Tag Archives: MET inhibitors

ASCO 2011: Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors

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Cabozantinib (XL184) demonstrated high rates of disease control in patients with prostate, ovarian and liver cancers. The investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. 

ASCO Releases Studies From Upcoming Annual Meeting – Important Advances in Targeted Therapies, Screening, and Personalized Medicine

The American Society of Clinical Oncology (ASCO) today highlighted several studies in a press briefing from among more than 4,000 abstracts publicly posted online at http://www.asco.org in advance of ASCO’s 47th Annual Meeting. An additional 17 plenary, late-breaking and other major studies will be released in on-site press conferences at the Annual Meeting.

The meeting, which is expected to draw approximately 30,000 cancer specialists, will be held June 3-7, 2011, at McCormick Place in Chicago, Illinois. The theme of this year’s meeting is “Patients. Pathways. Progress.”

“This year marks the 40th anniversary of the signing of the National Cancer Act, a law that led to major new investments in cancer research. Every day in our offices, and every year at the ASCO meeting, we see the results of those investments. People with cancer are living longer, with a better quality of life, than ever before,” said George W. Sledge Jr., M.D., President of ASCO, Ballve-Lantero Professor of Oncology and professor of pathology and laboratory medicine at the Indiana University School of Medicine.

“With our growing understanding of the nature of cancer development and behavior, cancer is becoming a chronic disease that a growing number of patients can live with for many years,” said Dr. Sledge. “The studies released today are the latest examples of progress against the disease, from new personalized treatments, to new approaches to screening and prevention.”

The study results from a phase II clinical trial involving cabozantinib (XL184) were highlighted today in the ASCO press briefing, as summarized below.

Novel Multi-targeted Agent Cabozantinib (XL184) Has Significant Effect on Several Advanced Solid Tumors, and Can Shrink or Eliminate Bone Metastases 

Cabozantinib (XL184) – an oral inhibitor of MET and VEGFR2 kinases involved in the development and progression of many cancers – showed strong responses in patients with various advanced cancers in a phase II trial. The drug demonstrated particularly high rates of disease control for advanced prostate, ovarian and liver cancers, which are historically resistant to available therapies. The drug also fully or partially eliminated bone metastases in patients with breast and prostate cancers and melanoma.

Michael S. Gordon, M.D., President & Chief Executive Officer, Pinnacle Oncology Hematology.

“Cabozantinib appears to have significant effects on several treatment-resistant tumors, as well as impressive effects on bone metastases. In addition, these effects are associated with rapid improvement in pain, a reduction in opiate narcotic requirements and improvement in anemia,” said lead author Michael S. Gordon, M.D., a medical oncologist at Pinnacle Oncology Hematology located in Scottsdale, Arizona. “The implications of these results are very exciting—it is unusual to find a targeted therapy, absent of a molecular mutation in tumors, that works in bony disease and has this activity.”

To be eligible for the study, patients had to have advanced, progressive solid tumors, with or without bone metastases. Of 398 evaluable patients (of 483 enrolled in the trial), 39 percent had bone metastases at baseline. Patients received cabozantinib over 12 weeks. The trial was designed as a “discontinuation” trial, in which those who had partial responses stayed on the drug; those with stable disease were randomized to cabozantinib or placebo; and patients with progressive disease were removed from the trial. This novel type of clinical trial design more quickly evaluates the disease-stabilizing activity of growth-inhibitory agents like cabozantinib, compared to the traditional model of randomizing all patients to either the experimental arm or placebo.

Among 398 patients evaluable with all types of cancer included in the trial, the collective overall response rate was 9 percent (34 of 398). The highest disease control rates (partial response and stable disease) at week 12 were 76 percent for liver cancer (22 of 29 patients), 71 percent for prostate cancer (71 of 100 patients), and 58 percent for ovarian cancer (32 of 51 patients). [emphasis added].

