2011 ASCO: Exelixis Reports Expanded Cabozantinib (XL184) Phase II Data For Advanced Ovarian Cancer; Six Deaths Reported

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the recent 2011 American Society of Clinical Oncology Annual Meeting. The overall solid tumor Phase 2 safety and tolerability data reference six deaths, including two ovarian cancer patients.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan

Exelixis, Inc. reported expanded Phase 2 study data with respect to cabozantinib (XL184) use in advanced ovarian cancer patients at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting . The overall solid tumor Phase 2 safety and tolerability data refers to six deaths, including two ovarian cancer patients.

On May 19, 2011, we reported promising cabozantinib phase 2 solid tumor (including ovarian) data, which was presented at an ASCO press briefing held in advance of the 2011 ASCO Annual Meeting. As noted in our May 19 article, cabozantinib demonstrated excellent activity against several solid tumors, including ovarian cancer. In addition, we reported that cabozantinib showed promising activity in ovarian cancer patients independent of prior response to platinum drug-based therapies.

Ronald J. Buckanovich, M.D., Ph.D., Assistant Professor, Departments of Internal Medicine & Obstetrics and Gynecology, University of Michigan, presented the expanded cabozantinib Phase 2 data relating to use of the drug in advanced ovarian cancer patients, on June 4 at the 2011 ASCO Annual Meeting.

Ovarian Cancer Patient Population & Overall Response Rate

(Image Source: Exelixis, Inc.)

The cabozantinib trial is an ongoing phase 2 adaptive randomized discontinuation trial. As of the February 11, 2011 cut-off date, accrual in the cabozantinib study cohort was complete at 70 patients.

The 70 patients enrolled in the ovarian cancer cohort received oral cabozantinib (100 mg) daily over a 12 week “Lead-in Stage.” These patients had a minimum follow-up of at least 12 weeks and were thus evaluable for safety and the primary efficacy endpoint of response per RECIST (Response Evaluation Criteria in Solid Tumors).

Patient tumor response was assessed every 6 weeks. Receipt of cabozantinib treatment beyond the 12 week open label Lead-in Stage was based upon patient response: (1) patients with a partial response (PR) or complete response (CR) continued taking cabozantinib, (2) patients with stable disease (SD) were randomized to the cabozantinib treatment arm or the placebo treatment arm (collectively referred to as the “Blinded Randomized Stage”), and (iii) patients with progressive disease (PD) discontinued study treatment. The study primary endpoint was overall response rate (ORR) per RECIST in the Lead-in Stage, and progression free survival (PFS) in the Blinded Randomized Stage. Accrual in any cohort could be halted for high ORR or PD.

Approximately half of the 70 patients enrolled in the cohort were considered platinum drug-refractory/-resistant (49%), defined as a platinum drug-free interval of 6 months or less, and the remainder of patients (51%) had platinum-sensitive disease based on a platinum-free interval greater than 6 months.

The baseline patient tumor histologic characteristics are as follows: serous ovarian cancer (79%), clear cell ovarian cancer (4%), endometrioid ovarian cancer (6%), and other forms of ovarian cancer (11%)

More than half the patients (57%) received 2 or more prior lines of platinum therapy prior to trial enrollment. Some patients also had additional prior lines of therapy with agents such as pegylated liposomal doxorubicin (brand name: Doxil®) or topotecan (brand name: Hycamtin®) (32%), gemcitabine (brand name: Gemzar®) (29%), and VEGF (vascular endothelial growth factor) pathway inhibitors (10%).

Evidence of objective tumor regression was observed in 73% of patients with at least 1 post-baseline medical imaging scan. The best overall response rate per RECIST criteria was 24% (16 PRs and 1 CR). The overall Week-12 disease control rate (DRC = CR + PR + SD) was 53%. The Week-12 DCRs in the platinum drug-refractory, -resistant, and -sensitive groups were 36%, 39%, and 67%, respectively.

Based on an observed high rate of clinical activity, randomization was halted, and randomized patients were unblinded.  At this point, the unblinded randomized patients that were treated with placebo were allowed to “cross-over” to treatment with cabozantinib. Disease stabilization was experienced by some ovarian cancer patients who had progressive disease prior to treatment cross-over.

