Drugs To Watch At ASCO 2012

by: Ohad Hammer

Below is a list of drugs and companies which will have meaningful data at this year's annual meeting of American Society of Clinical Oncology (ASCO). As I will be attending this year's conference, I will try to write updates on a regular basis. Feel free to send me questions or post them as comments to this post.

PD1 antibodies - the next big thing in oncology

BMS' (NYSE:BMY) anti-PD1 antibody BMS-936558 is expected to steal the show with results across three indications (melanoma, lung and renal cancer). The abstracts report an objective response rate of 22% in melanoma, 18% in NSCLC (non-small cell lung cancer) and 25% in renal cancer. BMS-936558's safety profile looks very good compared to Yervoy, which has a similar mode of action of promoting an immune response against cancer (as opposed to attacking cancer directly).

This type of response rate is impressive for any single agent drug in late stage patients, and even more so when it comes to immunotherapy drugs. Today it is clear that looking at response rate does not provide the full picture when it comes to immunotherapies, which tend to have a slow onset and long term effect compared to conventional drugs. For the sake of comparison, Yervoy, an immunotherapy which was the first drug to show an overall survival benefit in melanoma, has a response rate of only ~10% in melanoma. In addition, it appears that one of the doses is more effective (28% response rate in lung cancer) and this dose will probably be chosen for further studies.

At ASCO, investigators are expected to present updated results which are likely to be better due to longer follow up. It will be interesting to see whether responses are durable, an important hallmark of immunotherapies. Yervoy, for example, can lead to a remission of years in some patients. If BMS-936558 shows a "Yervoy-like" response durability in deadly indications such as lung cancer and melanoma, this could be a major breakthrough.

Lastly, there might be biomarkers for patient selection, which could shorten the route to market and enhance likelihood of success in pivotal trials. In earlier trials, there were indications that certain markers on tumors correlated to clinical benefit but this will have to be corroborated at the data set at ASCO.

BMS is leading the field of PD-1 antibodies, but there are several competing programs at various stages. These include an anti-PD-1 antibody from Merck (NYSE:MRK), which will also have data at ASCO. Other competing programs include PD-1 inhibitors from Curetech/Teva (NYSE:TEVA) and GSK (NYSE:GSK) as well as antibodies against PD-1 ligand (PD-L1) from BMS itself and Genentech.

I discussed PD-1 and why it is such a promising target in an earlier post.

MEK inhibitors - AstraZeneca, Array, GSK and Novartis

For almost a decade MEK inhibitors have been regarded as an unfulfilled promise. Despite their wide therapeutic potential, MEK inhibitors could not generate a real clinical signal with a clear route to market. While BRAF inhibitors, which inhibit the same pathway, generated spectacular responses (which turned out to be short lived) in melanoma patients, MEK had only a modest effect as single agents. 2012 looks like the turning point for MEK as a target with encouraging results for 3 different inhibitors.

AstraZeneca's (NYSE:AZN) selumetinib, which was licensed from Array Biopharma (NASDAQ:ARRY), generated excellent results in a Phase II in NSCLC patients with KRAS mutations. When given in combination with Taxotere, selumetinib had a dramatic increase in response rate (37% vs. 0%) and PFS (5.3 vs. 2.1 months), both were statistically significant. There was also a trend in overall survival (9.4 vs. 5.2 months) that was not statistically significant, not surprising given the small sample size of 87 patients. This is the first and most robust clinical proof of concept for a MEK inhibitor and AstraZeneca is expected to start Phase III in the near future.

Earlier this year, AstrzZeneca reported positive data with selumetinib from a single arm trial in heavily pre-treated ovarian cancer patients. The results compared favorably to historical data with approved agents.

GSK is presenting Phase III results for its MEK inhibitor, trametinib, compared to chemotherapy in BRAF mutated melanoma. Although the company already announced the drug improved PFS, the magnitude of effect remains to be seen. Results will automatically be compared to those of Zelboraf, which also demonstrated an improvement over chemo in a similar patient population.

Another interesting trial is a Phase I/II trial combining trametinib (MEK) and GSK's BRAF inhibitor, dabrafenib. The combination led to a PFS of 7.4 months, slightly better than what Zelboraf achieved in its Phase II (6.2 months). In patients who received the optimal doses of both drugs, PFS was 10.8 months, but the sample size was small. GSK recently advanced this combination to Phase III, implying that updated results from the Phase II portion are compelling.

