in pts who had PR and SD as best response was 2 (IQR 1, 5) (IQR1, 12), respectively, compared to a median of 3 (IQR 1, 7) in pts with PD, p< 0.001. The CBR was 49% (46/94). The median duration of clinical benefit was 7 months IQR (2, 16) with median overall survival of 13 months IQR (2.5, 39) compared to 5.7 months IQR (0.03, 27) in pts without clinical benefit (p< 0.001). 56.9% (62/109) of pts had HER2 low disease and the clinical benefit rate in this subgroup was 14.3% (23/62). Conclusion: In a heavily pretreated cohort, SG retains clinical activity and tolerability in mTNBC. This is reassuring given pts on clinical trials tend to be healthier compared to real-world clinical practice. Citation Format: Sabah Alaklabi, Arya Mariam Roy, Paola Zagami, Nicole Held, Saba Shaikh, Lubna Chaudhary, Yara Abdou, Shipra Gandhi. Real World Outcomes with Sacituzumab Govitecan in Metastatic Triple Negative Breast Cancer Patients: A Multi-Institution 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 PO3-06-10.

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events

IntroductionAs most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. Materials and MethodsICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. ResultsOf 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. ConclusionICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.

Efficacy and safety of tenalisib, a PI3K δ/γ and SIK3 inhibitor, in patients with locally advanced or metastatic breast cancer: Updated results from an on-going phase II study.

1064 Background: Several studies have shown that the upregulation of the PI3K–AKT–mTOR pathway interacts with the Estrogen Receptor pathway and confers endocrine resistance. Elevated Salt Inducible Kinase-3 (SIK3) expression, which often is overexpressed breast cancer, is shown to contribute to tumorigenesis. Tenalisib (RP6530), a highly selective, PI3Kδ/γ and SIK3 inhibitor, has shown promising efficacy in T-cell lymphoma with a distinct safety profile. Tenalisib’s major metabolite, IN0385 is a SIK3 inhibitor. Breast cancer cell line studies have demonstrated that tenalisib potentiated the activity of paclitaxel and doxorubicin. The aim of this phase II study was to investigate the efficacy and safety of single-agent tenalisib in patients (pts) with HR+ HER2- locally advanced or metastatic Breast cancer. Methods: This randomized, open-label study was designed to evaluate two doses (800 mg BID and 1200 mg BID) of Tenalisib in MBC pts (including TNBC) whose disease had progressed following at least one line of therapy. Tenalisib was administered orally daily for every 28 days cycles until the disease progression. The study would enroll forty pts (20 at each dosage level), with the primary outcome being the proportion of patients who did not have disease progression at the end of six months. Other outcomes were investigator-assessed ORR, PFS, DCR (DCR=CR+PR+SD) and Clinical Benefit Rate (CBR= CR+PR+SD≥24 weeks) as per RECIST v1.1 criteria. Results: The trial enrolled 40 pts. Pts had a median of 3 (range 1-7) prior therapies of which, 87% pts had prior endocrine therapy, which included 40% pts treated with an aromatase inhibitor and 30% of pts treated with fulvestrant as their last therapy respectively. Prior chemotherapy in any setting included taxane (60%), and anthracycline (47.5%). The median age was 63.8(31-71) years, 77.5% pts had visceral disease, and 95.0% had 2 or more metastatic lesions. As of 06-Feb-2023, of the 40 pts, 5 pts (12.5%) showed PR and 22 (55%) had SD. The CBR was 57.5% while the DCR was 67.5%. The median duration of response in PR pts and median duration of clinical benefit were 9.36 and 7.46 months respectively. The progression free survival (PFS) was 5.6 months (range: 0.93 to 15.26+ months). Drug related AEs were manageable. The most common AEs (≥10%) of any grade were transaminitis, GGT elevation, and rash. Grade 3/ 4 events were limited to GGT elevation (12.5%), and transaminitis (12.5%). Discontinuations due to related AEs were infrequent (<5%) and limited to two events (one event each of rash and GGT elevation). Conclusions: Based on the data from the ongoing study, tenalisib shows encouraging efficacy as a single agent in pts with relapsed/refractory HR+ HER2- difficult to treat MBC patients. Updated efficacy and tolerability data will be provided at the time of presentation. Clinical trial information: NCT05021900 .

