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Developing drugs to conquer cancer

Future treatments for suppression of antitumour activity, metastatic melanoma and NSCLC were showcased at ASCO 2012 with some exciting results

Conquering CancerConquering cancer is both serious and big business, not only for manufacturers and healthcare providers, but many support services also. The spin-off income benefit to the airline and travel industries alone at having an estimated 30,000-35,000 people from around the world attend the 2012 American Association of Clinical Oncology (ASCO) Annual Meeting in Chicago, June 1-5, 2012, is merely one microcosm of the serious money involved. 

So what happens when cutting-edge scientific presentations and comprehensive educational content are combined with oncology professionals from a broad range of specialties, all exploring the theme of the Meeting — Collaborating to Conquer Cancer? 

Approximately 25,500 professional representatives from 117 countries attended this year's annual meeting, Collaborating to Conquer Cancer.

American Association of Clinical Oncology
Comprising 28,000 members, the American Association of Clinical Oncology (ASCO) has representation from more than 100 countries, bringing together the world's largest collection of expertise and insight into the treatment and management of cancer patients.

By its own description: 'ASCO is the world's leading professional organization representing physicians who treat people with cancer.' Its members set the standard for patient care worldwide, and many lead the way in implementing clinical research aimed at improving the prevention, diagnosis and treatment of cancer.

Additionally, efforts are also directed toward advocating policies that provide access to high-quality care for all cancer patients and supporting the increased funding for clinical and translational research. Thousands of scientific abstracts and highly anticipated research news were released at the meeting. This year over 5,000 abstracts were submitted, and more than 4,600 were accepted for either presentation (2,744) or ePublication (1,859) in over 20 tumour types.
  
Clinical updates Continuing a familiar trend, pharmaceutical industry analysts and companies have been weighing in on their selections for the most noteworthy research presented at the conference.

The level of interest reflects the impact that ASCO research has not only upon clinical practice but also upon the financial fortunes of the companies developing the drugs and to their investors. Literally billions of dollars are at stake in terms of potential product sales, market performance of manufacturers' stock, as well as costs to the global healthcare systems. 

Many significant announcements have come out of previous ASCO Annual Meetings, some making headlines and some not, but all going in the direction of conquering cancer. On May 7, 2012, Gordon Gochenauer of Kantar Health wrote in a blog that perhaps 2012 could be designated as the 'Year of Many Cancers'. The blog highlights nine key phase III trials that are either known or strongly believed to have hit their primary endpoints, affecting a wide array of cancer types and possibly leading to broadening the labels of currently approved agents such as Zytiga (abiraterone, Johnson & Johnson) and Avastin (bevacizumab, Roche), and to regulatory approvals for the others. 

Clearly, all of these are very important developments for the manufacturers, with subsequent anticipated business return.
 
PD-1 debuts

PD-1 emerged as a hot new target for its role in supression of antitumour activity
This year, PD-1 emerged as a hot new target for its role in suppression of antitumour activity. Furthermore, a number of agents that block the interaction of PD-1 with PD-L1 are now in early stages of development and clinical data from these studies are released, generating considerable excitement. 

One example is the impressive results from a large phase I study of BMS-936558 (anti-PD-1; Bristol-Myers Squibb/Ono Pharmaceuticals), a fully human anti-PD-1 monoclonal antibody (Topalian, Abstract CRA2509). Consequently, registrational trials are planned in melanoma, non-small-cell lung cancer (NSCLC) and renal cell carcinoma (RCC). 

It is also important to note that these PD-1 blocking molecules appear to be very well-tolerated and exhibit efficacy in many advanced tumour types. As with any clinical development programmes, many questions remain unanswered about this novel approach to targeting cancer, including is efficacy limited to tumours that express PD-L1? 
ASCO 2012 was PD-1's debutant ball, but we may be only a few years away from its coronation. Because of the early development stage of these compounds few analysts have weighed in with estimates of their potential financial impact, but it's safe to assume that if successful, the potential value that PD-1 inhibitors could yield will be in the billions of dollars.

Metastatic melanoma

Following decades of frustration and failure, recent advances for the treatment of metastatic melanoma have resulted in approvals of Yervoy (ipilimumab) in 2011 and, for patients with BRAFV600E, Zelboraf (vemurafenib) in 2012 (Abstract LBA8500, Hauschild, and the METRIC trial of trametinib versus chemotherapy, Abstract LBA8509, Robert). 

GSK's franchise has promising drugs for BRAF-mutated metastatic melanoma and it is likely that dabrafenib and trametinib will receive regulatory approval, though GSK has yet to submit regulatory filings. 

With a somewhat better safety profile than Zelboraf, this combination will be a worthy competitor in the market and provide a treatment alternative for patients with BRAF mutations. Preliminary data from the combination of dabrafenib and trametinib looks very impressive in terms of safety and efficacy and may ultimately prove superior to the BRAF inhibitor monotherapy. 

Consensus analyst reports showed sales of $360m for melanoma (all of which was for Yervoy) in 2011, while analysts project category sales of $2.9bn in 2018, with Yervoy accounting for $2.0bn and Zelboraf $0.9bn (source: EvaluatePharma).

