Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘ESMO 2012’

Professor David Ferry presents at ESMO 2012 Press BriefingAt the European Society for Medical Oncology (ESMO) 2012 Congress in Vienna, David Ferry, Professor of Medical Oncology at New Cross Hospital in Wolverhampton, reported the results of the Cancer Oesophagus Gefinitib (COG) study, a UK 450 patient, multicenter, phase III clinical trial that looked at whether gefitinib (Iressa) could improve overall survival in esophageal cancer patients who had progressed after chemotherapy.

This is a disease for which there are no treatments that prolong life in the 2nd or 3rd line setting! Sadly, the trial results were negative; there was no difference in overall survival between the placebo and gefitinib study arms.

The results are shown in the graphic that Professor Ferry presented:

Overall Survival Curves for COG Trial presented at ESMO 2012

Placebo Arm (n=225): Median Overall Survival of 3.6 months

Gefitinib Arm (n=225): Median Overall Survival of 3.73 months

A non-significant difference. The data broken down by performance status shows:

  • PS0 – median OS = 6.03M
  • PS1 – median OS = 3.93M
  • PS2 – median OS = 1.97M

That you might think is the end of the story, just another negative trial, another example of the natural selection that takes place in the development of new cancer treatments.

“Gefitinib in Esophageal Cancer – just the beginning of a spicy story”

was the title given to the presentation by Arnaud D. Roth, MD Chief of Oncosurgery at Geneva University Hospital who discussed Professor Ferry’s paper at ESMO 2012.

There are a subgroup of patients who respond

Dr Roth pointed out that there were a subgroup of patients in the COG trial who responded well to gefitinib and lived longer as a result. In the waterfall plot he presented, you can see the partial response highlighted.

 Dr Roth discusses COG trial at ESMO 2012

Using crizotinib as an example, (it is effective in only 5.5% of NSCLC patients), Dr Roth challenged the audience as to why we couldn’t identify the subset of esophageal cancer patients who might respond well to gefitinib.

He noted that 50-70% of esophageal cancers overexpress EGFR protein, suggesting some basis for using an anti-EGFR agent such as gefitinib.

To define this subset of esophageal patients, “we need to go deeper into the biology of esophageal cancer,” Roth said.

His recommendations:

  • Do not lose too much time at looking for discreet mutations predicting response to gefitinib
  • Analyze the responding subpopulation by genomic profiling and examine if they correspond to a particular subtype
  • Validate findings in relatively small clinical studies

Dr Roth concluded that:

“Better knowledge in molecular biology in this disease might help to select patients who might benefit from anti-EGFR TKI’s”

In summary, while the COG trial showed that gefinitib does not improve overall survival in second or third line treatment of esophageal cancer, there is hope that in the future we may be able to identify those patients who might respond, and live longer as a result.

Mitesh J Borad MD presenting TH-302 data at ESMO 2012At the 2012 Congress of the European Society for Medical Oncology (ESMO 2012) in Vienna,  Mitesh J. Borad MD, Assistant Professor of Medicine at the Mayo Clinic in Scottsdale, AZ presented the results of the TH-CR-404 phase 2 clinical trial that compared the efficacy and safety of TH-302 (Threshold Pharmaceuticals) plus gemicitabine versus gemcitabine alone in patients with untreated advanced pancreatic cancer.

TH-302 is an experimental cancer drug in development that kills cells i.e. is cytotoxic under conditions of low oxygen (hypoxia) found in the microenvironment of cancer tumors. Sally Church, PhD on Pharma Strategy Blog has written about the mechanism of action for TH-302 and the results presented earlier this year at the 2012 annual meeting of the American Association for Cancer Research (AACR).

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In the phase IIb study presented at AACR 2012, TH-302 at a dose of 240mg/m² showed a progression free survival benefit of 2 months over gemcitabine. I encourage you to read her article.

ESMO 2012 Results

At ESMO 2012 in the Vienna, the TH-CR-404 data presented (abstract 6660 – full presentation available on the Threshold Pharmaceutials site) showed a benefit of 2.4 months in median progression free survival (PFS) for those patients receiving TH-302 at a dose of 340mg/m2 + gemcitabine compared to gemcitabine alone. The data is summarized in the following table:

ESMO 2012 TH-302 TH-CR-404 Trial Results

Table adapted from Ducreux, Poster Discussant ESMO 2012. * indicates statistically significant.

