A randomized phase II (RP2) trial of ridaforolimus (R) compared with progestin (P) or chemotheraphy (C) in female adult patients with advanced endometrial carcinoma

Reporter: J. Nicholas Lukens, MD
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 5 de junio del 2011

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Presenter: Amit M. Oza, MD
Presenter's Institution: Princess Margaret Hospital, Toronto, ON, Canada

Background/Introduction

  • Endometrial cancer is the most common gynecologic malignancy, with an estimated 43,470 new cases and 7,950 deaths in 2010.
  • Primary treatment consists of surgical resection including hysterectomy, bilateral salpingo-oophorectomy, abdominopelvic washings, and lymph node evaluation, followed by observation, or adjuvant radiation and/or chemotherapy depending on pathologic risk factors.
  • Recurrence occurs in approximately 7-11% of women with endometrial cancer. Local recurrences predominate in patients treated with surgery alone (75%) while distant recurrence is more common in patients treated with combined modality therapy. Many patients with local recurrence may be salvaged with surgery or radiation, especially if the recurrence is limited to the vaginal cuff.
  • First-line treatment for patients with metastatic disease, pelvic sidewall recurrence, or distant recurrence includes hormone therapy with progestins (9-25% response rate), or chemotherapy (platinum, taxanes, or anthracyclines).
  • Treatment options for advanced recurrent or metastatic endometrial cancer after first line chemotherapy are limited.
    • There are no established second line options, and novel therapeutic approaches in this area are desperately needed.
  • The PI3K-AKT-mTOR pathway is a key growth factor mediated signal transduction pathway that prepares the cell for growth and division, and mTOR is a key checkpoint in this pathway and represents a novel target.
  • mTOR has been identified as a target in endometrial cancer because there are a high proportion of endometrial cancer patients who have PI3K mutations or PTEN mutations (PTEN is upstream from PI3K), and therefore inhibition of this pathway may lead to cell cycle arrest.
  • Ridaforolimus is a novel mTOR inhibitor that has been formulated for oral and IV delivery.
  • Previous studies of the mTOR inhibitor temsirolimus had shown modest first line activity in endometrial cancer (24% response rate), and the IV formulation of Ridaforolimus had shown 9% response rate as second line therapy.
  • This study was conducted as a randomized Phase II study to evaluate oral Ridaforolimus in women with recurrent or metastatic endometrial cancer who had failed 1-2 lines of prior chemotherapy.

Methods

  • Eligibility criteria: Women with unresectable recurrent or metastatic endometrial cancer who had progressive disease following 1-2 prior lines of chemotherapy, with an ECOG PS of less than or equal to 1.
  • Exclusion criteria: chemotherapy within 6 months, prior hormonal therapy.
  • Randomized 1:1:
    • Oral Ridaforolimus 40 mg daily x5 days -> 2 days off, versus
    • Oral progestin or chemotherapy. The chemotherapy was added as an option for the control group after initiation of the trial.
  • The efficacy was assessed by CT scan every 8 weeks, using RECIST criteria.
  • Primary end-point: progression free survival (PFS) based on independent radiology confirmation
  • There was a built-in pre-specified, event-driven, interim analysis to evaluate proof of concept (POC), with plan to close enrollment if POC was confirmed.
  • 130 patients were randomized; the interim PFS analysis was based on 95 patients who received at least 2 cycles of therapy

Results

  • The experimental arms were well balanced.
  • 1/3 of patients had papillary serous carcinoma, and about 1/3 of women had high grade disease in both arms
  • The PFS analysis (with radiologic confirmation) revealed a significant improvement in median PFS in the Ridaforolimus arm, from 1.9 months to 3.6 months.
    • Based upon this analysis, further accrual was stopped.
  • In terms of response rates, significantly more patients in the Ridaforolimus arm had stable disease compared to the control arm (56% versus 28%, p = 0.003)
  • There was no difference in median overall survival between the 2 groups, 9.6 months for the Ridaforolimus arm and 9 months for the control arm.
  • Adverse events with Ridaforolimus were consistent with prior studies of mTOR inhibitors (class effect), including:
    • Mucositis, diarrhea, hyperglycemia, renal dysfunction, and pneumonitis (rare).
    • Serious drug-related adverse events occurred in 27% of patients.

Authors' Conclusions

  • This study demonstrates that Ridaforolimus nearly doubled the median PFS in this patient population with no approved therapies, with an absolute PFS benefit of 1.7 months.
  • There was no difference in OS, however the study was not powered to detect such a difference.
  • The safety profile of Ridaforolimus is consistent with previously reported toxicity with mTOR inhibitors and mostly consists of Grade 1/2 toxicity including diarrhea, mucosal inflammation, and hyperglycemia.

Clinical/Scientific Implications

  • Although the absolute benefit in progression free survival provided by Ridaforolimus is modest (1.7 months), this trial represents a therapeutic advancement for a group of patients with no real therapeutic options. The benefit in terms of prolonged PFS must be weighed against the rate of serious drug-related adverse events of 27%.
  • Among patients with endometrial cancer, there are molecular differences, such as mutations in the PTEN or PI3K pathways, which may be driving progression of disease in a certain subset of patients. Traditional clinical trials do not incorporate these molecular differences in their design. Perhaps by testing for molecular signatures in order to enrich for patients who are more likely to respond to a targeted agent, the therapeutic index of drugs like Ridaforolimus can be enhanced.
  • Given the complexity and redundancy of signal transduction pathways modulating the cell cycle, mTOR inhibitors like Ridaforolimus may be more efficacious in combination with other targeted agents or chemotherapy, which represents a promising avenue for research in this challenging patient population.

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