Of the 51 evaluable ovarian cancer patients noted above, 28 are platinum drug resistant, 17 are platinum drug sensitive, and 6 have unknown status. The median number of systemic treatments prior to trial enrollment was 2. The overall response rate (complete response and partial response based on modified RECIST criteria) for ovarian cancer was 12/51 (24%).  Upon breakdown, the response rate was 5/28 (18%) for platinum drug resistant patients, and 5/17 (29%) for platinum drug sensitive patients. Five additional partial responses await confirmation. After a median follow-up of 4 months (range: 1 to 11 months), the median duration of response and median progression free survival have not been reached. The most common related adverse events ( ≥grade 3) among ovarian cancer patients were hand-foot syndrome (10%), diarrhea (8%) and fatigue (4%). Drug dose reductions and permanent discontinuations for adverse events occurred in 43% and 10% of the ovarian cancer patients, respectively. Based on these findings, the investigators concluded that cabozantinib exhibits clinical activity in ovarian cancer patients with advanced disease, regardless of prior platinum drug status, as reflected by the high rates of response. [emphasis added] Accordingly, randomization in the ovarian cancer cohort was halted & patients unblinded due to the observed high efficacy.

Fifty-nine of 68 patients with bone metastases (including patients with breast and prostate cancers and melanoma) experienced either partial or complete disappearance of the cancer on bone scans, often with significant pain relief and other improved cancer-related symptoms.

The reduction of bone metastases and pain relief was an unexpected finding in this study, Dr. Gordon said. Independent review by radiologists confirmed that bone metastases disappeared in the majority of patients who had bone metastases when they entered the study. The majority of these patients had castration-resistant prostate cancer (CRPC), but patients with breast cancer and melanoma also had disappearance of bone metastases. Bone metastases greatly contribute to morbidity and mortality in patients with these types of cancer, which typically spread to the bone.

Due to these results, the study has been expanded to include more CRPC patients. Similarly, the high rate of lasting responses in ovarian cancer patients led researchers to also expand the study to evaluate the drug’s effect on patients with a particularly resistant form of the disease known as platinum drug resistant/refractory ovarian cancer. [emphasis added]

This study expansion results will help determine the design of future phase III trials, which will assess whether the drug extends patients lives or has other longer-term benefits among patients with specific cancer types. At present, cabozantinib is being investigated for use as a single agent. Additional studies will evaluate the efficacy and tolerability of appropriate combinations with other agents for future indications.

For the solid tumor patients collectively, the most common grade three or above adverse events were fatigue (9 percent) and hand-foot syndrome (8 percent). Dose reductions were required in 41 percent of patients due to side effects; 12 percent were removed from the trial for adverse events.

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Therapeutic Response To The Angiogenesis Inhibitor Sunitinib In Ovarian Clear Cell Cancer

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A group of international researchers reported sustained responses in two ovarian clear cell cancer (OCCC) patients with chemotherapy-resistant disease, who were treated with the anti-angiogenesis inhibitor sunitinib (Sutent®). The researchers emphasize the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer, and note significant common scientific characteristics possessed by both OCCC and renal clear cell cancer.

Clear Cell Carcinoma of the Ovary

Ovarian clear cell cancer (OCCC) is a rare form or subtype of epithelial ovarian cancer that is generally refractory to platinum-based chemotherapy. A group of international researchers from the United Kingdom, Australia, Japan, Canada and the United States recently reported results from comprehensive OCCC tumor gene expression and copy number testing, which was designed to identify potential therapeutic targets of OCCC.

Gene expression and DNA copy number testing was performed using primary human OCCC tumor samples, and the test findings were confirmed by immunohistochemistry (IHC) on tissue microarrays. Based on this testing, the researchers identified specific over-expression of the IL6 (interleukin-6)-STAT3 (signal transducer and activator of transcription 3)-HIF (hypoxia-inducible factors) cellular pathway in OCCC tumors, as compared with high-grade serous ovarian cancers. Expression of PTHLH (parathyroid hormone-like hormone) and high levels of circulating IL6 were also found in OCCC patients, and the researchers believe that this finding may explain the frequent occurrence of hypercalcemia and thromboembolic events in OCCC. Notably, the study results set forth a description of amplification of several RTKs (receptor tyrosine kinases), most notably MET (met proto-oncogene [hepatocyte growth factor receptor]), which certainly suggests other potential therapeutic targets for this hard-to-treat subtype of ovarian cancer.

