Welcome to the July, 2010 edition of OncoFacts. In this edition, I will be covering some interesting abstracts in gastrointestinal malignancies, lung cancer, genitourinary malignancies, and hematologic malignancies from the 2010 Annual Oncology Meeting.

Genitourinary Malignancies

Abstract LBA4504
Padraig Warde presented the results of an international phase III study of long-term androgen deprivation therapy (ADT) with or without radiation therapy (XRT) in patients with locally advanced prostate cancer T3, T4, or T2 with prostate-specific antigen (PSA) of >40 or a Gleason Score of >8. In this trial, 1205 patients were randomized between 1995 and 2005. The median follow-up is 6 years, and 320 patients have died. Ten-year disease specific mortality was 23% for ADT and 15% for ADT plus XRT. The addition of XRT significantly reduced the risk of death with a hazard ratio (HR) of 0.77. One hundred forty patients died of disease and/or treatment (89 patients on ADT and 51 patients on ADT + XRT). The trial demonstrated a substantial overall survival (OS) and disease specific survival benefit for ADT + XRT.

Abstract LBA4511
Kevin Kelly from Yale Cancer Center presented the results of the Cancer and Leukemia Group B (CALGB) 90401 Intergroup trial comparing docetaxel-prednisone-bevacizumab (DP+bev) with docetaxel-prednisone-placebo (DP-placebo) in metastatic castrate-resistant prostate cancer (CRPC). In this trial, 1050 chemotherapy-naïve patients with progressive disease despite castrate testosterone levels and anti-androgen withdrawal were enrolled. Ninety-five percent had ECOG performance status of 0-1 and many of those were asymptomatic. Overall survival was the primary endpoint. Despite statistically significant improvements in objective response rate (P = .0113), PSA response rate (P = .0002), and progression-free survival (PFS [P<.001]) there was no improvement in the primary objective of OS. Overall survival was 22.6 months for DP-bev and 21.5 months for DP-placebo with P = .18. Of note is the fact that in the TAX 327 study of docetaxel-prednisone, the reported OS was 19.2 months – over 2 months shorter than in this CALGB trial. The role that subsequent therapy, received by 30% of patients, played in these survival figures cannot be definitely stated. Those subgroups associated with a higher likelihood of benefit from DP+bev included those with high alkaline phosphatase, high LDH, low hemoglobin, and serum testosterone levels <20. In other words, the sicker patients received the most benefit from DP+bev. Grade 3 or higher adverse events were more frequent in the DP+bev arm as were treatment related deaths (4.4% versus 1.1%). Most treatment related deaths were due to neutropenia related infections.

Abstract 4510
A randomized phase II trial with a novel agent with anti-angiogenic and anti-tumor properties was presented. Patients with chemotherapy-naïve metastatic CRPC were randomized 2:1 to receive oral tasquinimod or placebo. The primary endpoint was PFS at 6 months. Median Karnofsky performance status for both groups was 95%, and their PSA doubling times were in the range of 4.5 months - 5.0 months. Progression-free survival was 24.7 weeks for tasquinimod versus 12.9 weeks for placebo. Six-month PFS was 57% for TASQ and 33% for placebo. Grade 3-4 adverse events were much more common in the tasquinimod group (38% vs 10%). A phase III trial is planned.

Abstract 4508
The TROPIC investigators updated the results of their trial originally presented at the 2010 Genitourinary Cancers Symposium. Men with metastatic CRPC who had progressed on or shortly after docetaxel-prednisone were randomized to receive either cabazitaxel-prednisone or mitoxantrone-prednisone, and 755 men were randomized. Median prior docetaxel exposure of the 2 groups was 576 mg/m² for cabazitaxel-prednisone and 529 mg/m² for mitoxantrone-prednisone. The intent-to-treat median OS for cabazitaxel-prednisone was 15.1 months and for mitoxantrone-prednisone was 12.7 months (HR = 0.70). However, for those patients whose disease had progressed more than 3 months after their last docetaxel dose, the OS was approximately 17 months for both the cabazitaxel-prednisone and mitoxantrone-prednisone arms. Progression-free survival was also better for the cabazitaxel-prednisone arm at 2.8 months versus 1.9 months for mitoxantrone-prednisone (HR = 0.75). Response rate by RECIST and by PSA also favored the cabazitaxel arm. Diarrhea and febrile neutropenia were increased in the cabazitaxel arm. Treatment related deaths were more common in the cabazitaxel arm, but only among the European patients. Increased deaths were not seen among US and Canadian patients.

