Dec. 15, 2005--Signs of the changes ahead were clearly visible at the American Association for Cancer Research (AACR)'s Molecular Targets and Cancer Therapeutics meeting, held in Philadelphia, November 14 through 18. Targeted therapies are being used earlier, in novel combinations, and increasingly in patient subgroups that are preselected via new types of markers, including emerging imaging approaches. A new wave of biological targets is also coming into play: Many of these molecules act downstream in the cancer-development process, where there are fewer redundant pathways. As a result, the next generation of cancer drugs should be both more powerful and more selective, leading to better responses and fewer side effects.

Targeted therapies such as Herceptin (Genentech/Roche's trastuzumab), Gleevec (Novartis's imatinib), and Avastin (Genentech's bevacizumab) have been a huge commercial boon to the pharmaceutical and biotech industries while rekindling hope that the war against cancer is actually winnable. The steps achieved so far are small, however, compared with what remains ahead. These drugs tend to help only subsets of patients, they may provide limited additional benefits, and resistance is still often a problem. Because the drugs are also very expensive, concern is growing about cost-benefit. Oncologists want a full menu of targeted drugs against all the major mutations fueling different cancers' growth, a matching set of biomarkers to guide drug selection, and a clear sense of how and when to use each tool.

Combining Targets
In one major new development, many studies now combine targeted therapies with established drugs. UCLA's Dennis Slamon exhorted AACR attendees to look beyond that step and to think about combining targeted therapies. Slamon provided a glimpse of just how promising this approach could be when he shared a small set of early results from combination Herceptin/Avastin therapy in breast cancer patients with no prior chemotherapy. Among nine patients, a couple experienced complete remission, and several more showed measurable responses. Although this set of patients is extremely small, Slamon said he was heartened by the clear correlation between laboratory data and effects in any patients.

"With the technologies we have, we can predetermine more-rational targeted combinations," Slamon said. Earlier lab work suggested that HER2-positive patients – the group most likely to respond to Herceptin -- also have elevated levels of vascular endothelial growth factor (VEGF), which Avastin targets. Many scientists have recently lamented the sometimes poor correlation between laboratory-generated hypotheses and clinical effects. "In this case, the preclinical models predicted exactly what was seen in the clinic," said Slamon.

Next-Generation Approaches
As their cancer pathway maps become increasingly detailed, researchers are also coming across new targets. Unfortunately, it takes a long time for these targets to move from the "theoretically attractive" into the "proven" category. One scientist joked, "You know your target is emerging if it's only been around ten years." The best targets will be those that are unique to tumors and that can deal lethal blows. "These central pathways, such as Akt and mTOR, are where we expect the next generation to come from," says Karol Sikora of London's Imperial College. Researchers now also have better tools for drug design and are developing creative new approaches, such as multi-targeting drugs and new types of conjugates, in which monoclonal antibodies act both as drug delivery vehicles and as therapeutics in their own right.

The explosion in these approaches has led to tremendous interest in oncology drug development: According to the Pharmaceutical Research and Manufacturers of America, almost twice as many (about 400) cancer drugs are in development today as were seven years ago, and there are at least 178 companies in the field.

The following are just a few of the intriguing relative newcomers featured at AACR's meeting:

*BCL-2, a key player in controlling cell death, is one of those targets that has been "emerging" for a long time. Ascenta Therapeutics' lead compound, AT-101, is now "the only orally bioavailable pan-Bcl-2 inhibitor currently under clinical investigation," according to the company. The drug can inhibit Bcl-2, Bcl-XL, and Mcl-1, which are proteins that help cancer cells survive. Ascenta presented results from a Phase I trial with almost 30 patients who had a range of different tumor types and who had all been previously treated with standard therapies. The company reports that the drug can be dosed at up to 40 mg/day and that "toxicity was manageable," in these very sick patients. (See abstracts C89 and C223.)

*ARIAD Pharmaceuticals' novel mTOR inhibitor, AP23573, is being tested in a Phase II trial involving patients with advanced bone and soft-tissue sarcomas. So far, 27% of the patients who could be evaluated have shown sustained tumor regression and/or disease stabilization. The six-month progression-free survival (PFS) rate is 22%, which is much better than would normally be expected among patients with such aggressive tumors. mTOR is a "master switch" that controls many processes related to tumor growth and spread, according to Sant Chawla, of Century City Hospital, who presented these results at AACR. (See abstract C272.)

*Fragment-based drug design pioneer, Plexxikon, has an early-stage B Raf inhibitor (PLX4032) in development. B Raf is mutated in up to 89% of melanoma patients.  Plexxikon scientists have studied the structural implications of a particular B-Raf mutation and have designed a series of compounds that neatly "discriminate between the mutated and wild type," says Peter Hirth, the company CEO. "We have good activity in animal models and can pre-select in clinical trials," Hirth adds.  PLX4032, the company's lead candidate, is orally available and is slated for clinical trials early next year. The drug's high selectivity for the mutation (V600E) is one of its most attractive features, but the compound also appears to be very potent. (See Figure 1, below.) In addition, a significant number of colorectal tumors and other cancers carry this particular B-Raf mutation, which is associated with more-aggressive tumors and poorer patient survival.  (See abstract C227.)

