Annual Meeting Proceedings Part 1 - American Society of Clinical ...

4524 Poster Discussion Session (Board #3), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Prognostic model for overall survival in patients with metastatic urothelial
cancer treated with cisplatin-based chemotherapy. Presenting Author:
Matt D. Galsky, Division of Hematology and Medical Oncology, The Tisch
Cancer Institute, Mount Sinai School of Medicine, New York, NY
Background: Patients with metastatic urothelial cancer (UC) treated with
cisplatin-based chemotherapy have heterogeneous clinical outcomes. Pretreatment
prognostic variables have previously been defined (Bajorin, JCO,
1999) but have not been extensively validated or expanded upon. Methods:
Pretreatment clinical parameters from 400 international patients with
metastatic UC treated on phase II and III first-line clinical trials with
cisplatin-based chemotherapy from 11/1997 to 10/2011 were evaluated
(cisplatin � gemcitabine �/- paclitaxel or �/- antiangiogenic agent � 235;
MVAC � 83; cisplatin � 5FU �/- paclitaxel � 79). Parameters were
subjected to multivariable regression analysis to determine which patient
characteristics had independent prognostic significance for survival. Results:
Complete data were available on 361 patients, median survival was 13.9
months (95% CI 12.4, 16.5); 247 have died. In multivariable analysis,
ECOG performance status (�1), visceral metastases (lung, liver, bone), and
white blood count (WBC, continuous variable) were significantly associated
with poor survival (P � .05), whereas perioperative chemotherapy, hemoglobin,
platelets, creatinine clearance, site of primary tumor, and number of
metastatic sites were not (Table). The cut-off for WBC was established at
10. Median survival times for patients with 0, 1, 2, or 3 risk factors were
26.9, 16.8, 12.8, 9.7 months (log rank p value � 0.0001). When
subjected to internal validation, the model achieved a bootstrap-corrected
c-index of 0.60. External validation is ongoing utilizing data from a phase
III trial (n�186) of MVAC versus docetaxel plus cisplatin. Conclusions: A
model derived from pretreatment parameters from an international cohort
of patients was constructed that confirmed, and expanded upon, known
prognostic factors in metastatic UC. This model may be useful for patient
counseling and clinical trial design. Better predictions require the identification
of additional factors that affect survival.
Prognostic model for overall survival.
Parameter Hazard ratio 95% CI P
WBC > 10 1.66 1.27, 2.18 0.0002
Visceral metastases 1.49 1.15, 1.93 0.0024
ECOG > 1 1.52 1.16, 2.00 0.0028
4526 Poster Discussion Session (Board #5), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive
bladder cancer: Results of a multicenter phase II study. Presenting Author:
Elizabeth R. Plimack, Fox Chase Cancer Center, Philadelphia, PA
Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin
(MVAC) demonstrates a survival benefit in the neoadjuvant setting for
patients (pts) with muscle invasive bladder cancer (MIBC). Compared with
standard MVAC, AMVAC yielded higher response rates with less toxicity in
the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with
CrCl ��50 and adequate hepatic and marrow function were eligible. Pts
received 3 cycles of AMVAC (methotrexate 30 mg/m2 , vinblastine 3 mg/m2 ,
doxorubicin 30 mg/m2 , cisplatin 70mg/m2 ) on day 1, with pegfilgrastim 6
mg day 2 or 3, every 2 weeks. Pts with CrCl � 60 could receive cisplatin
split over 2 days. Radical cystectomy (RC) with lymph node dissection was
performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint
was pathologic complete response (pCR) rate. Results: Accrual is complete
with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month
period. Median age 64 (range 45-83). Three withdrew from study early and
are not evaluable for response (2 physician discretion, 1 withdrawal of
consent). An additional 8 are currently receiving treatment on study with
toxicity and response data pending. Of the 33 evaluable pts for whom final
data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts
received � 3 cycles due to grade 3 fatigue (1), low platelets (1), and
disease progression precluding RC (1). 32/33 pts underwent RC, all within
8 weeks of last chemotherapy. Median time from start of chemotherapy to
RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI,
22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non
muscle invasive disease. For the intent to treat cohort (n�36) 8 pts had
grade 3-4 AMVAC related adverse events, the most common being anemia
(3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95%
CI, 20.4-51.8%). All pts will have completed study treatment by April
2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is
well tolerated and preliminary results show a pCR rate similar to that
reported for standard 12-week MVAC, suggesting that AMVAC for three
cycles (6 weeks) is a safe and efficient alternative.
