ASCO 2019: Biomarkers of Outcomes in a Randomized Phase II trial of first-line paclitaxel, ifosfamide, and Cisplatin versus Bleomycin, Etoposide, and Cisplatin for Intermediate- and Poor-Risk Germ Cell Tumors

Chicago, IL (UroToday.com) In a multicenter phase 2 randomized controlled trial of first-line Paclitaxel, ifosfamide and cisplatin (TIP) vs. bleomycin, etoposide and platinum (BEP) chemotherapy for patients with intermediate or poor risk germ cell tumor (GCT), there was no difference in the favorable response rate (FRR).1 Prior studies demonstrated the prognostic importance of tumor marker decline in advanced GCT patients receiving BEP.2-4 AKT and proteins involved in DNA damage repair (DDR) have been postulated to correlate with cisplatin sensitivity.5, 6 

In this study (Clinical trial information: NCT01873326), the authors evaluated the prognostic significance of marker decline and immunohistochemical (IHC) staining for DDR proteins and AKT within preplanned analyses of this phase 2 randomized controlled trial. 

For this study, all patients had elevated AFP (≥15) or HCG (≥10), and none of the patients received disease stabilizing chemotherapy. Assessing marker decline was done by two methods, as shown in Table 1. A total of 91 patients were included, with 46 randomized to BEP and 45 to TIP. The median follow-up was 2.9 years (range 1-5.3 years). There was no significant difference in FRR, overall survival, and progression-free survival. A total of 11 patients were unevaluable for marker decline analysis due to receiving disease stabilizing chemotherapy before TIP/BEP therapy. Overall, 79 patients were eligible for the MSK method analysis, and 75 patients were eligible for the GETUG method analysis.

Table 1 – Marker decline analysis methods:Table1_MarkerDeclineMethods.png

Sample marker decline plots are shown in Figure 1. The MSK marker decline after six months is shown in Table 2, and the progression-free survival and overall survival by the MSK marker decline is shown in Figure 2. The progression-free survival (PFS) and overall survival by the GETUG marker decline is shown in Figure 3.

Figure 1 - Progression-free, and overall survival by MSK marker decline:
Figure1_OS_PFS_MarkerDecline.png

Table 2 – Six months response by MSK marker decline:
Table2_6MonthResponseMSK.png

Figure 2 – Six months response by GETUG marker decline and progression-free and overall survival by GETUG marker decline: 
Figure2_SixMonthsResponse_Marker_Decline_PFS_OverallSurvival_GETUGMarkerDecline.png

Figure 3 – Six months response by PARP1 staining, and progression-free survival and overall survival by PARP1 expression:
Figure3_SixmonthsResponse_PARP1Staining_PFS_OS_PARP1_expression.png

When examining the IHC results, tumor tissue was available for 77 patients, with adequate analysis performed in 71-73 patients only. PARP1 H score was significantly correlated with outcome.

The authors concluded that unsatisfactory marker decline was strongly associated with inferior FRR, progression-free- and overall survival by the GETUG and MSK methods. PARP1 expression and tumor marker decline rates, particularly with the MSK method, were significantly associated with the outcome to initial chemotherapy in intermediate and poor risk GCT patients. Future trials incorporating marker decline into treatment decisions and allocation are warranted.

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

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Fizazi et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncology 2014
  2. Murphy R et al. CANCER 2005
  3. Motzer et al. Phase III Randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors. J Clin Oncol. 25, no. 3 (January 20 2007) 247-256. 
  4. Fizazi et al. Personalised chemotherapy based on tumour marker decline in poor prognosis germ-cell tumours (GETUG 13): a phase 3, multicentre, randomised trial. Lancet Oncology 2014 Dec;15(13):1442-50.
  5. Koster et al. Cytoplasmic p21 expression levels determine cisplatin resistance in human testicular cancer. Journal of Clinical Investi, 2010 Oct;120(10):3594-605. 
  6. Koberle et al. Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Curr Biology, 1999 Mar 11;9(5):273-6. 
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