Interim safety and efficacy results from AURELIO-03: A phase 1 dose escalation study of the IL-2/IL-15 receptor βγ superagonist SOT101 as a single agent and in combination with pembrolizumab in patients with advanced solid tumors.

2502 Background: SOT101 (previously SO-C101) is a fusion protein of IL-15 and the IL-15 receptor α sushi+ domain. Synergistic effects of SOT101 and an anti-programmed cell death protein 1 antibody have been validated in various tumor mouse models inducing a protective memory response. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of SOT101 administered subcutaneously were investigated in patients (pts) with advanced solid tumors as monotherapy (Part A) and in combination with pembrolizumab every 3-week cycle (Part B). Dose escalation followed a standard 3+3 design. Data cut-off was 26 January 2022. Results: Overall, 51 pts were treated: 30 in Part A monotherapy at 0.25 to 15 μg/kg SOT101 and 21 in Part B combination therapy (Tx) at 1.5 to 12 μg/kg SOT101. The median (range) number of previous lines of Tx was 3 (1-9) in Part A and 2 (1-6) in Part B. In Part A, 19 (63.3%) pts had previous check-point inhibitor (CPI) Tx, of whom 9 (30 %) were refractory, 5 (16.7%) relapsed. In Part B, 11 pts (52.4%) had previous CPI Tx, and the outcome was 9 (42.9%) pts relapsed, 1 (4.8%) refractory. The most common treatment-emergent adverse events (TEAEs) were transient, and included pyrexia, chills, lymphopenia, anemia, transaminase elevation and vomiting. Most TEAEs were ≤ Grade 2. No treatment-related death was reported. For both monotherapy and combination Tx, the recommended phase 2 dose of SOT101 was determined to be 12 μg/kg. In Part A, in 13 pts at 6 to 12 μg/kg SOT101, the observed clinical benefit rate was 38%. A partial response (PR) was confirmed in 1 pt with skin squamous cell carcinoma, CPI refractory, PR duration 46 days (d), on treatment 154 d. Four pts (all CPI pretreated) had stable disease (SD), range 33-183 d. Final median duration on treatment was 84 d, range 43-183 d. The median duration of clinical benefit was 190 d. In Part B, the observed clinical benefit rate across all SOT101 doses was 63%. A complete response (CR) was confirmed in 1 pt with mesothelioma, CPI naïve, starting at the first tumor assessment, and the pt is ongoing in cycle 5. Three pts, 2 CPI pretreated, had a PR, range 51-232 d, 2 ongoing with PR, and 1 Tx discontinuation while still on PR. Five pts, 3 CPI pretreated, had SD, range 92-340 d, 2 ongoing with SD. The 3 CPI pretreated pts had SD range 41-340 d, 1 pt ongoing. The preliminary median duration on combination Tx was 113 d, range 7-429 d. The preliminary median duration of clinical benefit was 131 d. Conclusions: SOT101 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing CR and several long-lasting PRs were reported in CPI-naïve and CPI pretreated pts, including CPI-resistant tumors. Clinical trial information: NCT04234113.

Immune characterization in platinum resistant ovarian cancer patients treated with pembrolizumab and guadecitabine

Abstract Immune checkpoint inhibitors (ICI) have limited activity in ovarian cancer (OC). Accumulating preclinical and early clinical results support that interventions targeting the epigenome could elicit an inflamed tumor milieu to augment ICI. Here we explore the clinical and biological activity of guadecitabine, a second generation Hypomethylating agents (HMA), given in low dose as a priming strategy before pembrolizumab, a humanized anti-PD1 antibody in a clinical trial for patients with recurrent, platinum-resistant OC. Among 35 evaluable patients, there were 3 partial responses (8.6%) and 8 (22.9%) patients with stable disease, resulting in clinical benefit rate (CBR) of 31.4%. Median duration of clinical benefit was 6.8 months. High dimensional immune profiling of PBMCs showed higher frequency of naive and/or central memory CD4+ T cells and of classical monocytes in patients with durable CBR. Higher baseline density of CD8+ T and CD20+ B cells and presence of tertiary lymphoid structures in tumors were associated with durable CBR. The molecular features such as expression levels of PD-L1 or A2AR linked to therapeutic benefit for resistant OC. Our study provides an in-depth view of the immune milieu of platinum resistant OC and of the effects of the combination of HMAs and pembrolizumab on the interactions between immune cell populations and tumor cells. Supported by USAMRMC/CDMRP (W81XWH170141)