Abstract LBA4507
An international group presented the results of a phase III trial comparing denosumab with zoledronic acid in patients with bone metastases from CRPC. In this trial, 1901 patients with at least 1 bone metastases were randomized to sub-Q denosumab + IV placebo or IV zoledronic acid + sub-Q placebo. All patients received supplemental calcium and vitamin D. The primary endpoint was time to first on-study skeletal related event (SRE). Time to first on-study SRE was 20.7 months for denosumab and 17.1 months for zoledronic acid with P = .008. Denosumab also reduced the incidence of multiple SREs by 18%. Reported first SREs included radiation therapy to the bone (20%), fractures (14.7%), spinal cord compression (3.3%), and bone surgery (0.3%). Markers of bone turnover were also suppressed to a greater degree by denosumab. There was no difference in the PSA time course between the 2 arms and OS and time to disease progression were similar in both arms. Serious adverse events were seen in approximately 60% of patients in both arms. Adverse events leading to drug discontinuation occurred in 15% of zoledronic acid treated patients and 17% of denosumab treated patients. Hypocalcaemia and osteonecrosis of the jaw were more common in the denosumab arm. Bone density was not measured at the beginning or at the end of the trial. The question was raised as to how much was gained by a trial in which there was no improvement in the quality of life or the duration of survival, but only a 3-month to 4-month delay in the development of SREs.

Abstract 4516
Bernard Escudier presented a phase II trial in untreated metastatic renal cell carcinoma. One hundred seventy-one patients were randomized in a 2:1:1 fashion to temsirolimus plus bevacizumab versus sunitinib alone versus bevacizumab plus α-interferon. The primary objective was non-progression at 48 weeks. Non-progression at 48 weeks was 43.2% for temsirolimus plus bevacizumab, 47.6% for sunitinib, and 65.9% for bevacizumab plus α-interferon. Best response rates were 25%, 24%, and 34%, respectively. There was no evidence of a synergistic or additive efficacy effect with the temsirolimus plus bevacizumab combination. Grade 3-4 adverse events were observed in 36% with temsirolimus plus bevacizumab, 12% with sunitinib, and 23% with bevacizumab plus α-interferon. The toxicity rate for temsirolimus plus bevacizumab was higher than expected leading to a high drop-out rate.

Abstract 4514
David McDermott from the Beth Israel Deaconess Medical Center presented the results of a prospective study in patients with histologically confirmed metastatic or unresectable renal cell carcinoma. Eligible patients received intravenous high-dose interleukin-II every 8 hours on days 1-5 and 15-19 every 12 weeks. One hundred twenty patients were treated. Ninety-nine percent underwent nephrectomy prior to treatment. Seventy-one percent had intermediate risk disease. Ninety-six percent of the patients had clear cell carcinoma. The investigator assessed response rate was 29%. There were 2 treatment related deaths. Median PFS was 4.4 months and 20 responses are ongoing from 4 months – 35+ months in duration. The response rate for clear cell renal cell carcinoma was 30%, which is significantly better than historical experience. Clear cell histology may select patients who respond to IL-2.

References
1. Warde PR, Mason MD, Sydes MR, et al. Intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). J Clin Oncol. 2010;28(15s). Abstract CRA4504.

2. Kelly WK, Halabi S, Carducci MA, et al. A randomized, double-blind, placebo-controlled phase III trial comparing docetaxel, prednisone, and placebo with docetaxel, prednisone, and bevacizumab in men with metastatic castration-resistant prostate cancer (mCRPC): Survival results of CALGB 90401. J Clin Oncol. 2010;28(15s). Abstract LBA4511.

3. Pili R, Haggman M, Stadler WM, et al. A randomized, multicenter, international phase II study of tasquinimod in chemotherapy naïve patients with metastatic castrate-resistant prostate cancer (CRPC). J Clin Oncol. 2010;28(15s). Abstract 4510.

4. De Bonno JS, oudard S, Ozguroglu M, et al. Cabazitaxel or mitoxantrone with prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel: Final results of a multinational phase III trial (TROPIC). J Clin Oncol. 2010;28(15s). Abstract 4508.

5. Fizazi K, Carducci MA, Smith MR, et al. A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2010;28(15s). Abstract LBA4507.

6. Escudier BJ, Negrier S, Gravis G, et al. Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial. J Clin Oncol. 2010;28(15s). Abstract 4516.

7. McDermott DF, Ghebremicahel MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) "SELECT" trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2010;28(15s). Abstract 4514.

Part 4: Hematologic Malignancies >>

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