Prior Lines Of Systemic Chemotherapy Research Articles

Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Patient-reported outcomes (PROs) from the TROPION-Breast01 study.

1006 Background: In the primary analysis of the Phase 3 TROPION-Breast01 study (NCT05104866), Dato-DXd showed a statistically significant and clinically meaningful improvement in progression-free survival vs investigator’s choice of CT (ICC) (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001) (Bardia et al, ESMO 2023). Here we report PROs from TROPION-Breast01. Methods: Patients with inoperable or metastatic HR+/HER2‒ BC, with disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1‒2 prior lines of systemic CT, were randomized 1:1 to Dato-DXd (6 mg/kg Q3W, n=365) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine, n=367). PROs were measured at prespecified timepoints, including secondary PRO endpoints of time to deterioration (TTD) in global health status (GHS)/QoL, physical functioning, and pain based on EORTC QLQ-C30, and exploratory PRO endpoints based on additional questionnaires. Results: PRO questionnaire compliance was 82.5% at baseline in both arms and remained similar across arms over time. TTD was delayed in Dato-DXd vs ICC arms for all secondary endpoints. In an analysis of time to first deterioration (primary analysis), median TTD (HR [95% CI]) in GHS/QoL was 3.4 vs 2.1 months (0.85 [0.68–1.06]), physical functioning was 5.6 vs 3.5 months (0.77 [0.61–0.99]), and pain was 3.5 vs 2.8 months (0.85 [0.68–1.07]); in an analysis of time to confirmed deterioration (sensitivity analysis), median TTD in GHS/QoL was 9.0 vs 4.8 months (0.76 [0.58–0.98]), physical functioning was 12.5 vs 6.2 months (0.77 [0.59–1.01]), and pain was 9.0 vs 5.5 months (0.72 [0.55–0.94]). The Table shows TTD in other selected functioning and symptom scales from EORTC. Patient-reported symptomatic AEs (measured by PRO-CTCAE and EORTC) were generally consistent with clinician-reported safety data, and patient-reported treatment tolerability (measured by PGI-TT) was comparable between arms. Conclusions: In TROPION-Breast01, TTD was delayed in the Dato-DXd vs ICC arms for GHS/QoL, physical functioning, pain, and most other symptoms and functioning scales. PRO data complement the improvement in efficacy and manageable safety profile demonstrated with Dato-DXd vs ICC in the primary analysis, supporting Dato-DXd as a potential new, well tolerated therapeutic option in this setting. Clinical trial information: NCT05104866 . [Table: see text]

Abstract GS02-01: Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs >12 months), prior use of endocrine therapy in the metastatic setting ( <6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [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 GS02-01.

TROPION-Breast01: Datopotamab deruxtecan vs chemotherapy in pre-treated inoperable or metastatic HR+/HER2- breast cancer.

Improving the prognosis for patients with metastatic HR+/HER2- breast cancer remains an unmet need. Patients with tumors that have progressed on endocrine therapy and/or are not eligible for endocrine therapy had limited treatment options beyond chemotherapy. Antibody-drug conjugates are a novel and promising treatment class in this setting. Datopotamab deruxtecan (Dato-DXd) consists of a TROP2-directed humanized IgG1 monoclonal antibody attached via a serum-stable cleavable linker to a topoisomerase I inhibitor payload. TROPION-Breast01 is an ongoing phase III study that is evaluating the efficacy and safety of Dato-DXd compared with investigator's choice of standard-of-care chemotherapy in patients with inoperable or metastatic HR+/HER2- breast cancer who have received one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. Clinical Trial Registration: NCT05104866 (ClinicalTrials.gov).

Phase I/II study of PexaVec in combination with immune checkpoint inhibition in refractory metastatic colorectal cancer

BackgroundOncolytic immunotherapy represents a unique therapeutic platform for the treatment of cancer. Here, we evaluated the safety and efficacy of the combination of pexastimogene devacirepvec (PexaVec) plus durvalumab (anti-programmed death...

TLD-1, a novel liposomal doxorubicin, in patients (pts) with advanced solid tumors: Dose escalation and expansion part of a multicenter open-label phase I trial (SAKK 65/16).