Phase 2 study of anastrozole in rare cohorts of patients with estrogen receptor/progesterone receptor positive leiomyosarcomas and carcinosarcomas of the uterine corpus: The PARAGON trial (ANZGOG 0903)

BackgroundAromatase inhibitors have been used empirically to treat a subset of patients with hormone receptor positive uterine leiomyosarcomas(LMS) and carcinosarcomas (UCS) mainly supported by retrospective data. We evaluated the activity of anastrozole in two rare cohorts; patients with recurrent/metastatic LMS and UCS enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER+)/progesterone receptor positive (PR+) gynecological cancers. MethodAn investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER &/or PR + ve LMS or UCS with measurable disease, treated until progression or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. Results39 eligible patients were enrolled, 32 with LMS and 7 with UCS. For the LMS cohort CBR at 3 months was 35% (95% CI: 21–53%) with a median duration of clinical benefit of 5.8 months. Best response was a partial response in one patient. Two patients remained on treatment for more than one year. The median progression-free survival was 2.8 months (95% CI: 2.6–4.9). For the UCS cohort CBR at 3 months was 43% (95% CI: 16–75%) with a median duration of clinical benefit of 5.6 months. Stable disease was seen in 3 patients but no objective responses were seen. The median progression-free survival was 2.7 months (95% CI, 1.1–8.2). Safety was acceptable with 5/39 evaluable patients showing grade 3 toxicities. ConclusionWhilst objective response rates with anastrozole are low, the clinical benefit rate and good tolerance suggests that aromatase inhibitor therapy may have a role in a subset of patients with metastatic LMS and UCS.

Abstract CT177: A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC)

Abstract Background: Improving outcomes of PDAC with checkpoint inhibitors (CPIs) have been ineffective, underscoring the need to co-target alternative pathways. Preclinical data showed that CXCR4-SDF1 axis modulates the tumor microenvironment (TME) in PDAC and that CXCR4 inhibition enhances T cell access to the TME, increasing tumor sensitivity to CPIs. This was confirmed in the COMBAT Cohort 1 (CC1) study showing that the dual combination M+P increases activated CD8+ T cells and decreases myeloid derived suppressor cells (MDSCs) within the TME. Moreover, our pre-clinical studies showed that adding C to M+P resulted in improved efficacy vs C alone. The COMBAT Cohort 2 (CC2) aims to test the safety and efficacy of the triple combination of M+P+C in 2L mPDAC. Methods: Single arm phase 2a study in mPDAC. In cohort 2, patients with stage IV PDAC at diagnose who had progressed to 1L gemcitabine-based C received 5 days M priming, followed by M BIW + P Q3W plus C [Irinotecan liposomal injection/5-FU/LV (OFL)] Q2W. The primary endpoint was RR. Results: A total of 43 patients with stage 4 PDAC, 98% of whom were diagnosed with stage 4 disease, were enrolled. Median age was 68 (40-85) and 74.4% had liver disease. The safety profile was consistent with the individual profiles of each treatment alone. Of note, the incidence of ≥G3 neutropenia (G3Neu) was 7% and ≥G3 infection was 7%, which is lower than expected for C (OFL) alone (20% and 17%, respectively). The levels of T-cells increased during M priming and returned to normal values, which remained stable across the study despite the OFL treatment. For the evaluable patients (N=38) the ORR was 21.1% with a 13.2% confirmed ORR (defined as two consecutive assessments showing PR) and a 63.2% DCR (PR+SD). Median duration of clinical benefit was 5.6 months. Median OS and PFS were 6.5 months and 4.0 months, respectively (6.6 months and 3.8 months, respectively, for the ITT population). Conclusions: The triple combination of M+P+C is tolerable and shows encouraging results with cORR 13.2%, mPFS 4.0 months and mOS 6.5 months (compared to 7.7%, ~3 months and 4.7 months, respectively, on a historical basis for OFL alone in the stage 4 diagnosis subpopulation). SD of 42.1% and DCR of 63.2% were also higher than historical data on SoC chemotherapy used in 2L patients. The incidence of severe neutropenia and infections is lower than the historical data on C. The results from the CC2 suggest that M+P may expand the efficacy and safety benefit of OFL in PDAC, and warrants further investigation in a randomized study. Citation Format: Manuel Hidalgo, Teresa Macarulla, Valerya Semenisty, Erkut Borazanci, Jaime Feliu, Mariano Ponz-Sarvise, David Gutierrez Abad, Paul Oberstein, Angela Alistar, Andres Muñoz, Ravit Geva, Carmen Guillén-Ponce, Mercedes Salgado Fernandez, Amnon Peled, Marya Chaney, Irit Glicko-Kabir, Liron Shemesh-Darvish, Debby Ickowicz, Ella Sorani, Shaul E. Kadosh, Abi Vainstein-Haras, Bruno Bockorny. A multi-center phase 2a trial of the CXCR4 inhibitor motixafortide (BL-8040) (M) in combination with pembrolizumab (P) and chemotherapy (C), in patients with metastatic pancreatic adenocarcinoma (mPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT177.

