A phase I study of neoadjuvant combination immunotherapy in locally/regionally advanced melanoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9586-9586 ◽  
Author(s):  
Yana Najjar ◽  
Dustin McCurry ◽  
Huang Lin ◽  
Yan Lin ◽  
Diwakar Davar ◽  
...  
Keyword(s):  
Immune Cell ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Post Treatment ◽  
Interferon Α ◽  
Clinical Activity ◽  
High Dose ◽  
Standard Regimen ◽  
Definitive Surgery

9586 Background: A trial of neoadjuvant pembrolizumab (P) in combination with high dose interferon-α (HDI) in high-risk patients (pts) with locoregionally advanced melanoma (mel) has completed enrollment. Methods: Primary endpoint: safety of combination P-HDI. Pts were treated with P x 2 doses followed by definitive surgery, then x1 year. HDI was given concurrently, and both agents were per standard regimen. Tumor and blood samples were obtained at baseline and at surgery (wk 6-8), blood at 6 wks, 3,6,12 months (mos). Results: 30 pts were treated (22 male, 8 female, age 26-83). 16 had cutaneous primary, 3 mucosal, 11 unknown. At enrollment, 16 had recurrent disease, 6 received prior adjuvant therapy with ipilimumab (4) or HDI (2). 16 had AJCC 7 stage IIIB, 9 IIIC, 5 IV. 332 P cycles have been delivered (median 13), 496 doses of HDI induction (median 17), 1329 doses of HDI maintenance (median 44). HDI was dose reduced in 20 pts, discontinued in 27, P discontinued in 8. Radiologic preoperative RR was 77% (95% CI, 59-88) (6 CR, 17 PR). 20% (6) had SD and 1 had PD. All pts underwent definitive surgery. The pathologic complete response (pCR) of 26 pts was 32% (95% CI, 18-51). 6 pts recurred and 3 died. No pt with pCR has recurred. Median f/u time is 17.4 mos, median PFS/OS not reached. Most common grade (Gr) 3 toxicities: hypophosphatemia (10; 33%), fatigue (10; 33%), ↑CPK (6; 20%), ↑lipase (4; 13%). 3 Gr 4 events (↑CPK, hyperglycemia, lymphocyte count decreased). 1 suspected grade 5 event occurred 6 months after completion of therapy. PD-L1 expression at baseline did not correlate with clinical outcomes. In 8 pts with pre and post treatment tumor samples, IHC expression of PD-1, PD-L1, CD11b, CD8, Foxp3 and CD25 increased post-treatment (p < 0.05). Conclusions: Neoadjuvant P-HDI has promising clinical activity, although treatment is limited by HDI toxicity. Treatment increases the immune cell infiltrate, and outcomes do not correlate with baseline expression of PD-L1. Longer follow up and further mechanistic studies are underway. Clinical trial information: NCT02339324.

Neoadjuvant combination immunotherapy with pembrolizumab and high dose IFN-α2b in locally/regionally advanced melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 181-181 ◽  
Author(s):  
Ahmad A. Tarhini ◽  
Yan Lin ◽  
Joseph J. Drabick ◽  
Rogerio Izar Neves ◽  
Marc S. Ernstoff ◽  
...  
Keyword(s):  
Response Rate ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Clinical Activity ◽  
High Dose ◽  
Risk Patients ◽  
Definitive Surgery ◽  
Pathologic Complete Response Rate ◽  
One Year