Novartis (NYSE:NVS) will present data for its MEK162, which it licensed from Array. In a Phase II study in melanoma, the drug demonstrated some efficacy in patients with NRAS mutation (3 responses in 13 evaluable patients). These patients are not candidates for BRAF inhibitors, and can therefore serve as an attractive route to market.

Antibody drug conjugates -Roche, Immunogen, Seattle Genetics Sanofi, Celldex and Pfizer

Antibody drug conjugates (ADC) are another hot segment in oncology. The two most successful ADCs to date are Roche's T-DM1, which is based on Immunogen's (NASDAQ:IMGN) technology, and Seattle Genetics' (NASDAQ:SGEN) Adcetris. At ASCO, investors will focus on T-DM1's Phase III data in breast cancer and Seattle Genetics' efforts to expand Adcetris' label. Although there will be data for additional ADC programs, next year's conference should see a flood of data sets from ADCs that got to the clinic in the past 18 months.

T-DM1 (Roche/Immunogen)

Roche will present preliminary results from a Phase III (EMILIA trial) where T-DM1 is compared to standard of care in 2nd line Her2+ breast cancer patients. The trial was successful in showing an improvement in PFS (progression free survival). Investors are expected focus on the extent of benefit as well as a potential trend for overall survival.

This will be the first ever Phase III data set for an ADC (earlier ADCs such as Adcetris and Mylotarg were approved with Phase II data), and should lead to an approval next year. Patients and physicians alike will be very receptive to T-DM1 for 2nd line patients as the currently approved alternative (Xeloda+Tykerb) is considered minimally effective and too toxic. In fact, even if T-DM1 had a comparable PFS to Xeloda+Tykerb, it would have become the gold standard due to safety and pricing issues.

EMILIA is viewed as an appetizer to another Phase III trial, in which T-DM1 is given to 1st line patients (MARIANNE study). In that therapeutic setting, the bar for efficacy is much higher and competition is expected to be stronger. The main competitor is another HER2-targeting from Roche, pertuzumab, which is expected to get approval based on excellent Phase III results. Therefore, in the 1st line setting, T-DM1's performance will be indirectly weighed against that of pertuzumab. Interestingly, the MARIANNE trial includes a combination arm for T-DM1+pertuzumab, which could become the new standard of care if proven effective.

Adcetris (Seattle Genetics/Takeda)

After establishing Adcetris as an important treatment option for late stage hodgkin's lymphoma (HL), Seattle Genetics is trying to broaden the drug's use using several approaches. The first strategy is getting Adcetris approved in 1st line HL as well as re-treatment of late-stage patients. Other trials look at additional blood cancers, where Adcetris' target (CD30) is known to be expressed. Lastly, the company initiated a "screen and treat" study where patients with a variety of cancers (except lymphoma) are screened for CD30 expression.

At ASCO, investigators will present data from the 3 initiatives:

In the re-treatment trial the abstract reports an impressive response rate of 65% and a duration of response of 11 months, which is encouraging given that these patients had already been treated with Adcetris. In the additional blood cancer trials (excluding HL), there are already signs of activity in CD30+ NHL patients. This complements the impressive activity the company reported earlier this year in 2 subtypes of NHL. In the "non-lymphoma" trial, the abstract reports presence of CD30 across a wide range of tumors including ovarian and breast cancer, but with low incidence.

Additional ADCs

Sanofi (NYSE:SNY) is expected to present data on SAR3419, its anti-CD19 ADC based on Immunogen's technology. Although Phase I data for this program have already been reported, Sanofi decided to use an amended regimen with an improved safety profile in Phase II. Results with this regimen will be presented at ASCO for the first time and according to the abstracts, the safety profile looks compelling with clear signs of efficacy in NHL. SAR3419 looks less potent than other CD19 therapies such as Micromet's (now part of Amgen) blinatumomab or CD19-targeted T cells (referred to as chimeric-antigen receptor or CAR).

Celldex (NASDAQ:CLDX) was hoping to present the long-anticipated Phase II data for CDX-011 at ASCO, but a "clerical" error prevented them from getting accepted. As a result, the company already published the results, which were overall positive with several caveats. The trial was unique as it compared CDX-011 to "physician's choice" (patients in the control arm could receive a drug based on their physician's decision). In other words, CDX-011 was rigorously compared to an active drug , not to placebo.

The results were positive because CDX-011 had comparable activity in the overall patient population and appeared more effective in two prospectively defined subgroups (tumors with high GPNMB expression and tumors that are negative to ER, PR and HER2, aka triple negative). It is important to note that the subset analysis is reliable as it was pre-defined before seeing the data, making it more reliable. The main issue with the results is the low number of evaluable patients in each subgroup (33 patients).

