ASCO GI Preview - Heads Up for GI Cancer Drug Development

Posted by Marne Wessner on Tue,Jan 15, 2013 @ 08:00 AM

ASCO GI Cancer Drug Development

Abstract titles are up for ASCO GI, and here’s a list of the abstracts we are looking forward to seeing next week.  (Note that full abstracts won’t be available until January 22, so it is impossible to comment on the significance of these results until then.)

Abraxane positive in phase III for pancreatic cancer

The Abraxane study in pancreatic cancer (abstract 67) is likely to be the major news from this year’s meeting. At ESMO in October, KOLs were indicating that the results might be positive, and indeed, Celgene announced in November that this trial met its primary endpoint of overall survival with a statistically significant improvement over gemcitabine alone. Now we will finally see the data. There have been so many notable failed trials in this disease (axitinib and ganitumab, for example) that it’s exciting to finally see something positive!

New biomarker and safety data for Stivarga (regorafenib)

Bayer’s Stivarga was just approved for third line CRC in September 2012, and presentations at this meeting include biomarker and safety data (abstracts 318 and 467). Hopefully the new data will shed light on which patients are most suitable for Stivarga and how oncologists can deal with toxicities.

Ramucirumab data notably absent

We also note that the phase III gastric cancer trial of ramucirumab (VEGF inhibitor, Lilly), which was announced as positive a few months ago, will not be presented. The next opportunity to present the data at an important venue will be at the main ASCO meeting in June.

New GI cancer drugs on the horizon at last

KOLs have been complaining that there hasn’t been anything new in CRC for a long time, but it looks like the tide is finally turning with two new approvals in 2012, and some promising new agents on the horizon. All of these developmental agents could eventually make an impact in standards of care for CRC.

In HCC, there are a few developmental agents with early-phase data that will be presented. Of note is the Pfizer CDK inhibitor, PD-0332991, in HCC. Last month at SABCS, this agent reported very promising phase II efficacy data in ER+ breast cancer, as well as a mild toxicity profile. Efficacy combined with good tolerability could make it an attractive compound in HCC.

 

Key presentations of interest for drug development at ASCO GI

  1. Final results of a randomized phase III study of weekly nab-paclitaxel [Abraxane] plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (Von Hoff, et al, abstract LBA148)
  2. Mutational analysis of biomarker samples from the CORRECT study: Correlating mutation status with clinical response to regorafenib (Jeffers et al, abstract 381)
  3. Time course of regorafenib-associated adverse events in the Ph III CORRECT study (Grothey, et al, abstract 467)
  4. Ph II study of PD-0332991 in advanced HCC (Littman, et al, abstract 321)
  5. Patient-reported outcomes from a phase III multicenter, randomized, double-blind, placebo-controlled trial of gefitinib versus placebo in esophageal cancer progressing after chemotherapy: Cancer Oesophagus Gefitinib  (Dutton, et al, abstract 6)
  6. Ph II study of vismodegib, a hedgehog pathway inhibitor, combined with FOLFOX in patients with advanced GaCa and GEJ: A NY cancer consortium led study (Cohen, et al, abstract 67)
  7. A randomized, double-blind, placebo-controlled trial of trametinib in combination with gemcitabine for untreated metastatic PnCa (Infante, et al, abstract 291)
  8. Ph I/II study of golvantinib in combination with sorafenib in patients with advanced HCC: Ph I results (O’Neil, et al, abstract 294)
  9. Long-term efficacy and pharmacodynamic parameter analysis in pretreated KRAS-mutant mCRC patients treated with RG7160 (GA201), an ADCC-enhanced monoclonal anti-EGFR antibody (Delord, et al, abstract 379)
  10. Second-line therapy of KRAS-mutated mCRC with the MEK inhibitor selumetinib in combination with irinotecan: An AGICC study (Hochster, et al, abstract 380)

 


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Drug Development, Biotech Consulting, Competitive Intelligence, Gastrointestinal Cancer, GI Drug Development

Breast Cancer Drug Development - Targeting HER2 Activating Mutations

Posted by Judi Space on Thu,Jan 10, 2013 @ 09:00 AM

A Possible Development Pathway for Biotech Companies with PanHER Inhibitors?

Many Breast Cancer Patients Not Helped by Herceptin

For more than ten years oncologists have been aware of the role that Herceptin (trastuzumab, Roche/Genentech) has played in extending the lives of women with HER2 overexpressed breast cancer. Herceptin works by blocking the HER2 receptor from receiving activating stimuli from outside of the cell. In addition there is a second agent, Tykerb (lapatinib, GSK) which is able to block signaling from the tyrosine kinase domain of the receptor, inside the cell. Still, there are many patients who are not helped by these agents. These targeted therapies work when the receptor is overexpressed, but may not work when the receptors are mutated.

Breast cancer drug development - exposure to neratinibSomatic Breast Cancer Mutations Identified

At December’s San Antonio Breast Cancer Symposium, there was a talk given by Ron Bose from Washington University, about other perturbances of the HER2 receptor[1][2]. Over the last year, the Cancer Genome Atlas Breast Cancer has conducted genome sequencing of breast cancers. This endeavor has identified several somatic mutations that appear on the HER2 receptors in some breast cancers. A majority of the mutations were found in the kinase domain of the receptor. Most of the lesions analyzed were considered HER2 negative as they did not achieve the 3+ score in IHC testing.  

Ph II Trial of Neratinib in Breast Cancer Patients

Because the mutations cause constitutive activation of the receptor (it is always turned on), Herceptin cannot block its signaling from outside of the cell. The mutations are rare, and it is estimated that only about 5000 women in the US with breast cancer would have them. In cell line studies, Tykerb has some effect on cells with these mutations, but the agent that appears to have the most activity is neratinib (Puma), a “pan-HER” inhibitor. To that end, there will be a fairly large Ph II trial of neratinib in breast cancer patients who test negative for HER2 amplification but positive for these somatic mutations.

Breast Cancer Drug Development - Targeting Somatic Cancer Mutations

There is precedent for targeting somatic mutations in malignant lesions. Even in the same family of receptors, there are three agents with activity against EGFR: Iressa (gefitinib, AstraZeneca), Tarceva (erlotinib, Roche/Genentech) and afatinib (Boheringer Ingleheim). This has implications for the larger world of breast cancer biotech drug development targeted at the EGFR family of receptors as there are many “pan-HER” inhibitors in development that could potentially be used to treat tumors with these mutations.

Barriers to Breast Cancer Drug Development

The biggest barriers for development would be working up accurate testing systems to detect the mutations as predictive biomarkers of drug efficacy, and then getting these tests included in the battery of diagnostics used to analyze both primary breast tumors and recurrent disease.     


[1] Bose, R Activating HER2 mutations in HER2 gene amplification negative breast cancers, SABCS December 2012, S5-6


Pennside Partners is a leading pharmaceutical and biotech consulting firm with over 25 years experience. They are headquartered in the United States, the United Kingdom and Switzerland.

Tags: Oncology, Predictive Biomarkers, Targeted Therapy, Breast Cancer, Breast Cancer Drug Development, Breast Cancer Oncology, Breast Cancer Therapy

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Posted by Tom Penrice on Mon,Jan 07, 2013 @ 04:59 PM

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