Pertuzumab and Herceptin Trail

[RobinP]

Is anyone at her2support on the new clinical trail for Herceptin and Pertuzumab that opened in Dec. 2005? As I understand it, the reason why some people MAY progress while they are on Herceptin is due to other infidel erbB family members, her1, and her3 heterodimering. Herceptin is only specific for her2. However, Pertuzumab is another monoclonal antibody, similar to Herceptin, that has the unique ability to attach to her1,3. Hopefully, results will be seen with the Pertuzumab, Herceptin combination to further increase DFS and OS. If results are seen with this combination in metastatic trails, it is likely that adjuvant trails will also run with this pair for a better efficacy than Herceptin alone. What would really make an interesting trail would be Lapatinib, Herceptin and Pertuzumab. As lapatinib would target her1 and her2. Herceptin would target her2 and Pertuzumab her1,2,3. That's it, just shut down the whole erbB pathway.

Robin, I attended a lecture given by Dr. Ellie Guardino of Stanford wherein she quoted an experiment wherein they sucessively blocked the different ERRB receptors in mice with her2 positive tumors and once 1 through 3 were blocked the tumors disappeared and did not recur. At that time they thought her4 actually was protective against breast cancer (or "good"), which is no longer thought to be the case (I seem to rememberan article which proposed that there are various isoforms of her4 which encode proteins with different functions leading to different prognoses). In any case, I will look for an article which fits the above description and get back to you if I find it.

[al from Canada]

Thanks Robin,
That's just a great article and a great thought on ERB expression elimination. Interestingly enough, I just ran across this article on combining targetted therapies. There is a lot of buzz around CA4P especially.
Al

Cancer Therapeutic Update from AACR: New Combinations, Targets, and Types of Markers
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.)

[lu ann]

Hi Al,

I thought I was the only one who stays up late to visit this board.

I'm going to save this post and e-mail it to my friend who was dx. with a reoccurrance of BC, just before Christmas. She is a single mom to a 17 year old daughter. My sister called me earlier to give me the news. She is just heartbroken over this. I told my sister about Linda and all of the rest of the survivors on this board and to let our friend know she is welcome to visit us on this site.

Tell Linda "Hello" from me and that I wish you both well.

Blessings, Lu Ann.

[RobinP]

Al thanks for your article submission; very interesting and encouraging for cancer treatment. I think as we know more about the molecular make-up of individual breast caner tumors, the better we can target therapy with various agents, not just with Herceptin alone, particularly in those who do not respond or have full or lasting response. I find it interesting that a lot of these target therapies work better together, ig Laptatinib and Herceptin. Avastin works better with Taxol we now know but perhaps even better Herceptin and Lapatinib and perhaps even with Maytasinoid. There's a lot of potential out there. However, I really think the targets must be defined better with more complex pathologies on tumors testing for such things as her1,2,3,4, bcl2, and various markers for kinase activity. Then rather than randomly treating patients with these therapies, we can specifically treat, save toxicities, not to mention money.