3027 Background: TLD-1 is a novel liposomal doxorubicin that compared favorably to conventional liposomal formulations of doxorubicin in preclinical in vivo mouse breast cancer models. This phase I first-in-human trial is aiming to determine the recommended phase II dose (RP2D), toxicity profile, pharmacokinetics and preliminary activity. Methods: Patients with a maximum of 3 prior lines of systemic chemotherapy and preferably anthracycline-sensitive disease were eligible. TLD-1 was administered on day 1 iv over 60-90 minutes (depending on individual dose) q 21 days, for up to 6 or 9 cycles (according to prior anthracycline-exposure) with premedication of 8mg dexamethasone. Dose escalation with dose levels (DL) 1-7 of 10, 16, 23, 30, 35, 40 and 45mg/m2 started with an accelerated titration design, treating one pt at each DL up to DL6 (40mg/m2) followed by a modified continual reassessment method at DL7 due to observed toxicity. Results: 30 pts (F:M = 24:6) have been treated, one each at DLs 1-6, 15 pts at DL7 and an additional 9 pts at DL6. Most frequent tumor types included breast (n = 13), ovarian (n = 6), cervical cancer (n = 2) and cholangiocarcinoma (n = 2). Median age was 67.5 years (range:38-83), 13 pts were exposed to prior anthracyclines. The median number of cycles was 4 (range:1-9). No dose-limiting toxicities (DLT) occurred during cycle 1. At DLs 1 to 5, no treatment-related G3 AEs (TRAE) were observed. At DL6, there was one case of mucositis G3, one of palmar-plantar-erythrodysesthesia (PPE) G3 and one of anemia and neutropenia G3 each. One patient with pre-existing valvular cardiopathy developed symptoms of heart-failure G3 after 8 cycles. Echocardiography showed severe mitral regurgitation with normal LV-EF. In addition one case of urinary-tract infection G3 was seen. Dose-modifications or -delays due to AEs occurred in 7/50 cycles. At DL7, one case of mucositis G3, 3 events of PPE G3 and one case of fatigue G3 were reported. In addition, one case of infection with shingles occurred. Dose-modifications or -delays due to AEs occurred in 12/61 cycles. Shingles and heart failure were reported as SAEs. All toxicities listed above were categorized as TRAE. 29/30 pts were evaluable for response. Three breast cancer pts had a partial response, 2 at DL7 and 1 at DL6, 14 pts had stable disease. Conclusions: No DLT was observed up to DL7. RP2D was defined at 40mg/m2 due to cumulative PPE G3 at DL7. The trial is ongoing with a comparative PK-part evaluating the two iv liposomal formulations of doxorubicin TLD-1 and Caelyx. Clinical trial information: NCT03387917.

Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial

Vaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.

A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing metastatic pancreatic adenocarcinoma (PDAC).

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .

Gls-010, a novel anti-PD-1 mAb in Chinese patients with recurrent or metastatic cervical cancer: Results from a multicenter, open-label and single-arm phase II trial.

6032 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase I study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase II Dose (RP2D). This Phase II clinical trial is aimed to further evaluate the safety and anti-tumor activity of GLS-010 in patients with recurrent or metastatic cervical cancer. Methods: PD-L1 positive (combined positive score (CPS) ≥1) patients with recurrent or metastatic cervical cancer who had received one or more lines of chemotherapy were enrolled and received GLS-010 240mg every 2 weeks. Primary endpoint was the objective response rate (ORR) per RECIST 1.1, secondary endpoints included duration of response (DoR) and safety. Results: From May 16th 2019 to December 24th 2019, 44 pts were enrolled and treated in the study. As of December 24th 2019,the median line of prior systemic chemotherapy was 2(range: 1~4), and 59% (26/44) of pts had received ≥2 previous lines of chemotherapy. The median number of GLS-010 doses was 1.5(range: 1~4). 25 pts received response evaluation per investigator review. With a median follow-up of 2.9 months, 7 of 25 evaluable pts achieved a partial response (PR). The ORR was 28% (95% CI, 12.07-49.39), with 7 pts achieving a PR ( 3 of 7 confirmed), 3 pts achieving stable disease (SD) and 15 pts with progressive disease (PD), 1 of which was assessed as dissociated response with treatment ongoing. Median duration of response had not been reached yet. 33 of 44 patients (75%) experienced one or more treatment-related adverse events (TRAEs) per NCI CTCAE v4.03, most of which were grade 1 or 2. The most common TRAEs were Anaemia (15/44), and 73.3% of them were grade 1 or 2. The most common ≥grade 3 TRAE included Anaemia (4/44). As data cut off, only 1 pt discontinued treatment due to adverse event. Conclusions: GLS-010 showed impressive therapeutic activity and manageable safety profile in Chinese recurrent or metastatic cervical cancer patients. Current evidence support further development of GLS-010 in this and more indications. This trial is still ongoing, and we are looking forward to further results. Clinical trial information: NCT03972722.

