Solid Tumor TIL Therapy Is Infiltrating Multiple Centers With Lympho-“sights” Set on Becoming Standard of Care

Abstract Context—Molecular testing of solid tumors is steadily becoming a vital component of the contemporary anatomic pathologist's armamentarium. These sensitive and specific ancillary tools are useful for confirming ambiguous diagnoses suspected by light microscopy and for guiding therapeutic decisions, assessing prognosis, and monitoring patients for residual neoplastic disease after therapy. Objective—To review current molecular biomarkers and tumor-specific assays most useful in solid tumor testing, specifically of breast, colon, lung, thyroid, and soft tissue tumors, malignant melanoma, and tumors of unknown origin. A few upcoming molecular diagnostic assays that may become standard of care in the near future will also be discussed. Data Sources—Original research articles, review articles, and the authors' personal practice experience. Conclusions—Molecular testing in anatomic pathology is firmly established and will continue to gain ground as the need for more specific diagnoses and new targeted therapies evolve. Knowledge of the more common and clinically relevant molecular tests available for solid tumor diagnosis and management, and their indications and limitations, is necessary if anatomic pathologists are to optimally use these tests and act as consultants for fellow clinicians directly involved in patient care.

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Assessment of the Fanconi anemia repair pathway as a predictor of clinical activity of pembrolizumab (PEM).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2555 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2555-2555

Author(s):

Miguel Angel Villalona-Calero ◽

John Paul Diaz ◽

Zuanel Diaz ◽

Wenrui Duan ◽

Eric Douglas Schroeder ◽

...

Keyword(s):

Fanconi Anemia ◽

Solid Tumor ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Standard Of Care ◽

Primary Objective ◽

Clinical Activity ◽

Functional Assay ◽

Phase 2 Trial

2555 Background: Given the activity of immune checkpoint inhibitors (ICI) in mismatch repair deficient tumors, we evaluated if homologous recombination repair deficiency associates with solid tumor response to ICI. Methods: We conducted a phase 2 trial (NCT03274661) of PEM in metastatic solid tumor patients progressing on standard of care and for whom PEM had no FDA approved indication. We evaluated a triple stain (FANCD2foci/DAPI/Ki67) immunofluorescence functional assay of the Fanconi Anemia pathway (FATSI) in treated patients’ archived tumors as a correlative biomarker. Patients with microsatellite unstable tumors were not eligible. The primary objective was objective response rate (iORR, CR+PR) by Immune Response Criteria, with the hypothesis that patients with FATSI negative tumors will have better clinical outcome. Secondary objectives were progression free survival (PFS), 6 months PFS and survival. PEM was given every 3 weeks and computed tomography scans were performed every 6 weeks. We utilized a two-stage phase II trial design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%. If ≥ 2 of the first 20 evaluable patients had an objective response the trial proceeded to full accrual of 39 evaluable patients. Outcomes were evaluated according to FATSI staining. Results: 42 patients (40 evaluable) (35F,7M; median age 62[36-83]) enrolled. Median # of prior regimens was 2[1-7]. Primary Dx included ovarian/fallopian (13), endometrial (10), colorectal (3), cervix (2), pancreatic(2), vaginal (2) and 1 each of various others. No unexpected toxicities occurred. Response evaluation showed 2 CR, 5 PR, 11 SD, 22 PD and 2 NE (iORR 18%). FATSI tumor analyses results are available in 34 patients; 25 FATSI positive, 9 negative. 2 PR, 8 SD, 14 PD, 1 NE occurred among the FATSI (+) (iORR 8%) and 2 CR, 2 PR, 2 SD, 3 PD among the FATSI (-) patients (iORR 44%). mPFS and 6m-PFS were 54 days and 12% (3/25) in FATSI (+), versus 248 days and 56% (5/9) in FATSI (-) patients; p = 0.017. Conclusions: PEM has meaningful antitumor activity in non MSI-high malignancies with no current FDA approved indications. Evaluation of FATSI as a biomarker supports a biomarker selected population approach. Clinical trial information: NCT03274661.