The PFS was only significant with the 340mg/m² dose and overall survival (OS) was not significant for either dose. However it should be noted that OS was not a primary endpoint for the study, nor was it powered to detect OS.

Hematological Toxicities may be difficult to handle

The 2.4 month (median) increase in PFS seen with TH-302 + gemcitabine does come with increased toxicities compared to gemcitabine alone.  These include an increase in Grade 3 or 4 thrombocytopenia (63%), and increase in Grade 3 or 4 neutropenia (60%). As a UK oncologist sitting next to me said after the presentation, “it is interesting, but quite toxic.” The following table shows some of the key toxicities:

ESMO 2012 TH-302 Adverse Events

Table adapted from Ducreux, Poster Discussant ESMO 2012.

Threshold plan to start a Phase 3 Trial

Dr Borad told the ESMO 2012 audience that Theshold planned to initiate a randomized phase III trial of TH-302 in advanced pancreatic cancer with the 340mg/m² dose.

Presentation Discussion at ESMO 2012

Michel Ducreux, Head of the Institut Gustave Roussy, Villejuif, France and Professor of Medicine at the University of Paris Sud was the discussant and put the data in context for the audience:

Some of the key points he made were:

  • A drug that targets hypoxia may be interesting in pancreatic cancer.
  • It was a well done, randomized phase 2 study
  • Concern about high level of hematological toxicity.

Professor Ducreux told the audience the hematological toxicity of TH-302 + gemcitabine would be difficult to handle in the many small hospitals in France if it becomes a standard of care. For these reasons, it also means such a combination may be disliked by community oncologists in the United States.  Similarly, FOLFIRINOX has shown efficacy versus gemcitabine, but more widespread uptake in first line has been limited by the severe toxicities (including chronic diarrhea) induced by the combination and is therefore not well liked by many oncologists.

“The results are not too bad” said Ducreux. However, he went on to to say “we have to remain suspicious” because positive phase 2 results can be followed by a totally negative randomized phase III trial. He gave axitinib as an example.

“The treatment of pancreatic cancer remains very difficult and I am happy to see new results, but again we have to stay on evidence based medicine, and it is good a phase 3 is planned to evaluate this new compound,” said Ducreux.

Why the results fail to impress

The ESMO 2012 data for TH-302 does, however, have to be considered in the light of the fact that there are other on-going trials that could change the standard of care.

One of trials highlighted by Ducreux in his discussion was Celgene’s nab-paclitaxel (Abraxane) phase III trial that I predict will have positive data in the near future. Here’s a link to my Storify from ESMO 2012 on Abraxane that discusses this.

Professor Ducruex told the ESMO 2012 audience that we will have the results for nab-paclitaxel probably for the next ASCO GI.

If nab-paclitaxel were to increase overall survival to 10-12 months, this would become the new standard of care that TH-302 would then have to beat.  Based on the TH-302 data presented at ESMO 2012, even if you ignore the hematological toxicity, this is hard to imagine from the phase II study, which is why the data failed to impress me.

However, until we have the TH-302 phase III data we will not know for sure. In the meantime I am looking forward to the possibility of the Abraxane pancreatic data at ASCO GI and a major breakthrough in the treatment pancreatic cancer. The prospect of this happening will offer hope to all those patients with pancreatic cancer, in a disease that for so long has been a graveyard of drug development.

 

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The 2012 Congress of the European Society for Medical Oncology in Vienna, Austria from 28 September to 2 October is a meeting I am looking forward to attending.

Last year at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO/ESTRO) in Stockholm we saw a lot of new data, including the phase III trial results for the ALSYMPCA trial with radium-223 (Alpharadin) in advanced prostate cancer and the Bolero-2 trial with everolimus (Afinitor) in ER/PR+ HER2- breast cancer.

What can we expect at ESMO 2012 this year? 

As we saw last year, the timing of the meeting provides the opportunity for presentation of data that matured after the early 2012 cut-off for submission to the ASCO annual meeting in June.