Figure 1:  Guided by co-crystallography, Plexxikon has developed a novel chemical scaffold into a series of potent, specific inhibitors of oncogenic B-Raf.  This graph demonstrates the robust efficacy of the company's compounds administered once daily orally in a COLO205 tumor xenograft model.

 

Source: Plexxikon

* Shortly after presenting preclinical data at the AACR meeting, OXiGENE announced the start of a Phase Ib trial with its lead vascular disrupting compound, Combretastatin A4 Phosphate (CA4P), in combination therapy with Avastin. The preclinical data suggested this could be a particularly powerful combination, and the trial follows the newer trend of pairing targeted therapies that act by different means. In this case, Avastin is known to disrupt new vessel formation, while Combretastatin A4P attacks the established blood vessels but apparently only in tumors. The company reports that the new trial is the first to pair these two types of agents in cancer, specifically in patients who failed previous treatment and who are in advanced stages of disease. One key advantage of combining targeted therapies is that patients should experience "none of the classic toxicities from chemotherapy, such as hair loss and bone marrow depletion," says David Chaplin, Ph.D., chief scientific officer and head of research and development at OXiGENE. CA4P is already being tested in a Phase I trial with the chemotherapies carboplatin and/or paclitaxel (BMS's Paraplatin and Taxol).  The company has also recently received regulatory clearance in the United Kingdom to begin a Phase III trial in the United Kingdom combining CA4P with radiotherapy or chemotherapy to treat advanced inoperable non-small-cell lung cancer. (See abstracts A12 and A13.)

*  Cancer drugs designed to hit multiple targets at once are also in vogue. Pfizer's Sutent (sunitinib malate) and Onyx/Bayer's sorafenib are ahead in this race, but more are following fast. At the AACR meeting, at least five studies were presented on BMS's dasatinib  (BMS-354825). (See abstracts A233, A234, A255, A256, A258, B178, and C145.) BMS is testing the drug in a range of cancers while also looking for biomarkers of activity. Dasatinib inhibits BCR-ABL as well as SRC kinases, and three SRC substrates have emerged as possible markers. Meanwhile, Exelixis reported on three such multi-targeting drugs, which the company has dubbed "spectrum selective kinase inhibitors" (SSKIs). According to the company, one of these drugs (XL 880) is the first c-met inhibitor to reach clinical trials. In addition to c-met, XL 880 also inhibits some players in angiogenesis (e.g., VEGF) as well as platelet-derived growth factor receptor (PDGFR), c-KIT, FLT3, and Tie-2. All three of Exelixis's SSKIs are in Phase I and appear headed toward Phase II. The abstracts describing results so far are A245 (XL 880), A261(XL 647), and C82 (XL 999).

* Genentech, the reigning superpower of targeted therapy, now has the pleasure of watching researchers battle for the right to combine their new drugs with its approved breakthroughs, such as Avastin and Tarceva (erlotinib). More than 400 trials are currently underway that involve Genentech oncology products, and 10 of those are Phase III trials sponsored by the company itself. But Genentech has not stopped innovating either. For example, its researchers demonstrated that Herceptin could be made even more powerful, at least in preclinical studies, when tied to a microtubule function inhibitor -- DM1 (maytansinoid). The trastuzumab-DM1 conjugate not only inhibits and suppresses tumor growth, it also causes tumor cell death by delivering DM1 into these cells. The conjugate seems to affect only tumor cells and only those that express high levels of HER2. (See abstract A74.)

Note: Abstracts are available at the AACR Website.

Major Advances in Imaging
Another area that's raising hopes for radical improvements is medical imaging. "The technologies and molecules being developed are pretty astonishing," says NCI's James Doroshow, one of the meeting organizers.

These new technologies include dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), diffusion MRI, magnetic resonance spectroscopy (MRS), and fluorodeoxyglucose uptake with positron emission tomography (PET).  Scientists can now do much more than simply check whether tumors are shrinking; they can measure in vivo pharmacodynamics and molecular end points such as hypoxia or changes in glucose metabolism. That's particularly good news because researchers are starting to discover that for some new agents, such as VEGF-inhibitors, the typical anatomical markers are not always good indicators.

"It would be the holy grail to be able to say you know you've hit the target, and then be able to tell, through functional markers, if you're having an impact on the tumor," Doroshow says. Imaging will also be used increasingly to predict drug response, and Doroshow expects that within ten years imaging probes will be developed simultaneously with new cancer drugs. One example, presented by David Mankoff of the University of Washington and Seattle Cancer Care Alliance, demonstrates how  the therapeutic target, in this case the estrogen receptor, and response to breast cancer drugs can be visualized using PET. (See Figure 2, below.)