Selinexor in combination with weekly paclitaxel in patients with advanced or metastatic solid tumors: Results of an open label, single-center, multiarm phase 1b study.

5565 Background: Selinexor is a first-in-class novel, oral potent selective inhibitor of nuclear export (SINE) which blocks Exportin-1 (XPO1) leading to nuclear accumulation and activation of tumor suppressor proteins and prevention of translation of proto-oncogenes. Weekly paclitaxel is a standard chemotherapy regimen used in various tumor types. Preclinical models show that selinexor with paclitaxel exerts antitumor activity against multiple solid tumors. Our objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of selinexor and weekly paclitaxel. Methods: This was an open label, single-center, multi-arm phase 1b study utilizing a “3 + 3” design and a “basket type” expansion. Selinexor (twice weekly orally) and weekly paclitaxel (80mg IV 2 week on, 1 week off) was employed as one of 13 parallel arms. Two dose levels (DL) of selinexor were explored: DL1 selinexor 60mg; DL2 selinexor 80mg. Patients (pts) with advanced or metastatic solid tumors were eligible if they had adequate bone marrow and organ function. There was no limit on prior lines of therapy. Efficacy was evaluated using RECIST 1.1. Progression free survival (PFS) was defined as time from treatment until disease progression or death. Results: Of 35 pts treated, all were evaluable for toxicity, and 31 (88%) were evaluable for response. Pt diagnoses included ovarian (n = 28), breast (n = 4), prostate (n = 2), and cervical (n = 1) cancer. Pts had a median of four prior therapies (range 1-10), and 47% had a prior taxane. All pts with ovarian cancer had platinum resistant/refractory disease; high grade serous histology was most common. There were no DLTs and DL1 was chosen as the RP2D given its long term tolerability. 97% of pts had at least one treatment-emergent adverse event (TEAE) and the most common TEAEs were anemia (74%), nausea (57%), fatigue (51%), leukopenia (51%), neutropenia (49%), thrombocytopenia (46%), and vomiting (31%). The most prevalent grade ≥ 3 TEAE were neutropenia (46%), anemia (31%), leukopenia (17%), and fatigue (9 %). Partial responses (PR) were noted in 4 pts (13%); 10 pts (32%) achieved stable disease for > 4 months for a clinical benefit rate (CBR) of 45%. 16 pts (47%) had prior exposure to a taxane, including 1 pt who achieved PR. Among 24 evaluable pts with ovarian cancer, response rate was 17%, CBR was 58%, and PFS was 6.83 months (95% CI 3.73, not reached (NR)). Median duration of clinical benefit in ovarian cancer was 7.57 months (95% CI: 4.43, NR). Conclusions: Oral selinexor in combination with weekly paclitaxel demonstrated promising clinical activity with manageable toxicity, and further evaluation with once weekly selinexor is warranted. This combination should be considered for further exploration in a randomized study, especially in ovarian malignancies. Clinical trial information: NCT02419495.