The titles of the late breaking abstracts have just been published in the ESMO 2012 searchable program. This offers some insight into what we can expect in the Presidential or Plenary Symposia at the meeting, where major trials and ground-breaking data are typically presented.

Presidential Symposia 1 – Sunday, September 30, 2012

  • LBA1_PR | Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007)
  • LBA2 | SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with hepatocellular carcinoma (HCC)
  • LBA3 | Cetuximab in combination with capecitabine and cisplatin as first-line treatment in advanced gastric cancer: Randomized controlled phase III EXPAND study
  • LBA4 | Adjuvant FOLFOX4 with or without cetuximab (CTX) in patients (pts) with resected stage III colon cancer (CC): DFS and OS results and subgroup analyses of the PETACC8 Intergroup Phase III Trial

Presidential Symposia II – Monday, October 1

  • LBA5 | PHARE Trial results comparing 6 to 12 months of trastuzumab in adjuvant early breast cancer
  • LBA6 | HERA TRIAL: 2 years versus 1 year of trastuzumab after adjuvant chemotherapy in women with HER2-positive early breast cancer at 8 years of median follow up
  • LBA7 | Results of a randomised phase III trial (EORTC 62012) of single agent doxorubicin versus doxorubicin plus ifosfamide as first line chemotherapy for patients with advanced or metastatic soft tissue sarcoma: a survival study by the EORTC Soft Tissue and Bone Sarcoma Group.
  • LBA8_PR | Randomized, open label, phase III trial of pazopanib versus sunitinib in first-line treatment of patients with metastatic renal cell carcinoma (mRCC); Results of the COMPARZ trial

ESMO 2012 also has a full program of keynote presentations, educational sessions and scientific symposia, so I expect it to be an interesting meeting. I am particularly looking forward to the poster presentations as, often at oncology/hematology scientific meetings, this is where you find useful insights into future new product development.

The twitter hashtag for the Congress is #ESMO12, so do follow this for conversation about the meeting over the next few weeks as the abstracts become available on Monday, September 17 and companies announce the data they expect to present.

At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Oliver Sartor, Professor of Cancer Research and Medical Director of the Tulane Cancer Center in New Orleans told attendees in the educational session on castration-resistant prostate cancer (CRPC) that he was tired of being asked the question of what is the optimal sequence for new advanced prostate cancer drugs?

ASCO 2012 CRPC Prostate Cancer Education SessionThere is “No data,” Sartor told the ASCO 2012 audience. As a result he recommended the use of less toxic therapies first and that patients be involved in the decision making. Not quite the guidance the audience perhaps hoped for.

Sartor is, however, correct that we don’t yet have the data – the clinical trials have yet to be done that will answer the question of what is the optimal sequencing of prostate cancer drugs?

The approval of abiraterone acetate (Zytiga®) for the treatment of men with advanced prostate cancer, post chemotherapy, and the expected approval of enzalutamide (formerly MDV3100) and radium-223 (Alpharadin) have focused attention on sequencing and combination options.

A poster at ASCO 2012 showed that cross resistance may occur between abiraterone and enzalutamide, suggesting that if resistance to one develops it may lower the efficacy to the other if given subsequently. More data and research is needed to validate this finding and understand how resistance develops.

Reciprocal feedback between the PI3-Kinase and androgen receptor (AR) signaling pathways means that blocking the androgen receptor may stimulate the PI3K pathway and vice versa, leading to the tumor trying to ensure its survival. This is particularly important in prostate cancers that have the PTEN tumor suppressor gene, the result is that the targeting of both PI3K and the AR to avoid crosstalk may be required.

The scientific rationale for combining enzalutamide with a PI3-kinase inhibitor was discussed on Pharma Strategy Blog in Sally Church’s video from the 2011 American Urological Association annual meeting. Clinical trials are being planned to investigate the use of PI3-kinase inhibitors in prostate cancer.

I have written more from ASCO 2012 about the emerging challenges in prostate cancer drug development in a guest post published on Xconomy.  Many thanks to Luke Timmerman, National Biotech Editor, for the opportunity to contribute.

Hopefully, there will be more insights available at ESMO 2012 later this year and at ASCO next year on prostate cancer drug resistance, optimal sequencing and the benefits that combinations therapies may offer.

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