“These latest results in metastatic ovarian cancer demonstrate the potential broad utility of cabozantinib beyond bone-predominant types of cancers such as castration-resistant prostate cancer. The high rates of durable response with our dual inhibitor of MET and VEGFR2 compare favorably to those of other single-agent targeted therapies and cytotoxic agents in development,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “These results underscore the potential of cabozantinib in metastatic ovarian cancer, and we are in discussions with leading cooperative groups to plan further evaluation of cabozantinib in randomized trials for this indication.”

Activity in Platinum Drug-Sensitive, -Refractory, and -Resistant Disease

Ignace Vergote, M.D., Ph.D., senior author of the cabozantinib (XL184) ASCO presentation & Chairman, Leuven Cancer Institute, University of Leuven, European Union

(Image Source: Exelixis, Inc.)

Two of 11 patients (18%) with platinum refractory disease, defined as a platinum-free interval of <1 month, achieved a confirmed response (1 CR and 1 PR).

In the subset of patients with platinum-resistant disease, defined as a platinum-free interval of 1-6 months, 5 of 23 (22%) achieved a PR.

Ten of 36 patients (28%) with platinum sensitive disease achieved a PR.

A total of 37 patients experienced reductions in the ovarian cancer tumor marker CA-125 (cancer antigen-125), including 8 with decreases greater than 50%. There is no consistent concordance between CA-125 changes and tumor regression. The median duration of response has not yet been reached with 36 weeks of median follow-up.

“The continued activity of cabozantinib in a larger population of ovarian cancer patients is very encouraging, especially with respect to the clinical benefit observed in both platinum-sensitive and platinum-resistant/refractory disease. This activity profile has not been observed with other single-agent TKIs [tyrosine kinase inhibitors], and cabozantinib has the potential to be an important new treatment for ovarian cancer,” said Ignace Vergote, M.D., Ph.D., senior author of the presentation and Chairman of the Leuven Cancer Institute at the University of Leuven, European Union. “The high rate of disease control in platinum-resistant and platinum-refractory disease suggests that cabozantinib may help to address the substantial unmet medical need faced by patients who have sub-optimal responses to platinum-based therapies. I believe that further evaluation will help to define the potential role of cabozantinib in the treatment of ovarian cancer.”

General Safety & Tolerability Data 

Safety data are available for the 70 patients in the Lead-In phase of the cabozantinib study. The most common CTCAE (Common Terminology Criteria for Adverse Eventsgrade 3 or 4 adverse events (AEs), regardless of causality, were diarrhea (10%), fatigue (9%), palmar-plantar erythrodysesthesia  syndrome (also referred as “hand-foot syndrome”)(7%), vomiting (4%), abdominal pain (3%), hypomagnesemia (3%), and nausea, constipation, rash, increased transaminase, and hypertension (each 1%). At least one dose reduction was reported in 37% of patients. Less frequent important medical events, regardless of causality, were hemorrhage (11% all CTCAE grades, 0% CTCAE grade 3 or 4), venous thrombosis (6% all CTCAE grades, 4% CTCAE grade 3 or 4), and gastrointestinal perforation (6% all CTCAE grades, 0% CTCAE grade 3 or 4).

To access the cabozantinib clinical study data information, please visit www.exelixis.com/sites/default/files/pdf/ASCO_2011-XL184-Ovarian.pdf

Six Deaths Reported (Including Two Ovarian Cancer Patients)

If you examine the Exelixis press release dated June 4 (entitled, Exelixis’ Cabozantinib Demonstrates Encouraging Clinical Activity in Patients with Metastatic Ovarian Cancer — Disease control rate of 53% at week 12, response rate of 24%), which addresses data for cabozantinib use in advanced ovarian cancer patients, pay particular attention to the wording under the heading entitled, “Safety and Tolerability.”  Within the wording set forth under that heading, you will find the following statement: “Two cabozantinib-related grade 5 AEs [adverse events], one enterocutaneous fistula and one intestinal perforation, were reported after the Lead-In phase.” Pursuant to the CTCAE guidelines, a “grade 5 adverse event” is defined as “death related to AE [adverse event].”

We should also note that the two ovarian cancer deaths were summarized briefly in the ASCO presentation regarding cabozantinib use in advanced ovarian cancer.