181 Background: Neoadjuvant pembrolizumab at 200 mg in combination with high dose IFNα2b (HDI) for locally/regionally advanced or recurrent melanoma may improve the clinical outcomes of these high risk patients (pts), and provide access to blood and tumor pre/post pembro-HDI to illuminate the host effector and suppressor immune mechanisms. Methods: Pts were treated with pembro 200 mg IV every 3 weeks (wk) x 2 doses followed by definitive surgery, then every 3 wks for up to one year. HDI (20 MU/m²/d IV x 5 days (d)/wk for 4 wks then 10 MU/m²/d SC every other d TIW for 48 wks) was given concurrently. Tumor samples were obtained at baseline and at definitive surgery (wk 6-8) and serum/PBMC at baseline, 6 wks, 3, 6, 12 months (mo). Results: Twenty evaluable pts (14 male, 6 female, 14 cutaneous primary, 4 unknown, 3 mucosal), age 29-82 were treated. 5 had Stage IIIB (N1b, N2b, M2c), 11 IIIC (N3) and 4 IV (M1a, M1b) melanoma. Over 230 cycles have been delivered to date (median 14). Worst toxicities included grade (Gr) 3: fatigue (8; 40%), ↑CPK (5; 25%), hypophosphatemia (5; 25%), ↑lipase (3; 15%), lymphopenia (3; 15%), hypertension (2; 10%), diarrhea/colitis (1; 5%), arthralgia (1, 5%), syncope (1, 5%), hyponatremia (1, 5%), neutropenia (1; 5%), anemia (1, 5.00%) nausea (2, 10%), flu like symptoms (1, 5%). There were 3 Gr 4 events (CPK, hyperglycemia, lymphopenia). One suspected grade 5 event occurred 6 months after completion of therapy with autopsy evidence of pneumonia and myocarditis. Among 20 evaluable pts, 4 relapsed and 1 died. Median follow-up for pts who have not relapsed is 11 months. The radiologic preoperative response rate (WHO; unconfirmed) was 65%. The pathologic complete response rate (no viable tumor on histologic assessment) was 35%. Conclusions: Neoadjuvant pembro-HDI exhibited promising clinical activity. Longer follow up is underway in order to define the long term benefits and risks. Clinical trial information: NCT02339324.

scholarly journals CTLA-4 blockade and interferon-α induce proinflammatory transcriptional changes in the tumor immune landscape that correlate with pathologic response in melanoma

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245287
Author(s):  
Arjun Khunger ◽  
Erin Piazza ◽  
Sarah Warren ◽  
Thomas H. Smith ◽  
Xing Ren ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Activation ◽  
Immune Cell ◽  
Expression Profiles ◽  
Pathologic Response ◽  
Interferon Α ◽  
High Dose ◽  
Combination Immunotherapy ◽  
Neoadjuvant Immunotherapy ◽  
Study Gene Expression

Patients with locally/regionally advanced melanoma were treated with neoadjuvant combination immunotherapy with high-dose interferon α-2b (HDI) and ipilimumab in a phase I clinical trial. Tumor specimens were obtained prior to the initiation of neoadjuvant therapy, at the time of surgery and progression if available. In this study, gene expression profiles of tumor specimens (N = 27) were investigated using the NanoString nCounter® platform to evaluate associations with clinical outcomes (pathologic response, radiologic response, relapse-free survival (RFS), and overall survival (OS)) and define biomarkers associated with tumor response. The Tumor Inflammation Signature (TIS), an 18-gene signature that enriches for response to Programmed cell death protein 1 (PD-1) checkpoint blockade, was also evaluated for association with clinical response and survival. It was observed that neoadjuvant ipilimumab-HDI therapy demonstrated an upregulation of immune-related genes, chemokines, and transcription regulator genes involved in immune cell activation, function, or cell proliferation. Importantly, increased expression of baseline pro-inflammatory genes CCL19, CD3D, CD8A, CD22, LY9, IL12RB1, C1S, C7, AMICA1, TIAM1, TIGIT, THY1 was associated with longer OS (p < 0.05). In addition, multiple genes that encode a component or a regulator of the extracellular matrix such as MMP2 and COL1A2 were identified post-treatment as being associated with longer RFS and OS. In all baseline tissues, high TIS scores were associated with longer OS (p = 0.0166). Also, downregulated expression of cell proliferation-related genes such as CUL1, CCND1 and AAMP at baseline was associated with pathological and radiological response (unadjusted p < 0.01). In conclusion, we identified numerous genes that play roles in multiple biological pathways involved in immune activation, immune suppression and cell proliferation correlating with pathological/radiological responses following neoadjuvant immunotherapy highlighting the complexity of immune responses modulated by immunotherapy. Our observations suggest that TIS may be a useful biomarker for predicting survival outcomes with combination immunotherapy.

scholarly journals Three Phase II Cytokine Working Group Trials of gp100 (210M) Peptide Plus High-Dose Interleukin-2 in Patients With HLA-A2–Positive Advanced Melanoma

2008 ◽  
Vol 26 (14) ◽  
pp. 2292-2298 ◽  
Author(s):  
Jeffrey A. Sosman ◽  
Carole Carrillo ◽  
Walter J. Urba ◽  
Lawrence Flaherty ◽  
Michael B. Atkins ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Clinical Activity ◽  
High Dose ◽  
Phase Ii Trials ◽  
Cell Immunity ◽  
Three Phase