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Profiling and prognostic implications of variants of unknown significance (VUS) in solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19012 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19012-e19012

Author(s):

Meena Sadaps ◽

Bassam N. Estfan ◽

Wei Wei ◽

Davendra Sohal ◽

Megan Lynn Kruse

Keyword(s):

Racial Disparities ◽

Solid Tumor ◽

Cleveland Clinic ◽

Standard Of Care ◽

Median Number ◽

Rank Test ◽

Precision Oncology ◽

Variant Of Unknown Significance ◽

Unknown Significance ◽

Prognostic Implications

e19012 Background: While precision oncology is becoming increasingly integrated into standard of care for most incurable solid tumor malignancies, there is paucity of data regarding the clinical significance of VUS. In this study, we aim to evaluate whether the number of VUS is associated with overall survival (OS). We also analyze racial disparities pertaining to the number of VUS present and identify which, if any, genes possess prognostic implications. Methods: This is a retrospective review of 389 consecutive patients seen at Cleveland Clinic from 2014 to 2016 with incurable solid tumor malignancies, for whom next-generation sequencing (NGS) was ordered using Foundation One™ (Cambridge, MA). Demographics, number of VUS, genes involved, and race were summarized. OS was estimated by Kaplan-Meier and compared by log rank test. Results: Median age was 60 years, 202 (52%) patients were female, 338 (86.7%) were Caucasian, and 31 (8.0%) were African American. On NGS, 376 (97%) patients had VUS reported. The median number of VUS was 9 (range 1-116). When dichotomized at the median, the number of VUS did not affect OS. Genes most commonly implicated in reported VUS were LRP1B (88, 22.6%), MLL3 (83, 21.3%), MLL2 (73, 18.8%), ARID1B (70, 18.0%), PRKDC (60, 15.4%), PREX2 (58, 18.7%), and SPTA1 (56, 14.4%). Patients found to have a variant of unknown significance in MLL2 had worse median OS as compared to those who did not (2.61 vs 3.76 years respectively; p = 0.033). When profiled by race, Caucasians had lower numbers of VUS (p = 0.002; Table). Conclusions: We did not find a clear association between the number of VUS and OS. MLL2, a gene known to predict poor prognosis as a pathogenic variant, was seen in our study to have similarly poor prognostic implications as a variant of unknown significance. Racial disparities in genomics exist as African Americans are under-represented and have greater numbers of VUS as compared to Caucasians. Further research is warranted to elucidate these disparities. [Table: see text]

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Ned-170: A combination anti-cancer therapy targeting late stage, heavily pre-treated solid tumor malignancies.

Journal of Global Oncology ◽

10.1200/jgo.2019.5.suppl.141 ◽

2019 ◽

Vol 5 (suppl) ◽

pp. 141-141

Author(s):

Edward Graeme Garmey ◽

Kristan Meetze ◽

Bridget Martell

Keyword(s):