The reporting of all six deaths is set forth in the Exelixis press release, dated June 5, 2011 (entitled, Exelixis’ Cabozantinib Demonstrates Broad Clinical Activity in Multiple Tumor Types), in similar fashion. Within this release, the sentence provided under the heading “Safety and Tolerability” states: “There were 6 (1%) cabozantinib-related grade 5 [adverse] events, all of which were reported after the Lead-In phase of the trial: respiratory compromise (breast cancer), hemorrhage (NSCLC [non-small cell lung cancer]), enterocutaneous perforation (ovarian cancer), intestinal perforation (ovarian cancer), gastrointestinal hemorrhage (pancreatic cancer), and death (CRPC [castrate resistant prostate cancer]).”

Exelixis Chief Executive Michael Morrissey said the safety statistics are consistent with targeted cancer therapies like cabozantinib that block a pathway used by tumor cells to secure blood vessels.

Cowen & Co analyst Eric Schmidt said the rate of cabozantinib treatment-related deaths — 1 percent — was “no different from what we have seen for every other Phase 1 and 2 trials here at ASCO.”

“While drug safety is of less concern in cancer indications than in others, the apparent morbidities associated with cabo[zantinib] use will confound interpretation of clinical benefit in a trial designed to show anything less than overall survival,” Canaccord analyst George Farmer said in a research note.

In a note to investors, Piper Jaffray analyst Edward Tenthoff said: “The company is exploring lower doses, but the concern is that cabo[zantinib] will not retain the impressive efficacy seen to date.”

Mr. Morrissey said Exelixis plans to move forward with the current daily 100 mg dose of the drug.

Dr. Nicholas J. Vogelzang (Director, Comprehensive Cancer Centers of Nevada) Discusses Mortalities in the Cabozantinib (XL184) Trial

Take Away Message

  • Cabozantinib demonstrates promising activity in both platinum drug-sensitive and platinum drug-resistant/-refractory ovarian cancer.
  • Week 12 overall disease control rate of 53%.
  • Response rates of 18% in platinum-refractory, 22% in platinum-resistant and 28% in platinum-sensitive patients.
  • Cabozantinib shows encouraging duration of response.
  • After 36 weeks of follow-up, median duration of response not reached.
  • Tolerability profile is consistent with that of other tyrosine kinase inhibitors (6 solid tumor patient deaths (1% of all solid tumor pts), including 2 ovarian cancer patients (3% of ovarian cancer pts)).
  • Discordant effects observed between CA-125 changes and clinical activity.
  • Simultaneous targeting of MET and VEGFR2 with cabozantinib results in robust effects in patients with advanced ovarian cancer.
  • Non-randomized expansion cohort is currently accruing in platinum-resistant/-refractory ovarian cancer.

About the MET & VEGFR2 Pathways

To learn more about (i) the role of MET in cancer, (ii) the relationship between the MET and VEGFR pathways, and (iii) the dual inhibition of MET and VEGFR2, visit http://www.metinhibition.com/.

About Cabozantinib (XL184)

Cabozantinib (XL184) is a potent, dual inhibitor of MET and VEGFR2. Cabozantinib is an investigational agent that provides coordinated inhibition of metastasis and angiogenesis to kill tumor cells while blocking their escape pathways. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions (i.e., deprivation of adequate oxygen supply) in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, anti-metastatic and anti-angiogenic effects, including: (i) extensive apoptosis of malignant cells; (ii) decreased tumor invasiveness and metastasis; (iii) decreased tumor and endothelial cell proliferation; (iv) blockade of metastatic bone lesion progression; and (v) disruption of tumor vasculature.

About Exelixis

Exelixis, Inc. is a biotechnology company committed to developing small molecule therapeutics for the treatment of cancer. Exelixis is focusing its resources and development efforts exclusively on cabozantinib, its most advanced solely-owned product candidate, in order to maximize the therapeutic and commercial potential of this compound. Exelixis believes cabozantinib has the potential to be a high-quality, differentiated pharmaceutical product that can make a meaningful difference in the lives of patients. Exelixis has also established a portfolio of other novel compounds that it believes have the potential to address serious unmet medical needs. For more information, please visit the company’s web site at www.exelixis.com

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Cabozantinib (XL184) Clinical Trial Information
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Exelixis Reports Promising Interim Data From Ovarian Cancer Patients Treated With XL184

Exelixis reports promising interim data from ovarian cancer patients treated with XL184, including:  a  32% confirmed response rate per RECIST in patients with platinum-resistant or platinum-sensitive disease, and a 64% overall week-12 disease control rate.