Abstract PD8-10: Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer - final results from an international Phase 2 randomized study

Abstract Introduction: Hormonal agents remain the most effective therapies for estrogen receptor positive (ER+) HER2- breast cancer. The androgen receptor (AR) is the most highly expressed steroid receptor found in up to 95% of ER+ breast cancer patients. Androgen agonists have antiproliferative activity in ER+ breast cancer and have been used in treatment, however their lack of availability and virilizing side effects have limited their use. Enobosarm is a non-steroidal tissue-selective AR modulator that that is being developed for AR targeted treatment of ER+/AR+ breast cancer. Methods: An international, Phase 2, open label, parallel design, randomized study was conducted in 136 patients (pts) to investigate the efficacy and safety of enobosarm in postmenopausal women with metastatic ER+/AR+ breast cancer that progressed on previous endocrine therapy. Pts were randomized to receive 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. The primary endpoint was clinical benefit rate (CBR) at 24 weeks (defined as CR, PR or SD) by RECIST 1.1. Secondary endpoints included objective response rate, best overall response rate (BOR), progression free survival (PFS), duration of clinical benefit. Results: The study population consisted of heavily pre-treated pts with a mean of 4 (range 1-6) prior hormone therapies and >90% receiving one prior course of chemotherapy. Median age was 60.8 years (35-83) for 9 mg and 62.1 (42-81) for the 18 mg cohort. AR positivity was centrally confirmed in 73.6% and 81.2% in the 9 and 18 mg cohorts, respectively. Efficacy: In the evaluable pts, 50 in the 9 mg arm and 52 in the 18 mg arm (AR confirmed), 32% of the 9mg cohort met the primary endpoint of CBR at 24 weeks (95% CI, 19.5%; 46.7%) and 29% (95% CI, 17.1%; 43.1%) in the 18 mg cohort. The BOR was 2 CRs, 10 PRs in the 9 mg and 3 CRs,7 PRs in the 18 mg group by central review. Median PFS was 5.6 (2.9 to 27.5) and 4.2 (2.8 to 11) months (mo) in the 9 mg and 18 mg groups. The median duration of treatment was 4.0 months (0.23-30.3 months) in the 9 mg group and 3.8 months (0.5-16.7 months) in the 18 mg group. At the time the study was terminated, the median duration of clinical benefit was not reached (NR) in the 9 mg group (range 8.2 mo to NR) and 14.1 mo (range 11.0 to 16.5) in the 18 mg group. QOL: Using a standardized instrument of generic health status (EQ-5D), a significant percentage of pts reported improvement in measurements including mobility (40%, 50%), anxiety/depression (50%, 29%) and pain discomfort (50%, 31%) for the 9 and 18 mg groups, respectively. Drug related severe adverse events (SAEs) (Grades 3-4) were observed in 6 (8.0%) at the 9 mg and 10 (16.4%) at the 18 mg dose. The SAEs (Grade 3-4) attributed to the study drug by the site investigator were for the 9 mg group: fatigue (1), elevated transaminases (2), headache (1), hypercalcemia (2) and anemia (1). For the 18 mg group the drug attributable SAEs (Grade 3-4) were: dry mouth (1), increased aminotransferase (2), decreased white blood cell count (1), fatigue (2), hypercalcemia (1), decreased appetite (1), headache (1), tumor flare (2), agitation (1), lymphadenopathy (1) and acute kidney injury (1). Conclusions: In this Phase 2 parallel design study, enobosarm (9 mg and 18 mg) has significant clinical activity and was well tolerated in heavily pretreated patients with ER+/AR+ metastatic breast cancer. Given the limited options of hormonal therapy for metastatic ER+ breast cancer, enobosarm merits further clinical development in a Phase 3 clinical program as an AR targeted treatment for metastatic ER+AR+ breast cancer. Citation Format: Carlo Palmieri, Hannah Linden, Stephen Birrell, Elgene Lim, Lee S Schwartzberg, Hope S Rugo, Patrick Cobb, Kirti Jain, Charles Vogel, Joyce A O’Shaughnessy, Robert H Getzenberg, Mitchell S Steiner, Adam Brufsky, Beth Overmoyer. Efficacy and safety of enobosarm, a selective androgen receptor modulator, to target AR in women with advanced ER+/AR+ breast cancer - final results from an international Phase 2 randomized study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD8-10.

