More melanoma breakthroughs
This year’s meeting will probably be remembered as a historical event with regards to melanoma. Last year, it was a phase III trial for BMS’ (BMY) Yervoy (ipilimumab), which was the first in history to show a survival benefit in advanced melanoma patients (discussed in my ASCO 2010 write up). This trial led to Yervoy’s historical approval 3 months ago.
This year, investigators will present studies evaluating Yervoy as well as Plexxikon/Roche’s vemurafenib in pretreated melanoma patients. Yervoy was evaluated in combination with chemotherapy while vemurafenib was compared with chemotherapy. According to BMS’ and Roche’s press releases, both studies were successful and each drug led to a survival benefit. The extent of this benefit is still unknown and will be revealed only at the conference.
It is hard to see the two drugs as direct competitors, as they represent such distinct approaches. Yervoy, which stimulates the patient’s immune system to fight cancer cells, rarely leads to profound tumor shrinkage but results in prolonged remissions and perhaps cures in 5-10% of patients. Vemurafenib, on the other hand, disrupts signaling in cancer cells and shrinks tumors in the majority of patients, but durable remissions are quite rare. One advantage vemurafenib has is its benign safety profile compared to Yervoy’s problematic safety profile which could be fatal in some cases. Yervoy’s biggest advantage is its intended use for all melanoma patients. This is in contrast to vemurafenib, which will be used only in patients with BRAF mutations (50-60% of melanoma patients).
Due to the distinct mechanisms, clinicians will probably use both drugs when possible. The current thinking is starting with vemurafenib to decrease tumor burden and improve patients’ status, and then introduce Yervoy to achieve maximal effect and long term remissions. This hypothesis is yet to be proven, even though it makes a lot of sense.
Lilly’s (LLY) Alimta has been able to capture market share in non-small cell lung cancer (NSCLC) thanks to impressive activity as second line or maintenance therapy (discussed in my ASCO 2009 write up) in a large subset (70%) of patients. This year, investigators will present results from a phase III trial which evaluated Alimta given both as first line and maintenance therapy. Although the drug is approved for both treatment lines separately, positive results could help Lilly drive sales even higher and increase the average number of cycles patients receive.
Good data will probably eliminate Alimta’s use as 2nd or 3rd line therapy, leaving the stage to Taxotere and Tarceva. In that sense, companies whose drugs are evaluated in combination with these agents for 2nd/3rd line NSCLC could enjoy easier market penetration, if their drugs get approved. Two such companies are Arqule (ARQL) and Synta (SNTA), who are evaluating their lead agents with Tarceva and Taxotere, respectively.
It remains to be seen how this trial will affect Roche’s Avastin, which is also used as first line and maintenance treatment in the same patient population. Hopefully, next year there will be data from another phase III trial evaluating Alimta and Avastin in combination.
Novartis (NVS) and Incyte (INCY) will present data from two pivotal trials evaluating ruxolitinib in myelofibrosis. Results for the first trial (COMFORT1) and top line results for the second (COMFORT2) were already announced, so there shouldn’t be any surprises on that front.
The drug will probably be approved in the US later this year, followed by EU approval next year, based on its dramatic effect on spleen size and constitutional symptoms. A trend in survival was mentioned by some analysts, which could be a huge catalyst, but the numbers will probably be too small to support any definitive conclusions.
Despite the almost certain approval and the blockbuster potential, Incyte’s biggest threat is from a competing drug (CYT387) by YM Biosciences’ (YMI) that uses a similar mechanism. YM’s drug is generating a lot of controversy as it appears to be as effective as Incyte’s drug but with an unexplained effect on anemia. This effect is not observed with ruxolitinib, which even leads to anemia in a portion of patients. Since both drugs were not compared head to head it is hard to tell whether the anemia effect with YM’s CYT387 is real, but it is definitely something Incyte’s shareholders cannot ignore.
In any case, Incyte has a 1-2 year head start over YM Biosciences which is only in phase II. On a more positive note, one of Incyte’s competitors, S*Bio, experienced a major setback after Onyx (ONXX) gave back rights to its Jak inhibitor.
Exelixis’ (EXEL) cabozantinib will continue to draw a lot of attention, thanks to an unprecedented effect in patients with bone metastases, primarily prostate cancer patients. At ASCO, the company will show more results in prostate cancer patients, both in terms of bone scans and more traditional endpoints such as soft tissue responses and progression free survival. Despite the sensational results earlier this year, it is still unclear what the clinical relevance of bone scan resolution is. For example, some argue that bone scans provide indirect evidence to the presence of bone metastases and as such are not reliable. Exelixis is expected to present cabozantinib’s anti-bone mets effect, assessed by other means such as MRI or biopsy.
The company might also shed more light on the phase III study it intends to launch this year, which will have a composite endpoint including bone resolution and other related comorbidities (pain, fractures, etc). The company stated it plans to obtain a SPA (special protocol assessment) for this trial, which seems tricky given the exploratory nature of this trial.
On top of the prostate cancer data, there should be new data in ovarian, renal and liver cancers. Cabozantinib appears to have promising activity in these tumor types as well.