Purpose High-dose interleukin-2 (IL-2) induces responses in 15% to 20% of patients with advanced melanoma; 5% to 8% are durable complete responses (CRs). The HLA-A2–restricted, modified gp100 peptide (210M) induces T-cell immunity in vivo and has little antitumor activity but, combined with high-dose IL-2, reportedly has a 42% (13 of 31 patients) response rate (RR). We evaluated 210M with one of three different IL-2 schedules to determine whether a basis exists for a phase III trial. Patients and Methods In three separate phase II trials, patients with melanoma received 210M subcutaneously during weeks 1, 4, 7, and 10 and standard high-dose IL-2 during weeks 1 and 3 (trial 1), weeks 7 and 9 (trial 2), or weeks 1, 4, 7, and 10 (trial 3). Immune assays were performed on peripheral-blood mononuclear cells collected before and after treatment. Results From 1998 to 2003, 131 patients with HLA-A2–positive were enrolled. With 60-month median follow-up time, the overall RR for 121 assessable patients was 16.5% (95% CI, 10% to 26%); the RRs were 23.8% in trial 1 (42 patients), 12.5% in trial 2 (40 patients), and 12.8% in trial 3 (39 patients). There were 11 CRs (9%) and nine partial responses (7%), with 11 patients (9%) progression free at ≥ 30 months. Immune studies including assays of CD3-ζ expression and numbers of CD4+/CD25+/FoxP3+ regulatory T cells, CD15+/CD11b+/CD14– immature myeloid-derived cells, and CD8+gp100 tetramer-positive cells in the blood did not correlate with clinical benefit. Conclusion The results again demonstrate efficacy of high-dose IL-2 in advanced melanoma but did not demonstrate the promising clinical activity reported with vaccine and high-dose IL-2 in any of three phase II trials.

High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9075-9075
Author(s):  
Diwakar Davar ◽  
Melissa Saul ◽  
Ahmad A. Tarhini ◽  
An Tran ◽  
Kerry Trent ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Interleukin 2 ◽  
Complete Response ◽  
Median Number ◽  
Cox Proportional Hazards ◽  
Advanced Melanoma ◽  
High Dose ◽  
Severe Toxicity ◽  
University Of Pittsburgh ◽  
Radiological Data

9075 Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR+PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p < 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3014-3014 ◽  
Author(s):  
Brendan D. Curti ◽  
Jon M. Richards ◽  
Sigrun Hallmeyer ◽  
Mark B. Faries ◽  
Robert Hans Ingemar Andtbacka ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Cell ◽  
Phase 1 ◽  
Unmet Need ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Potential Marker ◽  
Previously Treated ◽  
Coxsackievirus A21 ◽  
Melanoma Patients

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.

Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer.

1996 ◽  
Vol 14 (6) ◽  
pp. 1858-1867 ◽  
Author(s):  
J M Nabholtz ◽  
K Gelmon ◽  
M Bontenbal ◽  
M Spielmann ◽  
G Catimel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Low Frequency ◽  
Metastatic Breast ◽  
Therapeutic Index ◽  
Complete Response ◽  
Dose Effect ◽  
Clinical Activity ◽  
High Dose ◽  
Number Of Patients

PURPOSE AND METHODS The objective of this multicenter study was to compare the therapeutic index of two different doses of paclitaxel given as a 3-hour infusion in patients with metastatic breast cancer (MBC), who had failed to respond to previous chemotherapy. A total of 471 patients with MBC were randomized to receive intravenous paclitaxel at a dose of 175 or 135 mg/m2 every 3 weeks. RESULTS Better treatment results were achieved with high-dose (HD) versus low-dose (LD) paclitaxel: overall response rate, 29% versus 22% (P = .108); complete response (CR) rate, 5% versus 2% (P = .088); median time to disease progression, 4.2 versus 3.0 months (P = .027); and median survival time, 11.7 versus 10.5 months (P = .321). Patients previously exposed or resistant to anthracyclines were as likely to respond as those without such prior exposure. Treatment was well tolerated, as documented by the number of administered treatment courses (median, six v five; range, one 17 v one to 18), the low frequency of dose reductions (14% v 7%, P = .024), and the small number of patients (n = 9 or 4% vn = 5 or 2%) who required treatment discontinuation for adverse reactions. The incidence and severity of neutropenia and peripheral neuropathy were dose-related. After quality-of-life-adjusted time-to-progression analysis, the HD arm (175 mg/m2) retained its advantage over the LD arm (135 mg/m2). CONCLUSION The results of this trial substantiate the activity of paclitaxel in the treatment of MBC. The observed superior efficacy with a dose of 175 mg/m2 over 135 mg/m2 suggests a dose-effect relationship. The clinical activity in anthracycline-resistant patients is particularly noteworthy. Paclitaxel in breast cancer needs further evaluation in large trials that use combination chemotherapy and involve earlier disease stages.