Camrelizumab in advanced or metastatic solid tumor patients with microsatellite instability–high/mismatch repair-deficient: Results from an open-label exploratory study.

e15140 Background: PD-1 checkpoint inhibitor has been shown a significant effect in patients (pts) with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumor. Herein, we assessed the efficacy and safety of camrelizumab, a PD-1 checkpoint inhibitor, in advanced or metastatic solid tumor pts with MSI-H/dMMR. Methods: Pts with MSI-H/dMMR solid tumor who had received at least one line of prior systemic chemotherapy were recruited in this single-arm exploratory study. Pts received camrelizumab (200mg, ivd, D1/2W) until disease progression or intolerable toxicity. Response was assessed every 8 weeks. The primary endpoint was objective response rate (ORR) according to RECIST v1.1 criteria. This study was registered at Chinese Clinical Trial Registry, ChiCTR-OIC-17013249. Results: From November 2017 to February 27, 2019, 12 eligible pts were recruited, which covered 9 cancer types. The median age was 58 (range 27-72) years; male/female was 58.3/41.7%. 11 pts were confirmed as MSI-H status, and 1 patient as d-MMR status. All pts were included in efficacy and safety analysis. 2 pts achieved complete response (CR), 6 pts partial response (PR), 4 pts stable disease (SD), yielding the ORR of 66.7% (95% CI: 34.9-90.1), and the disease control rate of 100% (95% CI 73.5-100) at best. What’s more, cancer types of CR pts covered rectal cancer and bladder cancer (1 patient each); PR pts included colon cancer, liver cancer, endometrial cancer, ureteric cancer, intrahepatic cholangiocarcinoma, and small intestine cancer (1 patient each); SD pts contained 3 colon cancer pts and 1 retroperitoneal leiomyosarcoma patient. The overall incidence of adverse incidences (AEs) was 100%. The incidence of Grade ≥3 AEs was 58.3%, which mainly included anemia (16.7%), increased γ-transglutaminase (16.7%), increased alkaline phosphatase (16.7%), increased blood bilirubin (16.7%). As of Oct 30, 2019, 11 pts were still on study medication. Conclusions: Camrelizumab resulted in encouraging objective response and tolerable toxicity in MSI-H/dMMR advanced or metastatic solid tumor. The survival benefits will be further observed. Clinical trial information: ChiCTR-OIC-17013249 .

Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

The effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC. Patients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT. Fifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2. The combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.

THE EFFICACY AND TOLERANCE OF CHIDAMIDE, PREDNISONE, CYCLOPHOSPHAMIDE AND THALIDOMIDE (C‐PCT) IN RELAPSED OR REFRACTORY PERIPHERAL T‐CELL LYMPHOMA: A PILOT STUDY

Introduction: The aim of this study was to evaluate the clinical efficacy and safety of chidamide, prednisone, cyclophosphamide and thalidomide (C-PCT) in relapsed or refractory (R/R) Peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR). Methods: Between June 2015 and September 2016, 12 Chinese patients with R/R PTCL were enrolled in this study. The median age was 52 years (range 28−69). Four patients were males, and 8 were females. Four (33.3%) patients were diagnosed as subtypes of PTCL not otherwise specified (PTCL, NOS), 4 (33.3%) were angioimmunoblastic T-cell lymphoma (AITL), 2 (16.7%) were type II enteropathy-associated T-cell lymphoma (EATL-II), 1 (8.3%) was ALK negative anaplastic large-cell lymphoma (ALK- ALCL) and 1 (8.3%) was cutaneous T-cell lymphoma (CTCL). Majority (11/12, 91.7%) of patients had an Ann Arbor stage III or IV, the only patient with CTCL had a TNMB stage IIB; 75% (9/12) patients had poor performance status, with ECOG 2 or more. The median IPI score was 2 (range 1−5) and 50% of patients had IPI between 3 and 5. The median number of prior systemic chemotherapies was 2 (range 1−4), 10 (83.3%) patients presented with PD to last line of prior systemic chemotherapy at enrollment, 1 was in SD, only 1 achieved PR but failed to autologous stem cell mobilization. C-PCT regimen was administered orally until disease progression or unacceptable toxicity. Results: The median time on treatment was 12 months (range 3–18 months). The ORR was 83.3% (10/12), 5 (41.7%) and 4 (33.3%) patients achieved CR and PR, respectively, 1(8.3%) patients obtained SD and 2 (16.7%) patients presented with PD. The median time to response was 3 months (range 3−6 months). All (100%, 4/4) the AITL patients responded to C-PCT regimen, including 2 CR and 2 PR; Notably, the patient relapsed after autologous stem transplantation (ASCT) achieved PR at 3 months and experienced further CR at 9 months. Approximately 75% (3/4) of PTCL-NOS patients achieved CR and 2 patients of EATL-II achieved PR and SD, respectively. The patient with CTCL progressed to the previous systemic chemotherapies and achieved PR at 3 months. With a median follow-up of 13 (3–18) months, 2 patients relapsed and 3 patients died of PD. The median overall survival (OS) and progression-free survival (PFS) have not been reached. The most common grade 3/4 adverse events were neutropenia (22%), thrombocytopenia (16%) and anemia (20%). Moreover, one patient experienced epstein-barr virus reactivation. Conclusions: C-PCT as salvage therapy was effective with manageable toxicity for patients with R/R PTCL. Further prospective trials are warranted to validate the efficacy of C-PCT in a large cohort of patients. Keywords: Chemotherapy; peripheral T-cell lymphomas (PTCL).

