Preliminary efficacy data of platinum-pretreated small cell lung cancer (SCLC) cohort of NCI 9881 study: A phase II study of cediranib in combination with olaparib in advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9065-9065 ◽  
Author(s):  
Joseph W. Kim ◽  
Navid Hafez ◽  
Hatem Hussein Soliman ◽  
Siqing Fu ◽  
Shumei Kato ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Platinum Based Chemotherapy

9065 Background: Cediranib, a pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly-(ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrated clinical efficacy in patients with advanced solid tumors carrying a germline BRCA mutation. We therefore tested the anti-tumor activity of cediranib and olaparib combination in patients (pts) with advanced solid tumors. Here, we report the data from the SCLC cohort. Methods: This multi-institutional, two-stage, phase 2 study enrolled pts with metastatic SCLC previously treated with a minimum of one prior line of platinum-based chemotherapy in advanced setting. Patients were treated with cediranib 30mg po daily plus olaparib 200mg po BID until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST v1.1. Baseline tumor biopsies were obtained for biomarker analyses. Results: Baseline characteristics of the 25 pts enrolled are summarized below. The overall ORR rate was 28% (95% CI: 0.104,0.456). Median duration of response was 3.8 months (mos). Six of 8 pts had an objective response lasting longer than 3 mos up to 10.3 months. Disease control rate (# of pts with CR, PR or SD / # evaluable pts) was 88% (95% CI: 0.75,1.01). Median progression free survival was 4.1 mos (95% CI: 2.3, 6.2). Median OS was 5.5 mos (95% CI: 3.4, NA). Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 14 of 25 (56%). G3/4 AEs occurring in > 10% of pts were hypertension (21%), fatigue (17%) and weight loss (13%). Conclusions: The cediranib/olaparib combination resulted in promising clinical activity with ORR of 28% in biomarker-unselected pts with platinum-pretreated SCLC. The regimen required prompt initiation of antihypertensives, but AEs were overall manageable. Analyses of mutation status in homologous recombination DNA repair genes are going and will be correlated with clinical activity. Clinical trial information: NCT02498613. [Table: see text]

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11036-11036
Author(s):  
John H. Strickler ◽  
Shannon McCall ◽  
Andrew B. Nixon ◽  
Herbert Pang ◽  
Christel Rushing ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Exact Test ◽  
Src Activation ◽  
Expansion Cohort

11036 Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort= 12 pts; colorectal cancer [CRC] expansion cohort= 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]= PR+CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC=0/1); 8 tumors had moderate/strong src-a (IHC≥2). Benign colonic epithelium had no src-a (IHC=0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p =0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p=0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 111-111 ◽  
Author(s):  
Joseph W. Kim ◽  
Rana R. McKay ◽  
Mary-Ellen Taplin ◽  
Nancy B. Davis ◽  
Paul Monk ◽  
...  
Keyword(s):  
Dna Repair ◽  
Radiographic Progression ◽  
Kinase Inhibitor ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Tumor Biopsy

111 Background: Cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly (ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrates clinical efficacy in men with DNA repair deficient, mCRPC. We therefore performed a randomized phase 2 trial comparing olaparib with or without cediranib in men with mCRPC. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive cediranib 30mg po daily plus olaparib 200mg po BID (Arm A) or olaparib 300mg BID alone (Arm B). At radiographic progression, patients (pts) in Arm B could crossover to Arm A. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints were objective response rate (ORR) and PSA50 decline rate (PSA50). Tumor biopsy specimens were obtained for biomarker analyses pre- and on-treatment. Results: Baseline characteristics of the 90 pts enrolled are summarized below. The median rPFS was 11.1 versus 4.0 months in Arm A and Arm B, respectively (Hazard Ratio 0.54, 95% CI 0.317, 0.928, p=0.026). Trends toward a higher ORR (19% and 12%), Disease Control Rate (Stable Disease + Partial Response) (77% and 64%,) and PSA50 (29% and 17%) were observed in Arm A compared to Arm B, respectively. Thirteen pts in Arm B crossed over to Arm A. One pt had a PR after crossover. Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 77% and 58% of Arm A and Arm B pts, respectively. G3/4 AEs occurring in >10% of pts were hypertension (32%), fatigue (23%) and diarrhea (11%) in Arm A, and anemia (16%) and lymphopenia (11%) in Arm B. Conclusions: The cediranib/olaparib combination significantly improves rPFS in unselected, mCRPC pts. AEs were manageable. Analyses of mutation status in homologous recombination DNA repair genes are pending and will be key in interpreting the data. Clinical trial information: NCT02893917. [Table: see text]

Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 440-440 ◽  
Author(s):  
Petros Grivas ◽  
Yohann Loriot ◽  
Susan Feyerabend ◽  
Rafael Morales-Barrera ◽  
Min Yuen Teo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

Safety and activity of the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients (Pts) with molecularly selected advanced cholangiocarcinoma (CCA).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4074-4074 ◽  
Author(s):  
Jean-Charles Soria ◽  
John H. Strickler ◽  
Ramaswamy Govindan ◽  
Seungjean Chai ◽  
Nancy Chan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Performance Status ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 1 Study ◽  
Ecog Performance Status ◽  
Grade 3

4074 Background: Erdafitinib (JNJ-42756493) is a potent, oral pan-FGFR tyrosine kinase inhibitor that demonstrated encouraging preliminary clinical activity and manageable adverse events (AEs) in its first-in-human phase 1 study in advanced solid tumors (NCT01703481). Here we report results from pts with CCA from this study. Methods: This 4-part study enrolled pts age ≥ 18 years (y) with advanced solid tumors. Dose escalation (part 1) followed a 3+3 design, with pts receiving ascending doses of erdafitinib continuously or intermittently (7 days on/7 days off). Subsequent parts required FGFR gene alterations in the tumor, including activating mutations and translocations or other FGFR-activating aberrations. Part 2 was a pharmacodynamics cohort. Parts 3 and 4 were dose-expansion cohorts for recommended phase 2 doses of 9 mg once daily (QD) and 10 mg intermittently, respectively. Results: Eleven pts with FGFR-aberrant CCA were treated at 9 mg QD (n = 1) or 10 mg intermittent (n = 10). Median age was 60 y; 7 of 11 pts were female (64%). 73% of pts had ECOG performance status 1. All had prior systemic therapy. Median treatment duration with erdafitinib was 5.3 months (mo). Systemic erdafitinib exposure, per Cmax and AUC, in CCA pts was similar to other indications. The most common AEs were stomatitis (82%), hyperphosphatemia (64%), dry mouth (55%), dysgeusia (45%), dry skin (45%), and asthenia (45%), mostly grade 1/2 severity. No drug-related grade ≥3 AEs were reported in > 1 pt except grade 3 stomatitis (n = 2; 18%). The objective response rate, all confirmed partial responses (PRs) per RECIST 1.1, was 27.3% (3/11; 95% CI 6, 61); an additional 27.3% (3/11) had stable disease as their best response. Overall disease control rate was 55%. All 3 PRs were at the 10 mg intermittent dosage, and the median duration of response was 12.9 mo. With a median follow-up of 5.1 mo, median progression-free survival was 5.1 mo (95% CI 1.6, 16.4). As of the cutoff date, 2 pts continue on study treatment. Conclusions: Erdafitinib showed encouraging clinical activity and minimal toxicity in pts with advanced CCA and FGFR alterations. These results warrant further study. Clinical trial information: NCT01703481.

Safety and efficacy of PD-1 blockade-activated multiple antigen specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: A pooled analysis of two prospective trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14014-e14014 ◽  
Author(s):  
Lijun Liang ◽  
Yixuan Wen ◽  
Kaiyuan Hui ◽  
Xiaodong Jiang
Keyword(s):  
Solid Tumors ◽  
Cellular Therapy ◽  
Objective Response ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Multiple Antigen ◽  
Before And After

