ASCO 2018: Multicenter Randomized Phase 2 Trial of Paclitaxel, Ifosfamide, and Cisplatin Versus Bleomycin, Etoposide, and Cisplatin for First-line Treatment of Patients with Intermediate- or Poor-risk Germ Cell Tumors

Chicago, IL (UroToday.com) Approximately 50% of poor risk and 75% of intermediate risk germ cell tumor (GCT) patients are cured with 1st line bleomycin, etoposide, and cisplatin (BEP). Paclitaxel, Ifosfamide, and cisplatin (TIP) is a standard regimen for GCT patients requiring salvage chemotherapy with 70% complete response (CR) rate, 63% progression free survival (PFS) among relapsed GCT patients. A multicenter single arm phase 2 study published in the Journal of clinical oncology in 2016 demonstrated that TIP as first line therapy in poor- and intermediate-risk GCT patients, had a better response when compared to the historic standard of care of BEP, for poor- and intermediate- risk GCTs.[1] In this study TIP had an acceptable safety profile. The authors therefore, performed this randomized phase 2 study of TIP vs. BEP conducted across 7 centers.

The presented study (NCT01873326) in ASCO this year took place between July 2013 and July 2017. Only patients aged 18 or above were included in the study. All patients had an IGCCCG intermediate or poor-risk GCT. None of the patients had prior chemotherapy. Patients were randomized to 4 cycles of TIP (paclitaxel 120mg/m2 days 1-2; ifosfamide 1200mg/m2 days 1-5; and cisplatin 20mg/m2 days 1-5) or standard BEP. Patients were stratified by intermediate vs. poor risk, and by the need for disease stabilizing chemotherapy (EP *3 days). Prophylactic G-CSF was given to patients in both study arms, however, levofloxacin was optional but encouraged for TIP patients. Study design is illustrated in Figure 1.

image 29
The endpoints of the study included:
Primary endpoint was the 6-month favorable response rate (complete response + partial response with negative markers). Statistical analyses were performed and demonstrated that with an alpha of 0.1, a sample size of 88 pts produced 80% power to detect a one-sided increase in 6-month favorable response rate from 65% with BEP to 85% with TIP.
Secondary endpoints included progression free survival (PFS) and overall survival (OS).
Lastly, biologic correlates including next generation sequencing (NGS) was a secondary endpoint as well.

The data cutoff for this presentation was February 1st 2018. Patient characteristics are displayed in table 1.

image 29b
Of 91 eligible patients (n = 45 TIP, n = 46 BEP), 81 had nonseminoma,10 had seminoma; 37 had intermediate-risk and 54 had poor-risk disease. Primary site was testis in 69 patients, mediastinum in 19, and retroperitoneum in 3. A total of 42/45 TIP and 41/46 BEP patients received 4 cycles. Eventually, 86 patients (TIP: n = 42; BEP; n = 44) were available for evaluation for a 6-month favorable response with no difference demonstrated between the two arms (76% for TIP vs. 73% for BEP), for intermediate- (100% vs. 88%) and for poor-risk (57% vs. 63%) (Table 2).

image 29c
The study median follow-up was 1.71 years. Laboratory and gastrointestinal toxicities were worse for TIP whereas infections and respiratory toxicities were worse for BEP.

Additionally, the authors presented an exploratory analysis using next generation sequencing (NGS) by MSK-IMPACT. The authors looked at TP53 mutation among these patients. This mutation is known to be rare in GCT, and this may partially explain the unique cisplatin sensitivity. A prior study evaluated selected exon capture sequencing for >300 genes on GCT from 180 patients using MSK-IMAPCT. For this presented study, NGS data was available for 57 (63%) of the 91 patients (TIP 29, BEP 28). Out of the 57 patients, 10 (18%) had the TP53 mutation, all had non-seminoma GCT. Out of these 10 patients, 6 received TIP and 4 received BEP. The results demonstrated that favorable response was demonstrated in 50% of TP53 mutated patients and 83% of non- mutated patients.

The authors concluded that first-line TIP did not improve the 6-month rate of favorable response seen with BEP in patients with intermediate- or poor-risk GCT. However, this study shows that TIP could absolutely represent an alternative to BEP for patients with a contraindication to bleomycin. Improving the 1st line treatment for patients with intermediate- and poor- risk GCT remains un unmet need. TP53 mutations were found in 18% of patients tested with all patients with TP53 mutations having nonseminoma. These mutations were associated with adverse PFS and cisplatin resistance to both TIP and BEP either with viable GCT or secondary somatic malignancy.

Presented by: Dr. Darren R. Feldman, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter:@GoldbergHanan at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA

References;
Feldman, D.R., et al., Paclitaxel, Ifosfamide, and Cisplatin Efficacy for First-Line Treatment of Patients With Intermediate- or Poor-Risk Germ Cell Tumors. J Clin Oncol, 2016. 34(21): p. 2478-83.
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