According to Robert Gillies of the Arizona Cancer Center, another of the presenters at AACR, only about 10% of clinical trials currently use functional molecular imaging. However, these tools have multiple applications in drug discovery and development, including for pharmacodynamics (Phase I), as quantitative early end points (Phase II), and for patient segmentation (Phase IIb through IV).  Doroshow expects it will be several years before these tools come into widespread use. One thing that has helped move things along has been the development of advanced imaging equipment for use with laboratory animals. Today, many of these techniques are still just being tested in animals, but there is great anticipation of what they will allow in the clinic.

"We can image tumors with antibodies linked to some kind of imaging probe," Doroshow says. "But we're also going to see cases where the antibody is first used to image the cancer and then administered linked to a different type of agent, to have a therapeutic effect."

The Iressa Dilemma Resolved?
Among cancer drugs, AstraZeneca's Iressa (gefitinib) has had one of the most difficult launches on record. Despite some discouraging large-scale trial results, the drug squeaked through to approval because of some remarkable responses among the few patients it did help. Data hinted at a subpopulation effect, and until this year, there had been heated debate about how to select those patients. Just this summer, FDA issued a new label limiting the drug's use to patients already shown to be benefiting from it.

Now, a new set of studies presented at the AACR meeting appears to confirm earlier findings showing response to Iressa is best predicted by a fairly basic test – epidermal growth factor receptor (EGFR) gene copy number measured via fluorescent in situ hybridization (FISH). Fred R. Hirsch of the University of Colorado Cancer Center and colleagues presented this latest data. Their studies used samples collected during the Phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial. Hirsch's group found that FISH-positive patients taking the drug lived about 8.3 months, versus 4.5 months for those taking placebo. Meanwhile, the drug offered FISH-negative patients little benefit. His group also examined EGFR expression and Akt activation status, but they were not useful predictors.

Another study based on ISEL samples was presented by Brian Holloway of AstraZeneca. His group showed that some mutations in the EGFR gene could also be used to determine responders. Holloway's group also tracked mutations in B-Raf and K-Ras, which some experts have speculated might influence response to the drug. They found few K-Ras mutations, and no samples had mutations in both EGFR and K-Ras. None of the samples had K-Raf mutations. Overall, the EGFR mutations were not as predictive as EGFR-gene copy number, and most patients with the predictive mutations also had higher EGFR-gene copy numbers.

The most troubling and yet most inspiring feature of this "receptor-gene copy number" effect is that it mirrors the association found with Herceptin and HER2. "Herceptin is the paradigm," Hirsch says. That is good news for those working with newer receptor targeting therapies. But why did it take so long to get this answer? And why did earlier studies discount this association? "Perhaps people were doing the wrong type of tests, or they didn't have good ways to evaluate results," says Roy Herbst of the MD Anderson Cancer Center. "Doing these clinical correlates is extremely difficult," adds Sikora. "You need many patients and fresh tumor samples."

Regardless of the reasons for the delay in making the association, this realization opens a new door for Iressa and could impact other EGFR-targeting drugs, such as Erbitux (BMS/ImClone's cetuximab) and Genentech's Tarceva (erlotinib). "I think we will see new trials [with Iressa] going forward, with preselection of patients," says Herbst. "We now have reasonable markers to select patients who have a clear benefit," Hirsch says, although investigators are still looking for additional clues about what makes tumors sensitive to these particular drugs.

Outlook and Reflections
As targeted drugs come into wider use, the need for biomarkers is intensifying. Just this summer, results from a large-scale study of Herceptin demonstrated that this drug is also effective in early-stage breast cancer. "I suspect many of these drugs will be more powerful in the adjuvant setting," says Sikora. That is a wonderful possibility but one that raises new challenges because it is neither advisable nor possible to give these medicines to all comers: They are simply too expensive. "[In early-stage disease,] you have to know which patients to give them to unless you want a huge meltdown of the health care system," Sikora says.

Oddly, many of the companies now pursuing cancer drug development seem oblivious to this looming cost issue.  The first few of these breakthrough drugs have been embraced, but as the number of them increases, the burden on the health care system is becoming much more noticeable.  Last year, an editorial in the New England Journal of Medicine pointed out, "The fiscal impact of the FDA's approval [for Avastin in colorectal cancer] could exceed $1.5 billion each year."  (Mayer, RJ, 2005)  In addition to being the frontier of targeted therapy, oncology is also becoming the center of discussion around cost-benefit and drug pricing. 

There's a heap of controversy as well as tremendous excitement ahead in this field.  Now that so many new types of drugs are in trials and breakthrough products are being paired, a whole new era is opening up.  Over the next few years, the best targets will undoubtedly rise to the top and they will be even more successful when used with some of these other emerging tools, such as imaging biomarkers.  At the same time, society will be wrestling with some weighty issues, such as how much a few weeks of life is worth and how to pay for broader access to remarkable new treatments.

Figure 2