e14014 Background: The cancer-cell-killing property of Multiple Antigen Specific Cellular Therapy (MASCT) may be enhanced by blocking PD-1 in vitro and reversing vascular endothelial growth factor (VEGF)/VEGF receptor 2-mediated immunosuppression with apatinib. We analyzed pooled data from our phase Ⅰ/Ⅱ trials to assess the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in patients with advanced solid tumors. Methods: Patients with selected types of advanced solid tumors received aMASCT alone (n = 32) or aMASCT plus apatinib (500 mg q.d., n = 38) after standard treatment. The primary endpoint was the safety profile; antitumor response, progression-free survival (PFS), and overall survival (OS) were the secondary endpoints. Circulating regulatory T cells (Tregs) were quantified before and after aMASCT infusion. Results: Treatment-related adverse events (AEs) occurred in 18/32 (56.3%) and 25/38 (65.8%) patients in the aMASCT and aMASCT plus apatinib groups, respectively; fever and chills were the most frequently observed AEs. No serious AEs were reported, and apatinib did not increase immunotherapy-related toxicity. The objective response rate was improved with aMASCT plus apatinib group compared with aMASCT group (34.2% and 18.8%, respectively); PFS was longer (median, 6.0 and 4.5 months, respectively, P < 0.05), but OS was not improved (median, 10.0 and 8.2 months, respectively, P = 0.098). Multivariate analyses indicated that two or more cycles of aMASCT treatment was an independent favorable prognostic factor of PFS and OS. Circulating Tregs decreased in both groups after one cycle of aMASCT treatment (P < 0.05). Conclusions: Treatment with aMASCT plus apatinib was safe and effective in advanced solid tumors. Apatinib plus aMASCT may be beneficial for patients with advanced solid tumors. Clinical trial information: NCT02844881; NCT02858232.

scholarly journals Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors

2020 ◽  
Vol 8 (2) ◽  
pp. e001095 ◽  
Author(s):  
Lillian Siu ◽  
Joshua Brody ◽  
Shilpa Gupta ◽  
Aurélien Marabelle ◽  
Antonio Jimeno ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Palliative Radiation ◽  
Cell Counts ◽  
Palliative Radiation Therapy ◽  
Grade 3

BackgroundMEDI9197 is an intratumorally administered toll-like receptor 7 and 8 agonist. In mice, MEDI9197 modulated antitumor immune responses, inhibited tumor growth and increased survival. This first-time-in-human, phase 1 study evaluated MEDI9197 with or without the programmed cell death ligand-1 (PD-L1) inhibitor durvalumab and/or palliative radiation therapy (RT) for advanced solid tumors.Patients and methodsEligible patients had at least one cutaneous, subcutaneous, or deep-seated lesion suitable for intratumoral (IT) injection. Dose escalation used a standard 3+3 design. Patients received IT MEDI9197 0.005–0.055 mg with or without RT (part 1), or IT MEDI9197 0.005 or 0.012 mg plus durvalumab 1500 mg intravenous with or without RT (part 3), in 4-week cycles. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics, pharmacodynamics, and objective response based on Response Evaluation Criteria for Solid Tumors version 1.1. Exploratory endpoints included tumor and peripheral biomarkers that correlate with biological activity or predict response.ResultsFrom November 2015 to March 2018, part 1 enrolled 35 patients and part 3 enrolled 17 patients; five in part 1 and 2 in part 3 received RT. The maximum tolerated dose of MEDI9197 monotherapy was 0.037 mg, with dose-limiting toxicity (DLT) of cytokine release syndrome in two patients (one grade 3, one grade 4) and 0.012 mg in combination with durvalumab 1500 mg with DLT of MEDI9197-related hemorrhagic shock in one patient (grade 5) following liver metastasis rupture after two cycles of MEDI9197. Across parts 1 and 3, the most frequent MEDI9197-related adverse events (AEs) of any grade were fever (56%), fatigue (31%), and nausea (21%). The most frequent MEDI9197-related grade ≥3 events were decreased lymphocytes (15%), neutrophils (10%), and white cell counts (10%). MEDI9197 increased tumoral CD8+ and PD-L1+ cells, inducing type 1 and 2 interferons and Th1 response. There were no objective clinical responses; 10 patients in part 1 and 3 patients in part 3 had stable disease ≥8 weeks.ConclusionIT MEDI9197 was feasible for subcutaneous/cutaneous lesions but AEs precluded its use in deep-seated lesions. Although no patients responded, MEDI9197 induced systemic and intratumoral immune activation, indicating potential value in combination regimens in other patient populations.Trial registration numberNCT02556463.