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

Real-world assessment of response to anti-programmed cell death 1 therapy in advanced cutaneous squamous cell carcinoma

Prospective observational trial of low-dose skin electron beam therapy in mycosis fungoides using a rotational technique

Low-dose total skin electron beam therapy provides a durable treatment response for skin lesions caused by cutaneous T-cell lymphoma. We prospectively assessed the durability of response and quality of life for patients receiving low-dose total skin electron beam therapy using a novel rotational technique and dosing regimen. Patients completed baseline Skindex-29 quality-of-life surveys and had baseline Modified Severity-Weighted Assessment Tool score recorded. Patients received 12Gy in 12 fractions with a dual-field rotational technique. The primary outcome was overall response rate, with the secondary outcomes being time to treatment response, duration of clinical benefit, and quality-of-life change. We enrolled 20 patients and recorded an overall response rate of 90%. The median time to treatment response was 6.5weeks. The baseline Modified Severity-Weighted Assessment Tool score was 55.6 and it declined to a median of 2.2 at last follow-up (P<.001). The median duration of clinical benefit was 21months. There was a decline in the Skindex-29 total score and every subdomain when each follow-up visit was compared (P=.004). This prospective study demonstrated a very high overall response rate and improvement in skin-related quality of life. Low-dose rotational total skin electron beam therapy can be implemented routinely in clinical practice.

Prospective observational trial of low-dose skin electron therapy in mycosis fungoides using rotational technique.

e22077 Background: Low dose total skin electron therapy (TSET) utilizing 12 Gy in 12 fractions has been shown to provide a durable treatment response for dermal lesions caused by mycosis fungoides secondary to cutaneous T cell lymphoma (CTCL). We sought to prospectively assess the durability of response and quality of life (QOL) for patients receiving low dose TSET using the rotational technique technique. Methods: We prospectively enrolled patients with CTCL on an IRB approved study from 2016 to 2019 who had pathologically confirmed CTCL from stage IB-III. Patients completed a baseline validated Skindex-29 survey encompassing 29 questions assessing QOL. Physicians graded the appearance of the skin using the modified severity-weighted assessment tool (mSWAT) at baseline. Patients received 12 Gy in 12 Fractions on consecutive dates and patients were treated with a dual field rotational technique. The mSWAT was reassessed on ensuing follow-up visits along with the Skindex. The primary outcome was overall response rate with the secondary outcomes being time to treatment response, duration of clinical benefit (time to requiring an additional intervention), as well as improvements in Skindex questionnaire items. Results: We enrolled 20 patients and recorded an overall response rate (ORR) of 90% with four complete responses. The time to treatment response was 9.7 weeks. While the baseline mSWAT was 55.6 it declined to a median mSWAT of 2.2 at last follow-up (p &lt; 0.001) with there being a median decline of nearly 97% in the scores. The median duration of clinical benefit was 15.7 months. There was a precipitous decline in the Skindex total score and every subdomain when comparing each follow-up visit (p = 0.004) with post-hoc analysis demonstrating the decline between the baseline visit and first follow-up as the primary driver of the decline (p &lt; 0.0001). Conclusions: This prospective study demonstrates the subjective and objective clinical benefits of utilizing low dose TSE with a dual beam rotational technique. This control rates and QOL will continue to be observed for ongoing feasibility as a treatment modality.

Metronomic chemotherapy of cyclophosphamide plus methotrexate for advanced breast cancer: Real‐world data analyses and experience of one center

BackgroundReal‐world data of the CM regimen [cyclophosphamide (CTX) plus methotrexate (MTX)] in metronomic pattern for advanced breast cancer is limited to small‐sample or retrospective studies. This study was aimed to determine the effectiveness and safety of CM regimen in treating advanced breast cancer and to identify which patients are most likely to benefit from metronomic CM regimen.MethodsPatients with advanced breast cancer who received the metronomic CM regimen at least once between January 2009 and February 2019 in Sun Yat‐sen University Cancer Center were included. Clinicopathological characteristics were collected. Overall survival (OS) and progression‐free survival (PFS) were assessed using Kaplan‐Meier estimates. Characteristics between patients with PFS < 6 months and ≥6 months were compared using the Chi‐square test. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for PFS and OS.ResultsA total of 186 patients were included. The median age and follow‐up were 49 years and 13.3 months, respectively. Over 50% of the patients were estrogen receptor/progesterone receptor‐positive, and 60.8% had been heavily treated (≥3 lines). The objective response rate was 3.8%, the disease control rate at 12 weeks was 41.4%, and the clinical benefit rate at 24 weeks was 31.2% (58/186). The median PFS was 4.0 months [95% confidence interval (CI): 3.6‐4.7 months], the median duration of clinical benefit was 9.5 months (95% CI: 8.2‐10.8 months), and the median OS was 26.8 months (95% CI: 20.9‐37.7 months). Multivariate analysis for PFS revealed the CM regimen as maintenance therapy and no liver metastasis as favorable prognostic factors. Furthermore, patients without liver metastasis were more likely to have a PFS over 6 months than those with liver involvement (P = 0.022). Liver, lymph node, and brain metastases were unfavorable prognostic factors for OS. The CM regimen was well‐tolerated without newly reported adverse events.ConclusionsThe CM regimen was effective in selected patients. In clinical practice, it would be better used as maintenance therapy and in patients without liver metastasis. Further follow‐up investigation should be performed to examine its effect when used in combination with other treatments and determine predictive biomarkers.