A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.

8521 Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631.

Determinants of patient screen failures in Phase 1 clinical trials

Certain eligibility criteria for Phase 1 cancer clinical trials may impede successful patient enrollment onto a study. We evaluated patient-specific or study-specific reasons for screen failures on Phase 1 oncology clinical trials and discuss factors which may inhibit subject enrollment. Thirty-eight Phase 1 clinical trials for solid tumors meeting eligibility criteria and opened for enrollment between February 2006 and February 2011 at one oncology Phase 1 program were examined. Categorical reasons for screen failures and patients' demographics were examined and compared to characteristics of patients that successfully enrolled on a Phase 1 trial. There were a total of 583 successful Phase 1 enrollment and dose administration events out of 773 Phase 1 consent events (75.4 % dose success rate). The three most common reasons for screen failure were: out of protocol-specified range for chemistry, development of an interval medical issue that precluded proceeding with study participation, and subject declining participation after signing consent. Living further away from the Phase 1 program and receipt of fewer prior lines of systemic chemotherapy were significantly associated with increased screen failures. Screen failures for Phase 1 studies are not uncommon (24.6 %). When a protocol required tumor or host analyte is not required, most screen failures are due to out of protocol-specified range for chemistry or the development of an interval medical issue. Screen failure rates were increased when patients had longer travel distances and fewer prior lines of systemic chemotherapy.

A phase II study of RO4929097 in metastatic colorectal cancer

BackgroundThe Notch signalling pathway is activated in a variety of malignancies and has been implicated in colorectal cancer progression. One of the first steps in the Notch pathway activation is mediated by γ-secretase, a proteolytic enzyme which produces an activated intracellular Notch (ICN). RO4929097 is a selective inhibitor of γ-secretase. We tested the activity of RO4929097 in patients with metastatic, refractory colorectal cancer. Patients and methodsPatients with metastatic colorectal cancer who had received at least two prior lines of systemic chemotherapy were enrolled on the study. Patients were treated with RO4929097 at its recommended phase II dose of 20mg daily, 3days on and 4days off continuously. Cycle length was 28days. Imaging was performed every two cycles. Archival tissue specimens were stained immunohistochemically for components of the notch pathway: Notch1, ICN and the downstream target HES1. ResultsThirty-seven patients were enrolled of whom 33 were evaluable for toxicity and response. Immunohistochemical analysis of archival tissues demonstrated positive staining for the notch receptor as well as intracellular notch and the downstream gene HES1 in the majority of patients. Nevertheless, no objective radiographic responses were observed in this group and only six patients had stable disease as their best response. Median PFS was 1.8months and median overall survival (OS) was 6.0 months. ConclusionIn this study of RO4929097 in patients with refractory metastatic colorectal cancer, no radiographic responses were seen and time to progression was short, which suggests that RO4929097 at the study dose and schedule has minimal single agent activity in this malignancy.

Abstract No. 168: Yttrium 90 resin microspheres as a salvage treatment for colon cancer liver metastases progressing after at least two prior lines of systemic chemotherapy: preliminary results

Retrospective evaluation of the safety and effectiveness of Selective Internal Radiation Therapy (SIRT) using yttrium 90 (Y90) microspheres in patients with colon cancer liver metastases (CLM) who have failed at least two prior lines of systemic chemotherapy.