"I think anti-PD1 combined with anti-CTLA4 (Ipilimumab) will be shown to be too toxic and ineffective to ever be approved as a standard therapy..."
Perhaps, but here is the rationale that I think will be used to justify the filing and if the data justifies it, the approval. Most of the stage 4 indications we discuss here are a virtual death sentence. Occasionally there is the rare durable complete response to treatment and even a handful of spontaneous inexplicable remissions, but these are exceedingly rare events. FDA has approved some of the harshest treatments imaginable because of a demonstrated very low rate of durable complete responses. Interferon, IL2, and Ipilimumab are examples.
Nivo/Ipi is already approved for frontline melanoma including BRAF+ patients in part because of a 9% complete response rate. I suggest checking the "Expanded cohort results from Checkmate 016: an expanded phase 1 study of Nivolumab in combination with Ipilimumab in metastatic renal cell carcinoma." If BMY's phase 3 trial comes back with similar results, I see a very likely approval. The Nivo 3/ Ipi1 arm (same dose as melanoma approval) has an 8.5% complete response rate with many durable responses at 2 years duration. OS and PFS look good, no grade 5's and a reasonable safety profile.
"This is in contrast w/ another presentation "Abstract 5497: Cabozantinib eradicates de novo castrate-resistant PTEN/p53 deficient murine prostate cancer via activation of neutrophil-mediated anti-tumor innate immunity" which seems to indicate that Cabozantinib induces immunogenic death in cancer cells."
Let me list some of the reasons why I weight clinical data so much more heavily than pre-clinical work.
Pre-clinical work is done with what are considered representative cell lines. These are immortalized cancer specimens saved from tumor samples of various patients. Each and every cancer is genetically unique and a therapy effective on a single cell line might not be effective universally.
Tumors evade immune response by inducing anergy (lack of a reaction). They do this by interacting with the immediate microenvironment. Much pre-clinical work is done by transplanting human tumor tissue into various strains of mice specifically bred to accept xenographic tissue. It a drug has an immune component to its means of action, the tumor is something of a sitting duck. It is human tissue in a rodent and when it tries to dampen the immune response, it finds that it cannot manipulate mouse cytokines and other proteins the way it could in a human host.
Immune response is poorly understood and incredibly complex. There are feedback loops and crosstalk among all the different components. A single observation of a single component like M1 macrophage count or neutrophil proliferation is a clue, but only a tiny part of an overall picture.
I remember when Dr Judah Folkman made national headlines with a mouse cure for cancer based on VEGF inhibition. It opened a whole new direction for research, but his drugs were a big disappointment clinically. Dr Apolo's results will give us a first look at Cabo/PD1 therapy and then hopefully we will have something a little less theoretical and conflicted to discuss.
"You don't need to thumb your nose at me to enable theoretic discussion..."
I give you more credit than to include you in "select group." I appreciate your posts and I actually agree with everything you had to say in this thread. You have my apology for quoting you and using it as a launch pad to thumb my nose at the naysayers.
Cabo is being looked at by Dr Apolo in bladder cancer with Cabo/Nivo/Ipi vs Cabo/Nivo. This trial has no Cabo monotherapy arm or Nivo monotherapy arm. It is a freebee. It will answer some important questions about safety, tolerability and perhaps efficacy. It is supported by BMS only to the extent of supplying free drug. Meanwhile the PD1 companies march on with in house combinations and in some cases outside collaborations running their drugs in pivotal trials. I've described this situation in the past as a sort of musical chairs and it looks to me as if EXEL is very much on the outside so far without much chance of grabbing a chair for themselves.
The last few investor presentations by EXEL have left me with the impression that development beyond Celestial is tied to Cabo/PD1. I'm just wondering how they plan to accomplish this. Maybe they are working on a collaboration, but if they are and it is not with BMS, any effort will have to start from scratch.
"Without quantitative analysis, the true nature of M1 macrophage reduction in this study will likely remain a mystery. Importantly, the potential for synergy with immunotherapy remains intact, as yet giving Cabo a "leg up" amongst TKIs in developing combo rationale."
As long as I am irritating a select group, I may as well go all in. I agree with you on this point. Nothing in that abstract supports or detracts from the notion that a Cabo/PD1 combination could be successful. The interactions are of such complexity, that only clinical data will provide definitive answers. I do have issues with Cabo/PD1 development and they have little to do with theoretical efficacy.