Cabozantinib (XL184, Exelixis) is an inhibitor of multiple receptor tyrosine kinases (RTKs), including RET, c-MET and VEGFR2. Mutations in the RET proto-oncogene play an important role in the development of medullary thyroid cancer (MTC), and cabozantinib has shown activity against the common mutant forms of RET and MET. With the positive data, cabozantinib will clearly represent a new treatment option for MTC when it is commercialised. 

DRIVERS FOR nsclc advances

Treatment of advanced NSCLC has become increasingly driven by tumour characteristics, with choice of systemic therapy now largely decided based on tumour histology, EGFR mutation status, and ALK translocation status. Additionally, several drugs in late-stage clinical development focus on patient subpopulations identified through specific biomarkers. In our opinion, it all comes down to toxicity in the battle for first-line EGFR mutant NSCLC patients.

Despite the high use of Tarceva in the US, it currently is not FDA approved in the first-line setting. This lack of approval created an opportunity for afatinib to enter this market without directly challenging the market leader in a head-to-head clinical trial. The LUX-LUNG-3 results might push Roche into finally filing for Tarceva approval in the US. 

Additionally, investigators are already calling for a head-to-head trial and LUX-LUNG-7 (NCT01466660) will compare afatinib to Iressa (not available in the US) in 264 del19/L8585R mutant patients in an attempt to answer the question of which agent is superior. Product sales history and consensus analyst projections for Tarceva show product revenue growing from $1.2bn in 2009 to nearly $1.7bn by 2015, then falling back to about $1.4bn by 2018 (source: EvaluatePharma).

HER2 DEVELOPMENTS

HER2-targeted therapy was another star of ASCO at a plenary session. T-DM1 (trastuzumab emtansine) is Genentech/Roche's antibody-drug conjugate, consisting of a potent microtubule polymerization inhibitor conjugated to the trastuzumab monoclonal antibody via a highly stable linker. 

Given the presentation of impressive data, it will be interesting to see exactly where TDM-1 fits into the treatment paradigm once it is approved. With the success of the CLEOPATRA trial and Perjeta's (pertuzumab, Roche/Genentech) recent approval in combination with first-line Herceptin, this raises the question of whether TDM-1 will occupy the second line after Herceptin/pertuzumab, or whether Herceptin 'rechallenge' will remain the second-line treatment of choice, followed by third-line TDM-1. 

Roche/Genentech have been successful in muscling out most competitors in this tumour subtype, and TDM-1 gives the company some protection from potential future biosimilar competition that they face for Herceptin. Consensus analyst projections for these products in 2018 estimate pertuzumab sales at $2.5bn and Herceptin sales at $5.3bn (source: EvaluatePharma).

In October's PME, Kantar will explore data and policy perspectives on treatment of colorectal cancer and renal cell carcinoma, the possible paradigm shift in treating late-stage disease and the evolution of cancer treatment in emerging markets.

Highlights from ASCO 2012

Other key information that Kantar noted but did not blog on includes the following: 

  • Bayer HealthCare discussed phase III results concerning regorafenib in gastrointestinal stromal tumour (GIST) and in colorectal cancer, as well as the final overall survival analysis of radium-223 (Alpharadin) data in castration-resistant prostate cancer with bone metastases. http://goo.gl/nb6ue  
  • Bristol-Myers Squibb presented new data about ipilimumab (Yervoy) in melanoma as well as presentations with its partner Otsuka Pharmaceutical about dasatinib (Sprycel) in Philadelphia chromosome-positive chronic myeloid leukemia and cetuximab (Erbitux) in solid tumours such as colorectal and head and neck cancers. http://goo.gl/ozfqA  
  • Dendreon made several presentations of new research into sipuleucel-T (Provenge) in a variety of clinical settings in prostate cancer, including updated analysis of overall survival data from the IMPACT trial. http://goo.gl/hUl8f 
  • Eisai reported new results on eribulin (Halaven) in early-stage breast cancer and decitabine (Dacogen) in acute myeloid leukemia, as well as new data on several phase I agents under investigation in various tumour types.http://goo.gl/lrOic 
  • Eli Lilly & Company presented updates on ramucirumab, which is in phase III development in colorectal cancer, gastric adenocarcinoma and hepatocellular cancer, and under phase II study in recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.  http://goo.gl/buq25 
  • Novartis presented updated data from the BOLERO-2 trial involving everolimus (Afinitor) in breast cancer and phase III studies in nilotinib (Tasigna) in Philadelphia chromosome-positive chronic myeloid leukemia. http://goo.gl/Ig1Lv 
  • Pfizer Oncology released new data about axitinib (Inlyta) and sunitinib malate (Sutent) in renal cell carcinoma; crizotinib (Xalkori) and dacomitinib (PF-00299804) in non-small cell lung cancer; and bosutinib and inotuzumab ozogamicin in hematologic malignancies. http://goo.gl/JZmqg 
  • Sanofi presented data on aflibercept (Zaltrap) in colorectal cancer and small cell lung cancer and cabazitaxel (Jevtana) in prostate cancer, along with research into several investigational compounds. http://goo.gl/ptZbx

The Authors
Tony Faustino, Chris Gage, Ian Hicks, Anne LaPrade and Song Li.
www.kantarhealth.com or contact our team at www.kantarhealth.com/contactus

1st October 2012

From: Research

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