MET inhibition becomes more crowded
One of the most intriguing data sets will be for Roche’s Metmab, an antibody targeting the MET receptor. This phase II evaluated the antibody in combination with Tarceva in lung cancer patients.
According to the already published results, when combined with Tarceva, Metmab led to a dramatic effect in patients who overexpressed MET on their tumors. The drug appeared deleterious in MET negative patients. Although the number of patients is relatively small, the overall survival benefit was astounding (12.6 vs. 4.6 months). This trial will surely lead to a phase III study in MET positive lung cancer in the coming future.
Given the spectacular results, Metmab has become a real threat to Arqule’s ARQ197, a small molecule MET inhibitor that also generated a positive signal in combination with Tarceva in lung cancer. It is very hard to compare the two drugs due to patient selection and stratification issues (discussed here). Arqule is currently evaluating patients in its phase II trial retrospectively using the same criteria used for Metmab, so it would be very interesting to see whether a similar trend is observed.
Amgen (AMGN) will present results for another combination using a MET inhibitor and an EGFR inhibitor. In contrast to Roche, Amgen’s agent is an antibody against HGF, a soluble protein that binds and activates MET. AMG102 was given in combination with Vectibix to colon cancer patients and appeared more active than Vectibix alone based tumor shrinkage and PFS, even though the numbers were small and the difference was limited in the overall population. Amgen will present biomarker data and potentially survival data.
Antibody drug conjugates – Sanofi and Immunogen back in the game
Despite all the hype around antibody drug conjugates, this year’s meeting will have only few studies with antibody drug conjugates (ADCs).
After over 3 years in clinical testing, Sanofi’s SAR3419 finally generates enough positive data to justify further clinical development in Non Hodgkin’s Lymphoma (NHL). SAR3419 is an ADC targeting CD19, a protein widely expressed in many blood cancers. It is based on Immunogen’s (IMGN) technology. According to the abstract, the drug was active, leading to a 32-36% response rate in the higher doses. Although this kind of response rate is low compared to the top 3 NHL drugs in development (Calistoga’s CAL-101 , Micromet’s (MITI) blinatumumab and Pharmacyclics’ (PCYC) PCI-32765), it is very hard to compare SAR3419 to other investigational agents. NHL is a very heterogeneous disease in terms of disease subtypes and treatment lines so SAR3419 could have an advantage in certain subtypes or in more heavily pretreated patients.
Seattle Genetics (SGEN) will provide an update for its anti-CD70 ADC (SGN-75), which is being evaluated in NHL and renal cancer patients. Based on the abstract, this agent is active but the response rate is modest so far even though clinically relevant doses were reached. The efficacy profile could improve as more patients are enrolled at the higher cohorts. Another interesting observation is a correlation between uniform expression of CD70 and response, which could guide investigators towards better patient selection.
Progenics (PGNX) will report data for its ADC against PSMA in prostate cancer patients. Results with this agent, which utilizes Seattle Genetics’ technology continue to be disappointing, with no meaningful signs of clinical activity. The fact that Bayer is not presenting any data for its CA-IX ADC (also utilizing Seattle Genetics’ technology) does not bode well for this program as well.
Next year, however, Seattle Genetics will have multiple shots on goal thanks Genentech’s accelerating ADC pipeline. In less than a year, Genentech advanced 7 new ADC to phase I, all of which are based on Seattle Genetics’ technology. If only one or two of these demonstrate good activity, they could represent important value creation events for the company.
Combination of investigational agents
One of the main themes this year is combination of targeted agents that are still in clinical development. Until recently, combining two agents in development was rare, but the strong biologic rationale coupled with the limited activity as single agents, prompted drug companies to combine drugs already as part of their clinical development programs.
The most promising trial so far is evaluating Genentech’s PI3K inhibitor with a MEK inhibitor that was licensed from Exelixis. Genentech will present a highly anticipated update from a combination trial after initial results two months ago looked promising. According to the abstract there appear to be more signs of efficacy.
GSK (GSK) will present two trials evaluating such combinations for its MEK inhibitor, GSK1120212. The first trial will evaluate the combination with the company’s BRAF inhibitor. The rationale in this study is reaching a more profound inhibition of the MAPK pathway and counter potential resistance mechanisms against each drug separately. The second trial evaluates GSK’s MEK inhibitor with an Akt inhibitor, where, based on the abstract there is some degree of activity in the form of tumor shrinkage but the data are premature. One issue that emerged in this trial was a substantial amount of side effects. The rationale in this study was shutting down the two main cancer related pathways: PI3K and MAPK. AstraZeneca (AZN) and Merck (MRK) will also present results from a similar combination using Merck’s Akt inhibitor and AstraZeneca’s MEK inhibitor, licensed from Array Biopharma (ARRY)
GSK will also present data for its MEK inhibitor in AML. According to the abstract, investigators were able to identify patients who are more responsive to the drug, which could open up the first fast route indication for MEK inhibitors.
siRNA alive (and kicking?)
siRNA has gone out of flavor in the past 2 years due to delivery and safety issues. But the sentiment towards this field could change with the help of some encouraging yet very preliminary data.