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

Evaluating Luspatercept Responders in the Phase 3, Randomized, Double-Blind, Placebo-Controlled BELIEVE Trial of Luspatercept in Adult Beta-Thalassemia Patients (Pts) Who Require Regular Red Blood Cell (RBC) Transfusions

Evaluating Luspatercept Responders in the Phase 3, Randomized, Double-Blind, Placebo-Controlled BELIEVE Trial of Luspatercept in Adult Beta-Thalassemia Patients (Pts) Who Require Regular Red Blood Cell (RBC) Transfusions

Assessment of Longer-Term Efficacy and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled MEDALIST Trial of Luspatercept to Treat Anemia in Patients (Pts) with Revised International Prognostic Scoring System (IPSS-R) Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

Assessment of Longer-Term Efficacy and Safety in the Phase 3, Randomized, Double-Blind, Placebo-Controlled MEDALIST Trial of Luspatercept to Treat Anemia in Patients (Pts) with Revised International Prognostic Scoring System (IPSS-R) Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions

PARAGON: A Phase II study of anastrozole in patients with estrogen receptor-positive recurrent/metastatic low-grade ovarian cancers and serous borderline ovarian tumors

ObjectiveTreatment options are limited for patients with recurrent/metastatic low-grade ovarian cancers (LGOCs) and serous borderline ovarian tumors (SBOTs) as response rates to chemotherapy are low. A subset of patients appears to derive clinical benefit from antiestrogens, but most studies have been retrospective and clinical benefit rates (CBR) remain uncertain. The primary aim of PARAGON was to prospectively investigate the CBR of anastrozole, an aromatase inhibitor, in patients with estrogen receptor (ER) and/or progesterone receptor (PR) positive LGOC and SBOT. MethodsPost-menopausal women with ER-positive and/or PR-positive recurrent/metastatic LGOCs and SBOTs and evaluable disease by RECIST v1.1 or GCIG CA125 criteria were treated with anastrozole 1 mg daily until progression or unacceptable toxicity. ResultsThirty-six patients were enrolled. Clinical benefit at 3 months (primary endpoint) was observed in 23 patients (64%, 95% CI 48%–78%) and was similar at 6 months (61%, 95% CI 43%–75%). The median duration of clinical benefit was 9.5 months (95% CI 8.3–25.8). Best study response was partial response by RECIST in 5 patients (14%), stable disease in 18 patients (50%) with progressive disease in 13 patients (36%). Median PFS was 11.1 months (95% CI 3.2–11.9). Anastrozole was well-tolerated. Patients with evidence of clinical benefit at 3 months reported less pain, fatigue, and improved physical and role functioning as early as 1 month of commencing treatment. ConclusionsAnastrozole was associated with a CBR of 61% of patients with recurrent ER-positive and/or PR-positive LGOC or SBOT for at least 6 months with acceptable toxicity.