Pfizer (NYSE:PFE) will present results for its anti-CD22 ADC in acute lymphocytic leukemia (NYSE:ALL). The abstract discloses a 40% complete response rate in advanced stage patients, which is impressive but pales in comparison to Micromet's (now part of Amgen) blinatumomab. The latter will have updated results in ALL, with a reported response rate of 68% and encouraging overall survival.

MET inhibitors - Arqule, Amgen and Exelixis

MET continues to be a very hot target in oncology. The two leading selective MET inhibitors, Daiichi-Sankyo/Arqule's (NASDAQ:ARQL) tivantanib and Roche's Metmab are in Phase III in lung cancer based on positive Phase II studies. Exelixis' (NASDAQ:EXEL) cabozantinib, which is a dual MET/VEGFR inhibitor, is in Phase III in prostate cancer.

At this year's meeting, Arqule will report Phase II results for tivantinib in 2nd line liver cancer. The drug led to a negligible PFS improvement in the entire patient population, however, the effect was more profound in patients whose tumors had high MET expression. In these patients, tivantinib led to a statistically significant benefit (2.4 vs. 1.5 months). These results are somewhat disappointing and the decision to go for Phase III in 2nd line patients will probably depend on an overall survival signal, which will be presented at the conference.

Amgen is presenting data in gastric cancer for its anti-HGF antibody, rilotumumab, in combination with chemotherapy in gastric cancer (HGF is the ligand that activates MET). This program had been terminated by Amgen last year, but was recently re-activated based on a subset analysis in the trial. Although the drug had no effect in the intend-to-treat population, there was a near doubling of survival in patients with high MET expression.

Exelixis will have multiple presentations for cabo, including Phase III data in medullary thyroid cancer (MTC) and Phase II data in prostate cancer and renal cancer. Investors' main focus will be the effect on bone metastases, which appears to be a unique feature of the drug.

Cabo continues to demonstrate the bone effect across several indications, primarily in prostate cancer, where 60% of patients experienced a bone scan response. Resolution in bone scans was observed in breast cancer and lung cancer as well.

The drug continues to demonstrate more "traditional" anti-cancer effect on soft tissue solid tumors. Promising activity has been observed across the different studies, including a large PFS benefit in the medullary Phase III trial (11.2 vs. 4.0 months) and impressive activity in heavily pretreated renal and prostate cancer patients.

ALK/ROS1 inhibitors - Pfizer, Novartis and Roche

Pfizer's Xalkori is the only approved ALK inhibitor in the market. It is currently approved for patients with ALK mutated lung cancer, but data at ASCO could lead to label expansions. The most important data set is in lung cancer patients with mutated ROS1, another target inhibited by Xalkori. An abstract reports impressive clinical activity, similar to the one observed in ALK-mutated patients. Of 13 patients, 7 (54%) experienced objective responses, which appear durable. Another trial in various childhood cancers that are ALK-driven, Xalkori induced multiple responses.

I discussed ROS1 as a new indication for Xalkori in an earlier post.

Other companies will report initial data with their ALK inhibitors. Both Novartis and Chugai (Roche) will report Phase I results with their ALK inhibitors, both appear active in ALK-mutated patients. Interestingly, the abstract for Novartis' drug mentions responses in Xalkori pre-treated patients.

Immunokinase inhibitors - Pharmacyclics, Celgene and Gilead

Pharmacyclics (NASDAQ:PCYC) will present data for its ibrutinib, its Btk inhibitor in elderly patients with CLL (chronic lymphocytic leukemia). The drug continues to demonstrate unprecedented activity with a 73% response rate and an excellent safety profile. Combination trials with approved agents also demonstrated robust efficacy.

Celgene (NASDAQ:CELG) will present data for its own Btk inhibitor in CLL and NHL. The abstract includes very preliminary data, making it hard to interpret given the fact that Btk inhibitors take several months to reach full effect.

Gilead (NASDAQ:GILD) will present combination data for its PI3K-delta inhibitor,GS-1101, which recently entered Phase III in CLL. Initial data from a combination study with Arzerra demonstrated promising activity. Of note, Gilead is evaluating the combination in its Phase III study in CLL.

In my previous post there is a full list of immunokinase drugs and licensing deals and acquisitions.

Disclosure: I am long ARQL, EXEL, ARRY, SGEN, CLDX.