Alnylam (ALNY) will present results from a phase I trial evaluating two siRNA drugs with its delivery system in patients with metastases to the liver. Based on the abstract, there was one partial response in an endometrial cancer patient and the portion of patients achieving disease stabilization was proportional to the dose. Other measurements that can be viewed as surrogates for activity were target inhibition in tumors and a decrease in blood flow assessed by imaging.
Germany- based Silence Therapeutics will also present results for its siRNA agent, where preliminary evidence of anti-tumor activity was observed.
New Angiogenesis Targets
Despite Avastin’s phenomenal success, there are currently no other anti-angiogenic antibodies on the market. Angiogenesis, the formation of new blood vessels, is a critical process for tumor growth and metastasis. It involves a host of factors besides VEGF, Avastin’s target, some of which are targeted by antibodies in clinical development.
One of the high profile targets is angiopoietin, which includes two members (Ang1 and Ang2) that have a complex (sometimes contradicting) interaction with VEGF. Amgen’s AMG386 binds Ang1 and Ang2 is about to enter phase III based on encouraging results in ovarian cancer together with chemotherapy. This year, investigators are presenting another phase II trial in breast cancer, where AMG386 did not demonstrate any activity when added to chemotherapy and Avastin.
An additional target that looks interesting is ALK1 (activin receptor like kinase 1). The two leading ALK-1 antibodies are Pfizer’s (PFE) PF-03446962 and privately held Acceleron’s ACE-041. Based on the abstracts, both antibodies led to tumor regressions as single agents in a small fraction of patients. It is important to note that objective responses are quite rare with anti-angiogenic antibodies, which should be given in combination with other drugs. ALK1 is still not a validated target but the available data certainly merits advancing them to randomized combination studies. At the moment neither Pfizer nor Acceleron have announced future plans with their respective programs.
Immunotherapy with a twist
On top of Yervoy’s phase III trial in 1st line melanoma, there are several interesting presentations for other immunotherapy treatments.
Two early cancer vaccine studies will be presented at the meeting, both involve a similar approach. The two vaccines are based on dendritic cells, similarly to Dendreon’s (DNDN) Provenge, but they also engineer the cells so that they can be activated by a second drug once inside the body.
Bellicum will present updated results for its prostate cancer vaccine. According to the abstract, the vaccine led to two cases of clear tumor shrinkage (of 12 evaluable patients), which is very uncommon with cancer vaccines. It will be interesting to see whether the updated results will include more signs of efficacy or some sort of correlation between tumor shrinkage and an immune response.
Ziopharm (ZIOP) will present first results with its cancer vaccine (originally developed by Intrexon) in melanoma. Based on the abstract, when injected into patients’ tumors, the vaccine led to shrinkage of the injected lesions, and more importantly, of distant lesions in 2 out of 7 patients. This approach is similar to Biovex’s (recently acquired by Amgen) Oncovex, where a local injection leads to a systemic anti-tumor response. Data at ASCO should include additional patients.
Another interesting approach to harness the immune system against cancer will be presented by a group from The Chaim Sheba Medical Center in Israel. This approach involves harvesting immune cells from the patient’s tumor (tumor-infiltrating lymphocytes, or TILs), growing them in the lab and injecting them back to the patient. This approach has been pioneered by Steven Rosenberg from the NIH and has already demonstrated impressive clinical activity, but the main drawback is the time it takes to prepare the patients and generate the TILs as well as hospitalization costs. At ASCO, investigators will present results using a modified protocol of TIL therapy which simplifies and shorten this procedure. Results look impressive, with 16 out of 38 (42%) evaluable patients achieving objective responses, some of which were quite durable. There were 15 patients who got on the study and did not receive the treatment due to early disease progression and technical issues. Although not ideal, this drop out rate (15 out of 65 enrolled patients) compares very favorably to prior studies using TIL therapy and could represent a major step forward in the field.
Lastly, there is an intriguing study which combines Yervoy with Avastin in melanoma patients. Although the trial was small, the combination appears very active and warrants future investigation in phase II.
CDG Therapeutics – cancer breakthrough?
The most provocative abstract so far is from CDG Therapeutics, a small private company based in Illinois. The company’s lead agent, p28, is a short peptide with a unique mechanism of action that appears to be very active. According to the abstract, p28 led to an objective response in 8 of 14 (57%!) patients, which is highly unusual for any investigational agent, let alone in a phase I trial. p28 is believed to work by increasing the level of P53 in cancer cells. P53 is considered one of the most important genes in preventing cancer and its central role as a tumor suppressor earned him the title “The guardian of the genome”. It is commonly dysregulated in about 50% of cancer patients, which led to numerous attempts for the past 30 years to restore or upregulate its activity, so far with limited success.
If p28 continues to demonstrate this level of efficacy, it would be the first active P53 modulator. This represents a real breakthrough in the field of cancer research with broad applicability and obvious synergism with existing treatments. One potential issue with this drug is the frequent administration (3 injections per week) but this might be dealt with technical means or alternative schedules.