Circulating IL6 levels were measured in the blood serum from patients with OCCC or high-grade serous ovarian cancers and corresponded to progression-free and overall survival. Two OCCC patients were treated with sunitinib and their therapeutic responses were measured clinically and by positron emission tomography (PET). The researchers reported sustained clinical and functional imaging responses in two OCCC patients with chemotherapy-resistant disease who were treated with sunitinib, thereby showing  significant scientific parallels with renal clear cell cancer.

Based upon the findings above, the researchers highlighted the importance of specific therapeutic targets in the treatment of OCCC, and suggested that more extensive clinical trials with sunitinib in OCCC patients are warranted.  The overarching findings of this study provide significant impetus to the growing realization that OCCC is molecularly and clinically distinct as compared to other forms of ovarian cancer.

Source: Anglesio MS, George J, Kulbe H, et. al. IL6-STAT3-HIF Signalling and Therapeutic Response To The Angiogenesis Inhibitor, Sunitinib, In Ovarian Clear Cell Cancer. Clin Cancer Res. 2011 Feb 22. [Epub ahead of print] PubMed PMID: 21343371.

Additional Information:

  • Dedicated Ovarian Clear Cell Cancer Clinical Trials (currently recruiting as of 3/25/11).

A Phase II Evaluation of SU11248 (Sunitinib Malate) (IND #74019, NSC #736511) in the Treatment of Persistent or Recurrent Clear Cell Ovarian Carcinoma, Clinical Trial Summary, NCT00979992, ClinicalTrials.gov.

A Phase II Evaluation of Temsirolimus (CCI-779) [Torisel®] (NCI Supplied Agent: NSC# 683864, IND# 61010) in Combination With Carboplatin and Paclitaxel Followed by Temsirolimus (CCI-779) Consolidation as First-Line Therapy in the Treatment of Stage III-IV Clear Cell Carcinoma of the Ovary, Clinical Trial Summary, NCT01196429, ClinicalTrials.gov.

  • Open Ovarian Cancer and Solid Tumor Clinical Trials Testing MET Inhibitors (as of 3/25/11)

We provide below a list of MET inhibitors that are currently available through open ovarian cancer and solid tumor clinical trials.  A few caveats are noteworthy.

First, the association between MET inhibiton and ovarian clear cell cancer inhibition has NOT been established as a form of treatment in large randomized, prospective clinical trials.

Second, most of the clinical trials listed below are phase I studies designed to test the biological activity and safety of the drug — not the effectiveness.  Patients enrolled in a phase I trial are generally the first humans to receive the study drug.

Third, all patients should seek advice from their doctor in advance of deciding to enroll in a clinical trial. Many of the clinical drugs listed below inhibit one or more cellular functions in addition to MET.

List of open solid tumor clinical trials testing AMG 208.

List of open solid tumor clinical trials testing MGCD-265.

List of open solid tumor clinical trials testing PF-2341066 (crizotinib)(NCT01121588 & NCT00585195).

List of open ovarian cancer clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing sunitinib (SU11274)/Sutent®.

List of open solid tumor clinical trials testing cabozantinib (a/k/a XL184 or BMS-907351).

List of open solid tumor clinical trials testing ARQ197.

List of open solid tumor clinical trials testing INCB28060.

List of open solid tumor clinical trials testing E7050.

List of open solid tumor clinical trials testing MGCD265.

  • Genetic Similarity Between Ovarian Clear Cell Cancer & Renal Clear Cell Cancer

Yoshida S, Furukawa N, Haruta S, et. al. Theoretical model of treatment strategies for clear cell carcinoma of the ovary: focus on perspectives. Cancer Treat Rev. 2009 Nov;35(7):608-15. Epub 2009 Aug 8. Review. PubMed PMID: 19665848.

Rauh-Hain JA, Penson RT. Potential benefit of Sunitinib in recurrent and refractory ovarian clear cell adenocarcinoma. Int J Gynecol Cancer. 2008 Sep-Oct;18(5):934-6. Epub 2007 Dec 13. PubMed PMID: 18081793.

Zorn KK, Bonome T, Gangi L, et. al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res. 2005 Sep 15;11(18):6422-30. PubMed PMID: 16166416.

Exelixis Reports Promising Interim Data From Ovarian Cancer Patients Treated With XL184

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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 platinum–refractory 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].