A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3087-3087
Author(s):  
David Michael Jackman ◽  
Opeyemi Jegede ◽  
Marjorie Glass Zauderer ◽  
Edith P. Mitchell ◽  
James Zwiebel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Stable Disease ◽  
Objective Response ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Outcome Analysis ◽  
Clinical Activity ◽  
Match Trial ◽  
Best Response

3087 Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (< 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]

Phase 1/2 study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with solid tumor malignancies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3161-TPS3161
Author(s):  
Ecaterina Elena Dumbrava ◽  
Amit Mahipal ◽  
Xin Gao ◽  
Geoffrey Shapiro ◽  
Jason S. Starr ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mononuclear Cells ◽  
Phase 1 ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Tumor Growth Inhibition ◽  
Advanced Solid Tumors ◽  
Peripheral Blood Mononuclear

TPS3161 Background: The p53 pathway has been implicated in antitumor immunity, including antigen presentation and T-cell proliferation. Loss of p53 function can increase resistance to immunotherapy across many tumor types. Eprenetapopt (eprenet) is a small molecule that stabilizes the folded structure of p53, resulting in activation of mutant p53 and stabilization of wild-type (WT) p53. It also targets the cellular redox homeostasis, resulting in induction of apoptosis in tumor cells. In vivo, mice carrying supernumerary copies of the TP53 gene harbor a pro-inflammatory tumor microenvironment, an effect recapitulated in TP53 normal-copy mice treated with eprenetapopt. Combining eprenetapopt and anti-PD1 or anti-CTLA4 therapy resulted in enhanced tumor growth inhibition and improved survival in TP53 WT mice inoculated with B16 melanoma and MC38 colon adenocarcinoma cells . Based on these results, we hypothesized that eprenet-induced p53 stabilization may augment response to immunotherapy. To test this hypothesis, we are conducting a phase 1b/2 study of eprenet in combination with pembrolizumab (eprenet+pembro) in pts with solid tumors. Methods: The primary objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) and to assess the safety and tolerability of eprenet+pembro in pts with advanced solid tumors. The secondary objectives are to estimate the anti-tumor activity and to describe the pharmacokinetics of the combination. Exploratory objectives include assessing predictive and pharmacodynamic markers of response. The study includes a safety lead-in with a 3+3 dose de-escalation design for pts with advanced solid tumors with known tumor TP53 mutation status ( TP53 WT is acceptable) (max 18 pts), followed by expansion cohorts in pts with NSCLC, gastric/GEJ and urothelial cancer (max 100 pts). In expansion, pts with urothelial and gastric cancers must be naïve to anti-PD-1/ L1 therapy. Eprenet is given IV once daily on Days 1–4 while pembro is administered on Day 3 of each 21-day cycle. The RP2D of eprenet+pembro is considered the dose at which ≤ 1 of 6 pts in a cohort has a dose-limiting toxicity (DLT). Primary endpoints are occurrence of DLTs, adverse events (AEs) and serious AEs with eprenet+pembro. Key secondary endpoints are best objective response, progression free survival and overall survival. Exploratory endpoints include gene mutations by next generation sequencing (including TP53), mRNA expression, multiplex immunohistochemistry and transcriptomics, multiplex flow cytometry on peripheral blood mononuclear cells and cytokines in serum. Continuous monitoring of toxicity will be conducted. The trial opened in May 2020 and is actively enrolling patients. Clinical trial information: NCT04383938.

Response to selpercatinib versus prior systemic therapy in patients (pts) with RET fusion+ non-small-cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9032-9032
Author(s):  
Alexander E. Drilon ◽  
Oliver Gautschi ◽  
Benjamin Besse ◽  
Vivek Subbiah ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Survival Duration ◽  
Prior Therapy ◽  
Platinum Based Chemotherapy ◽  
Systemic Therapies

9032 Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.

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