Clinical Trial ◽

Tumor Growth ◽

Solid Tumor ◽

Late Stage ◽

Phase 1 ◽

Xenograft Model ◽

Standard Of Care ◽

Tumor Growth Inhibition ◽

Tumor Growth And Metastasis ◽

Grade 3

141 Background: NED-170 is a 7-component regimen of both marketed drugs and nutraceuticals with established safety and tolerability profiles and antineoplastic activity. These components, including metronomically-dosed cyclophosphamide (CTX), metformin, naltrexone, alpha lipoic acid, genistein, curcumin, and melatonin, target four key pathways driving tumor growth and metastasis. Methods: NED-170 was evaluated pre-clinically for tolerability and efficacy using a murine CT-26 syngeneic xenograft model. After tumor volume reached 80-120 mm³, mice were randomized into three groups of 10. Experimental arms included: NED-170 allometrically scaled to provide comparable exposure to human clinical trial doses, vehicle, CTX alone, or an anti-PD-1 antibody. In parallel to these studies, a compassionate expanded access program (EAP) was established in 2013 as a precursor to formal clinical trials. To date, 21 pts. with stage IIIc/IV advanced solid tumor malignancies (5 ovarian, 6 sarcoma, 4 Br. Ca, 2 NSCLC, & 4 other cancers) who either sought alternatives to standard-of-care (SOC) chemotherapy or whose tumors progressed through available SOC options have been enrolled. Results: In pre-clinical studies, NED-170 demonstrated 78% tumor growth inhibition (TBI) which exceeded vehicle in a statistically significant fashion (p < 0.001). In contrast, anti-PD-1 treatment failed to achieve anti-tumor activity and CTX alone achieved 50% TBI. In parallel, 21 EAP pts. have been treated with a combined 1,217 months (mos.) of NED-170 therapy (median = 11.8 mos; range = 1.0-60.2). For all pts., the regimen has been safe and well-tolerated with no drug-related grade-3-4 adverse events or dose reductions/discontinuations reported. Observational data reported by pts. or physicians demonstrated that 81% of pts. derived benefit and improved quality of life in this late stage setting. Conclusions: Based on these encouraging data, NED-170 may provide late stage cancer pts. with a safe, effective, and lower cost alternative to standard chemotherapy. A multinational phase 1-2b clinical trial commencing in late 2019 is planned.

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Clinical Trial of NPI-0052 (2nd generation proteasome inhibitor) in Patients Having Advanced Malignancies with Expanded RP2D Cohorts in Lymphoma and CLL

Blood ◽

10.1182/blood.v112.11.4934.4934 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4934-4934 ◽

Cited By ~ 1

Author(s):

Timothy Price ◽

Peeter Padrik ◽

Amanda Townsend ◽

Paul Mainwaring ◽

Lawrence Catley ◽

...

Keyword(s):

Solid Tumors ◽

Solid Tumor ◽

Proteasome Inhibitor ◽

Standard Of Care ◽

Proteasome Inhibition ◽

Hematologic Malignancies ◽

Preclinical Research ◽

Novel Structure ◽

Advanced Malignancies ◽

Mantle Cell

Abstract Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of the 20S proteasome. NPI-0052 has a novel structure leading to a unique proteasome inhibition, toxicology and effect profile. Preclinical research suggests an improved therapeutic ratio and activity in hematologic and solid tumor malignancy models. Secondary to these findings, clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Materials and Methods: In this study patients with solid tumor, lymphoma or leukemia diagnoses were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles in a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1 & D15) and pharmacokinetics PK (D1 & D15) were assayed in blood. Once a Recommended Phase 2 Dose (RP2D) is identified, RP2D cohorts of 10 patients in each lymphoma and CLL are enrolled. Results: 25 patients have been treated at doses ranging from 0.1 mg/m2 to 0.7 mg/m2. The AE profile has been very tolerable with fatigue, transient peri-infusion site discomfort and lymphopenia being commonly ascribed to NPI-0052. Whole blood pharmacokinetics were calculated for all patients on study. At the highest dose assessed PK parameters were (mean ± SD) AUCtot =215±129 ng/mL*min; Cmax =22.8 ±14 ng/mL; t1/2 =13.5 ± 9.2 mins; clearance= 7.8 ± 8.2 L/min and Vss = 132 ± 192 L. AUC and Cmax increased linearly with dose and the kinetics are apparently not dose dependant. PI has been assayed in blood, indicating a dose:response relationship with inhibition of chymotrypsin-like activity up to 100% observed and mean Day 1 inhibition of 78%. This level of proteasome inhibition is higher than that reported with standard doses of bortezomib, yet the profile of adverse drug reactions associated with bortezomib has not been observed. A total of 7 patients (33%) have had stable disease for at least 2 cycles (8 weeks; 2months), including one each with mantle cell lymphoma (4 cycles), Hodgkin’s lymphoma (4 cycles), follicular lymphoma (4 cycles) and sarcoma (5 cycles) and prostate adenocarcinoma, and two with melanoma (4 cycles). Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range while producing a toxicity profile that is tolerable and dissimilar to that of the standard of care proteasome inhibitor bortezomib. These data have supported additional studies being initiated in hematologic malignancies and solid tumors.

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