Ignace Vergote, M.D., Ph.D., Head, Department of Obstetrics & Gynecology and Gynecologic Oncology, Catholic University Hospital, Leuven, Belgium

Exelixis, Inc.  today reported interim data from the cohort of patients with advanced epithelial ovarian cancer, primary peritoneal, or fallopian tube carcinoma treated with XL184 in an ongoing phase 2 adaptive randomized discontinuation trial (RDT) [1]. Ignace Vergote, M.D., Ph.D., Head of the Department of Obstetrics and Gynecology and Gynecologic Oncology at the Catholic University Hospital Leuven, Leuven, Belgium, will present the data in the Molecular-Targeted Therapies-Clinical Trials poster session (Abstract #407) on Thursday, November 18th, at the 22nd EORTC-NCI-AACR [2] Symposium on Molecular Targets and Cancer Therapeutics, being held in Berlin, Germany.

XL184 Activity in Patients with Ovarian Cancer

XL184 is an oral, potent inhibitor of MET, VEGFR2 and RET. MET overexpression has been observed in advanced ovarian cancer, and anti-VEGF pathway agents have shown clinical benefit in ovarian cancer patients. For these reasons, co-targeting of the MET and VEGF signaling pathways using XL184 may represent a promising treatment strategy.

As of the November 1, 2010 cut-off date, a total of 51 patients were enrolled into the ovarian cancer cohort, with 31 evaluable for response, and 41 evaluable for safety. The median number of prior systemic treatments was 2. Tumor shrinkage was observed in 30 of 37 (81%) patients with measurable metastatic lesions. Of 31 patients evaluable for response per RECIST (Response Evaluation Criteria In Solid Tumors), 10 (32%) achieved a confirmed partial response (PR). Stable disease (SD) was reported in 15 patients (48%) including 3 patients who achieved unconfirmed PRs. The overall week-12 disease control rate (DCR)(complete responses + partial responses + stable disease responses = DCR) was 64%.

Upon subset analysis, 5 of 17 platinumrefractory or –resistant patients (29%) evaluable for response per RECIST achieved a confirmed PR. SD was reported in 7 patients (41%) including 2 patients with unconfirmed PRs. The week-12 DCR was 59% in platinum-resistant/refractory patients. Durable responses have been observed, including 2 patients with platinum-refractory or resistant disease who remain on study for 34+ and 36+ weeks, and 3 patients with platinum-sensitive disease on study for 24, 24+, and 28+ weeks. Some patients have experienced reductions in the ovarian cancer blood marker CA125, but in general no clear concordance between CA125 changes and tumor shrinkage has been observed.

Safety data are available for 49 patients who had at least 6 weeks of follow-up. The most common grade greater-than or equal to 3 adverse events, regardless of causality were PPE (Palmar-Plantar Erythrodysesthesia) syndrome (also referred to as “hand-foot syndrome”) (12%), diarrhea (7%), fatigue, vomiting (each 5%), nausea, rash, abdominal pain, hypertension, and hypomagnesemia (each 2%).

“The activity of XL184 in women with both platinum-sensitive and platinum-resistant/refractory disease is unique and encouraging. The response rate and overall disease control rate of this oral agent are impressive especially in the group of patients with platinum refractory/resistant ovarian cancer, and compare favorably to other targeted and systemic agents in development,” said, Dr. Vergote. “I believe these encouraging data warrant further evaluation of XL184 in ovarian cancer.”

Michael M. Morrissey, Ph.D., President & Chief Executive Officer, Exelixis, Inc.

“The high response rate in patients with ovarian cancer is reflective of the broad anti-tumor activity of XL184 observed in multiple tumor types to date,” said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. “The data from the RDT underscore the novel and differentiated clinical activity of XL184 in diverse tumor indications with predominance of either soft tissue or bone involvement.”

To access the clinical data poster mentioned in this press release, please visit www.exelixis.com.