Genitourinary Cancer
283s
4525 Poster Discussion Session (Board #4), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Correlation of progression-free survival at 6 months (PFS6) with overall
survival at 12 months (OS12) in an analysis of 10 trials of second-line
therapy for advanced urothelial carcinoma (UC). Presenting Author: Benjamin
Maughan, University of Utah, Salt Lake City, UT
Background: Second-line therapy of advanced UC is a significant unmet
need. While phase II trials have relied on response rate (RR) as a primary
endpoint, response may not be suitable for assessing cytostatic agents and
does not capture duration of benefit. We hypothesized that PFS6 correlates
with OS12 and may be a robust intermediate endpoint for phase II trials.
Methods: Ten trials with individual patient progression and survival data
(n�646) evaluating chemotherapy and/or biologics following chemotherapy
were combined. Progression was defined as tumor progression
(RECIST 1.0 in 9 trials, WHO in 1 trial), or death from any cause.
Unadjusted and adjusted binomial confidence intervals for PFS6, OS12
and response were reported, with adjustment for variability between trials
using random effects models. The relationship between PFS6 and OS12
was assessed at the trial level using Pearson correlation and weighted linear
regression with larger studies having more influence. The relationship
between PFS6 and OS12 at the individual level was assessed using
Pearson chi-square test with Yates continuity correction. Statistical analyses
employed “R” statistical computing software, version 2.8.0. Results:
59% had visceral metastasis and performance status was 0, 1 and 2 in 50,
39 and 8%, respectively. Median age was 65 years (31-88) and 77% were
male. PFS6 was 22% (95% CI: 17-24%), and adjusted PFS6 was 23%
(95% CI: 15-34%). The OS12 was 20% (95% CI: 17-24%), and adjusted
OS12 was 21% (95% CI: 15-29%). The Pearson correlation between trial
level PFS6 and OS12 was 0.66 (p � 0.037). The individual level
agreement between PFS6 and OS12 was seen in 82% of patients (kappa �
0.45). Among 560 patients evaluable for response and OS, the RR was
22% (95% CI: 18-25%) and adjusted RR was 21% (95% CI: 13-32%).
Trial level Pearson correlation between response and OS12 was 0.37 (p �
0.30), and individual level agreement was seen in 78% (kappa�0.36).
Conclusions: PFS6 is associated with OS12 at the trial and individual levels
in patients receiving second-line therapy for advanced UC. The association
of response with OS was suboptimal. Validation of PFS6 is warranted.
4527 Poster Discussion Session (Board #6), Sat, 8:00 AM-12:00 PM and
12:00 PM-1:00 PM
Defining the genetic basis of everolimus sensitivity in metastatic bladder
cancer (MBC) by whole-genome sequencing (WGS). Presenting Author:
Gopa Iyer, Memorial Sloan-Kettering Cancer Center, New York, NY
Background: MBC is rarely cured with standard chemotherapy and novel
agents are clearly needed. A phase II trial of everolimus in MBC resulted in
1 near-complete response (CR), 1 partial response, and 3 minor responses.
We used WGS and a Next Generation exon capture assay to identify the
genetic aberrations underlying treatment response. Methods: In the near-CR
case, tumor and peripheral blood DNA was subjected to WGS (Illumina)
using 2x100 bp paired-end libraries for 40X haploid coverage. Raw
sequence data was aligned to hg19 and somatic point mutation detection
was performed. Tumor DNA from 13 additional patients on the trial was
analyzed using an exon capture sequencing assay. Results: 184 exonic
somatic mutations were identified in the everolimus complete responder by
WGS, including a2bpframeshift truncation in TSC1 and a nonsense
mutation in NF2. Sanger sequencing of an additional 96 high-grade
bladder tumors found 5 (6.2%) tumors containing TSC1 alterations and no
NF2 mutations. Of the 13 patients on the trial who underwent targeted
exon sequencing, 3 (23%) possessed nonsense TSC1 mutations and 2 had
minor treatment responses (17% and 24% tumor regression). 1 patient
with a 7% tumor regression had a somatic missense TSC1 variant. 8 (89%)
of 9 patients with tumor progression as best response were TSC1 wild-type.
Patients with TSC1-mutant tumors remained on drug for longer duration
(7.7 vs. 2 months, p�0.004, Wilcoxon rank sum test). Conclusions:
Everolimus is an active agent in MBC in patients with TSC1 mutant tumors.
The pattern of co-mutation in patients with TSC1 mutant tumors is complex
and combination therapies will likely be required to achieve durable
responses in most patients. Our results also highlight the potential utility of
WGS in identifying novel predictors of response to targeted inhibitors.
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