Phase 2 study of anastrozole in recurrent estrogen (ER)/progesterone (PR) positive endometrial cancer: The PARAGON trial – ANZGOG 0903

BackgroundThe clinical benefit rate with aromatase inhibitors and the impact of treatment on quality of life (QOL) in endometrial cancer is unclear. We report the results of a phase 2 trial of anastrozole in endometrial cancer. MethodsInvestigator initiated single-arm, open label trial of anastrozole, 1 mg/d in patients with ER and/or PR positive hormonal therapy naive metastatic endometrial cancer. Patients were treated until progressive disease (PD) or unacceptable toxicity. The primary end-point was clinical benefit (response + stable disease) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life (QOL) and toxicity. ResultsClinical benefit rate in 82 evaluable patients at 3 months was 44% (95% CI: 34–55%) with a best response by RECIST of partial response in 6 pts. (7%; 95% CI: 3–15%). The median PFS was 3.2 months (95% CI: 2.8–5.4). Median duration of clinical benefit was 5.6 months (95% CI: 3.0–13.7). Treatment was well tolerated. Patients who had clinical benefit at 3 months reported clinically significant improvements in several QOL domains compared to those with PD; this was evident by 2 months including improvements in: emotional functioning (39 vs 6%: p = 0.002), cognitive functioning (45 vs 19%: p = 0.021), fatigue (47 vs 19%: p = 0.015) and global health status (42 vs 9%: p = 0.003). ConclusionAlthough the objective response rate to anastrozole was relatively low, clinical benefit was observed in 44% of patients with ER/PR positive metastatic endometrial cancer and associated with an improvement in QOL.

Response rate to chemotherapy after disease progression with anti-PD-1/PD-L1 in metastatic cancer.

e14088 Background: The checkpoint inhibitor (CPI) immunotherapy class of drugs is redefining how we treat cancer. The US FDA has approved CPI drugs as 1st, 2nd or salvage line after progression on conventional chemotherapy (CTX) for multiple cancers including melanoma, lung, bladder and other cancers. However, many questions remain regarding optimal treatment post-progression. Indeed, it has been noted that the patterns of response and relapse to CPI agents are quite different from those of standard cytotoxic agents and that response to CTX AFTER CPI may be different than in the de novo setting. The purpose of this retrospective analysis is to evaluate the activity (response rate (RR), response duration (DOR) and progression free survival (PFS)) of subsequent CTX after disease progression following treatment with CPI. Methods: In this analysis, patients (pts) were enrolled under an IRB approved waiver of consent. We identified pts treated with CPI agents between Jan, 2011 and Dec, 2018 at a multi-site community cancer program who received subsequent CTX as a result of disease progression (PD). We assessed the RECIST RR to subsequent therapy, DOR from onset of response, and PFS from the onset of post CPI CTX, identifying index lesions from the most recent pre-treatment anatomic scan. Results: A total of 47 cases satisfying the above criteria were found; 31 NSCLC, 8 melanoma, 1 SCLC, 1 GEJ, 1 gastric, 2 head/neck, 1 large cell neuroendocrine tumor, 2 bladder cancer. 25 pts had PD as best response to post-CPI CTX. 9 pts (19%) achieved a partial response (PR) with a median DOR of 99 days. 22 pts achieved a PR or stable disease (SD) for a clinical benefit (CB) rate of 47%. The median duration of CB was 92 days. Of the 9 patients who achieved PR, 5/6 had achieved response to CTX prior to CPI . The median PFS for the entire cohort was 97 days. Conclusions: While an expected RR could not be calculated in this heterogenous group of pts, the number and degree of responses suggests CPI possible “priming” that may enhance response to CTX. Post-CPI CTX may be of value and in this retrospective study of a heterogenous group of pts, responses may be more frequent than expected. A larger further study is warranted.

Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: A nationwide case series of 35 patients in The Netherlands.

BackgroundSalivary duct carcinoma, an aggressive subtype of salivary gland cancer, is mostly androgen receptor‐positive. Only limited data are available on androgen deprivation therapy (ADT).MethodsPatients with advanced androgen receptor‐positive salivary duct carcinoma treated with first‐line ADT were retrospectively evaluated for clinical benefit (ie, partial response [PR] and stable disease, progression‐free survival [PFS] and overall survival [OS]). The OS was compared with patients with advanced salivary duct carcinoma who received best supportive care.ResultsThirty‐four of 35 patients who were ADT‐treated were evaluable: 6 patients had a PR (18%) and 11 had stable disease (32%) leading to a clinical benefit ratio of 50%. The median PFS for the ADT‐treated patients was 4 months and the median duration of clinical benefit was 11 months. The median OS was 17 months versus 5 months in 43 patients receiving best supportive care (P = .02).ConclusionWe recommend ADT in advanced androgen receptor‐positive salivary duct carcinoma given its response and clinical benefit. © 2017 Wiley Periodicals, Inc. Head Neck, 2017