Broad Clinical Activity of XL184 – Randomized Discontinuation Trial

XL184 has demonstrated anti-tumor activity in 9 of 12 indications studied to date. In ongoing trials, compelling activity has been observed in medullary thyroid cancer, glioblastoma, and clear cell renal cancer. In the RDT, XL184 is being evaluated in nine different tumor types, with clear signals of activity in six: prostate, ovarian, hepatocellular, breast, non-small cell lung cancer and melanoma. The adaptive RDT design allowed for rapid simultaneous assessment of the activity of XL184 across nine different tumor indications. As of the November 1, 2010 cut-off date, a total of 397 patients have been enrolled into the nine disease-specific cohorts, with 273 evaluable for response, and 312 evaluable for safety. Of 273 patients evaluable for response per RECIST, 39 achieved a PR (either confirmed or unconfirmed) and 100 had SD at week 12. The week-12 DCR for the overall population was 49%, with the highest rates occurring in hepatocellular cancer (75%), castration-resistant prostate cancer (71%), ovarian cancer (64%), melanoma (45%), non-small cell lung cancer (42%) and breast cancer (42%). Of note, a breast cancer patient with evidence of bone metastasis on bone scan demonstrated evidence of resolution on bone scan accompanied by 29% reduction in tumor size. XL184 has been generally well tolerated with a consistent adverse event profile across the nine different RDT tumor types.

About XL184

XL184, an inhibitor of tumor growth, metastasis and angiogenesis, simultaneously targets MET and VEGFR2, key kinases involved in the development and progression of many cancers, including ovarian cancer. It has recently been shown in preclinical models that treatment with selective inhibitors of VEGF signaling can result in tumors that are more invasive and aggressive compared to control treatment. In preclinical studies, upregulation of MET has been shown to occur in concert with development of invasiveness after selective anti-VEGF therapy, and may constitute a mechanism of acquired or evasive resistance to agents that target VEGF signaling. Accordingly, treatment with XL184 in similar preclinical studies resulted in tumors that were less invasive and aggressive compared to control or selective anti-VEGF treatment. Therefore, XL184 has the potential for improving outcomes in a range of indications, including those where selective anti-VEGF therapy has shown minimal or no activity.

About Exelixis

Exelixis, Inc. is a development-stage biotechnology company dedicated to the discovery and development of novel small molecule therapeutics for the treatment of cancer. The company is leveraging its biological expertise and integrated research and development capabilities to generate a pipeline of development compounds with significant therapeutic and commercial potential for the treatment of cancer. Currently, Exelixis’ broad product pipeline includes investigational compounds in phase 3, phase 2, and phase 1 clinical development. Exelixis has established strategic corporate alliances with major pharmaceutical and biotechnology companies, including Bristol-Myers Squibb Company, sanofi-aventis, GlaxoSmithKline, Genentech (a wholly owned member of the Roche Group), Boehringer Ingelheim, and Daiichi-Sankyo. For more information, please visit the company’s web site at http://www.exelixis.com.

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1/Rosner GL, Stadler W, Ratain MJ. et. al.  Randomized discontinuation design: Application to cytostatic antineoplastic agents. J Clin Oncol 20:4478-4484, 2002.  Pursuant to this design, all patients receive the investigational drug for an initial period of time. Patients with standard radiologic tumor shrinkage within that timeframe would continue investigational therapy, while those with radiologic progression or unacceptable toxicity would discontinue therapy. All patients with radiologic stable disease after the initial therapy period are then randomized to continuing or discontinuing therapy in a double-blind placebo-controlled manner. This is an enrichment strategy in which patients with the end point of interest are preferentially enrolled in the randomized portion and in which the heterogeneity of the randomized population is decreased. These two factors result in an increased power for detecting a clinically relevant difference and decrease the number of patients exposed to placebo. Importantly, the enrichment is driven by the properties of the investigational drug as opposed to clinical prognostic factors identified in historical untreated patients or patients treated with a different class of agents. In addition, the statistical behavior of the trial is not highly dependent on investigators’ assumptions regarding the “no dose effect” (i.e., non-receipt of drug = no effect)  for time to progression or stable disease rate, and thus effectively deals with uncertainty in this variable. Finally, patients may find such a trial design more appealing, resulting in brisk accrual.

2/EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute], AACR [American Association for Cancer Research].