Phase II trial of weekly docetaxel (D) and complete androgen blockade (CAB) prior to radical prostatectomy (RP) in high-risk localized prostate cancer (PC) patients (pts)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14515-14515 ◽  
Author(s):  
B. Mellado ◽  
A. Font ◽  
L. A. Aparicio ◽  
E. Gallardo ◽  
J. R. Mel ◽  
...  
Keyword(s):  
High Risk ◽  
Neoadjuvant Therapy ◽  
Liver Toxicity ◽  
Clinical Stage ◽  
Pathologic Complete Response ◽  
Dose Intensity ◽  
Complete Response ◽  
Clinical Activity ◽  
Increased Risk ◽  
Radiotherapy Alone

14515 Background: Pts with high-risk localized PC have an increased risk of positive margins and recurrence after RP or radiotherapy alone. Neoadjuvant hormonotherapy (HT) has not shown a survival benefit prior to surgery, while outcomes are improved when HT is combined with radiotherapy. D-based chemotherapy improves survival in metastatic PC. These data support the investigation of multi-modality approaches to improve the aggressive behavior of high-risk localized PC. The main objective of this study was to assess the pathologic complete response (pCR) rate of the study combination. Secondary objectives were clinical activity, toxicity profile, time to progression and survival. Methods: Pts with clinical stage T1–2 (+ Gleason ≥ 7 (4+3) and/or PSA≥20 ng/mL) and T3 PC received 3 cycles of D (35 mg/m2 i.v. days 1, 8 and 15, every 28 days) concomitant with a depot goserelin (10.8 mg sc) plus flutamide (750 mg po daily for 3 months). RP was performed 2–4 weeks after the end of neoadjuvant therapy. Results: Fifty six pts have been included into the trial. Available data from 32 pts receiving neoadjuvant therapy were analyzed for this presentation. Median age was 69 years (53–75). Median follow-up was 3.6 months. Clinical stage was T1 (20%), T2 (53%) and T3 (27%); Gleason was ≥ 7 (4+3) in 25 (78%) pts. Eight (28%) pts had a PSA ≥ 20 ng/ml. A total of 85 cycles were administered (median 3) with a 100% median relative dose intensity for D. Grade III/IV toxicities per patient were liver toxicity (15.6%) and diarrhea (9.4%). Among the 16 pts who underwent RP to date, one (6%) achieved pCR, 11 (69%) had negative surgical margins and 9 (56%) had organ-confined disease. Conclusions: Neoadjuvant weekly D plus 3-month CAB is well tolerated and induces pCR in high-risk localized PC pts. Updated results will be available for the meeting. These results are encouraging while the true impact of neoadjuvant chemo-HT in this group of pts has to be determined in randomized trials. No significant financial relationships to disclose.

Paclitaxel (P) and cisplatin (C) concurrent with radiotherapy (RT) for larynx preservation (LP) in advanced resectable laryngeal (L) and hypopharyngeal (HP) squamous cell carcinoma (SCC): Final results of a prospective phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16046-e16046
Author(s):  
Ulisses Ribaldo Nicolau ◽  
Thiago Bueno Oliveira ◽  
Andre Lopes Carvalho ◽  
Rosane O Santana ◽  
Adriana D Valadares ◽  
...  
Keyword(s):  
Phase Ii ◽  
Salvage Surgery ◽  
Comparative Trial ◽  
Standard Of Care ◽  
Residual Tumor ◽  
Complete Response ◽  
High Dose ◽  
Standard Regimen ◽  
Term Survival ◽  
Larynx Preservation

e16046 Background: Since the results of the RTOG 9111 trial, cisplatin based chemoradiation (CRT) has been the standard of care for LP in advanced laryngeal SCC. Recently, the role of taxanes in managing head and neck SCC has been studied. In 2002 we reported the interim results of a phase II clinical study designed to test the efficacy of P and C concurrent with RT for organ preservation in advanced L and HP SCC. Here we report the long term survival and LP rates. Methods: Eligible patients had untreated advanced L and HP SCC, stage T3N0 or higher and suitable for radical total laryngectomy. Treatment consisted of weekly P (30 mg/m2) and C (20 mg/m2) concurrent to RT up to 7040 cGy in 180 cGy/day fractions. Response evaluation was performed at 5040 cGy and at 4 weeks after completing RT. Salvage surgery was planned for patients not responding at 5040 cGy, residual tumor at the end of RT or at the time of local recurrence. Neck dissection was planned for clinically positive neck (cN1-3). Results: Between 06/1999 and 10/2001, 48 patients were enrolled in a single institution (35 L; 13 HP), 40 male and 8 female with a 58-year median age (39-74). The majority had T3 (64%) N1-3 (52%) disease and 38% needed tracheostomy prior to treatment. Grade (G) 3 and 4 mucositis was noted in 27% of patients, G 3-4 odynophagia in 50%, G 3-4 radiodermatitis in 35% and G 3-4 leucopenia in 13%, with no treatment related death. Two patients needed salvage surgery, one after 5040 cGy and one after 7040 cGy. The complete response rate to treatment was 95%. At a median follow up of 66 months the LP rate at 2 and 5 years were 88% and 54%, respectively. Recurrence free survival (RFS) was 51% at 2 and 47% at 5 years and overall survival (OS) was 81% and 52% at 2 and 5 years, respectively. Conclusions: The finding of similar LP rate and survival compared to the recent reports of high dose cisplatin CRT and neoadjuvant 3 drug CT followed by CRT in an advanced disease population suggests a role for platinum plus taxane as a radiosensitizer regimen in this scenario with acceptable toxicity, but further evaluation in a direct comparative trial with the standard regimen is needed.

Clinical evaluation of cisplatin sensitivity germ line polymorphisms in neoadjuvant chemotherapy (NAC) for urothelial cancer (UC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 342-342
Author(s):  
Peter H. O'Donnell ◽  
Ilana Rebecca Garcia-Grossman ◽  
Hongyuan Cao ◽  
Irina Ostrovnaya ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Germ Line ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Nucleotide Polymorphisms ◽  
Primary Analysis ◽  
Spurious Association ◽  
Multivariate Logistic Model ◽  
Cisplatin Sensitivity ◽  
Definitive Surgery ◽  
Surgery Rates

342 Background: Cisplatin-based NAC in UC confers a survival benefit, but prediction of which patients (pts) will benefit is not possible. We attempted to validate pharmacogenomic (PGx) markers of cisplatin sensitivity derived from a cell-based model and previously associated with response in a population of pts receiving NAC. Methods: Three germline single nucleotide polymorphisms (SNPs) were previously associated with pathologic response at cystectomy in a single-institution discovery set of 59 cT2 UC pts. These SNPs were tested for association with NAC response in a prospectively-identified, multi-institution, independent cohort. The primary analysis tested for association between rs244898 and rs7937567 and pathologic complete response (pT0). A replication set of 134 pts would provide 80% power to detect effects of both SNPs at p=0.05 independently using a multivariate logistic model. Results: N=146 pts with ≥cT2 N0 disease were identified from three institutions. All pts received ≥3 cycles of cisplatin-based NAC and underwent definitive surgery. Rates of pT0 and <pT2 were 26% and 50%, respectively, comparable to the discovery population. Though each SNP had a >5 odds ratio of effect on pT0 in the discovery set, neither was associated with achievement of pT0 in the replication set. The third SNP (rs10964552) which was associated with pathologic downstaging in the discovery set, also failed to replicate. All three SNPs were in Hardy-Weinberg equilibrium, and minor allele frequencies were similar between discovery and validation. Conclusions: Three germline SNPs previously associated with platinum sensitivity in pre-clinical and clinical models were not associated with NAC response in a large replication cohort of UC pts. Reasons for failure may include unmeasured clinical differences between the pt cohorts, a higher proportion of MVAC use in the replication set compared to gemcitabine/cisplatin in discovery pts, or simply spurious association in the discovery cohort. These results emphasize the need for replication when evaluating PGx markers, and demonstrate that multi-institutional efforts are feasible and will likely be necessary to achieve advances in UC PGx.

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