First, some realities of the market need to be understood. It is possible, but unlikely that patients will benefit from more than one course of a PD1 treatment. Once a PD1 regimen is approved in a frontline indication, you will not see further competitive PD1 development in follow on treatments.
For instance, In RCC, BMS's Nivo is approved in 2nd line. BMS is also running a frontline phase 3 Nivo/Ipi vs Sunitinib. My guess is that it will succeed. If Nivo/Ipi becomes the standard of care in frontline, it is unlikely that you will see any further PD1 trials in 2nd or 3rd line settings. Any frontline trials subsequent to a Nivo/Ipi approval would be required to use N/I as the control treatment. That would be a tough nut for Cabo/PD1 to crack. BMS owns both Nivo and Ipi. There is no financial incentive for them to explore a Nivo/Cabo combination in RCC.
Roche has Atezo, a PDL1 drug in development. They are running an Atezo/Avastin ph3 trial in frontline RCC and earlier stage trials in other indications. Roche owns both of those drugs. If/when they have a successful result, they will have no desire to look at Atezo/Cabo.
Cabo is being looked at by Dr Apolo in bladder cancer with Cabo/Nivo/Ipi vs Cabo/Nivo. This trial has no Cabo monotherapy arm or Nivo monotherapy arm. It is a freebee.
"Once again, you have displayed your sanctimonious, condescending know-it-all attitude and assumed that we (the poor and huddled masses) have no clue what we are reading."
With the thumbs up count at 11-0, I felt pretty safe assuming that at least 11 folks did not understand it was a mixed bag and not an unqualified endorsement. Maybe you would prefer that no one should explain it, but I suspect a few might appreciate the clarification.
Can you find an error or misrepresentation in what I posted??? Did I try to mislead anyone?? I would make a poor politician. You, on the other hand would fit in rather nicely. Let's tell them what they want to hear until I have what I want and then I don't care what happens.
"Further, in a novel and surprising discovery, we found that cabozantinib alters the immune microenvironment by reducing the M1 macrophages. However, cabozantinib depleted both basal and luminal epithelial progenitor cells in vivo. Taken together, we found that cabozantnib can have a tumor potentiating role by limiting M1 macrophages, yet the down regulation of carcinoma associated fibroblasts and associated epithelial progenitors could suggest interesting combination therapies."
"M1 macrophages" Macrophages are immune cells. They are large ameba like cells that engulf and digest dead cells and harmful microbes. Importantly, they interact with other immune cell types and produce downstream effects. M1 macrophages play an important role in generating an inflammatory immune response. M1 macrophage interaction with cancer is complex and poorly understood, but the abstract quoted is making the point that by limiting M1 proliferation Cabo is "potentiating," ie increasing the likelihood of tumor growth. Not a good thing. On the plus side they are making the point that Cabo also down regulates cancerous fibroblasts (connective tissue cells that produce collagen) and progenitor cells (cells that function to produce new cells of a specific type).
So the point they are making is that they believe Cabo is a mixed bag and its shortcomings might be shored up by various combination strategies. Frankly, I don't get too wrapped up with pre-clinical work like this. The results might be false, misinterpreted or inconsequential. I'm posting this because I noticed all the thumbs up on it and I think most readers saw some key words and jumped to a conclusion that it must be great news.
"Don't they have to have income to fund a Roth?"
They both had part time jobs through high school and college so I used the earned income to start their Roths. I gave them both short lists of investment choices and it made them feel a sense of ownership and participation.
"hi ernie, please have a look at IMGN and SGEN."
Maybe in a few weeks. I'm a little bet familiar with them both, but not enough to offer a reliable opinion. I have to finish the kids' taxes and figure out how much I can stick in their roths.
For those of you with X'ers or Millenials and you will be leaving an inheritance, a great strategy is to fund their Roth's now.
"Hey Errnie, I hope you have a core position cuz I think you might miss the boat on this one"
Workin on it, first buy today @ 4.33.
"If you had kept your doubled down shares purchased @ 3.79 on March 15, against more recent trading, would the outcome be more or less $."
I made 3 purchases on 3/15. If I had simply done buy and hold with the total of those three purchases I would be ahead of my subsequent trading gains. Compared to the single best purchase on that day at $3.79, my subsequent trading in and out is ahead by a small margin.
"how long is your longer term?"
There is a real good chance I will sell on the RCC approval announcement. I will be looking at the open tomorrow to try to begin building up a respectable position. The volatility has decreased with the daily gap from low to high of less than 20 cents for a number of days. The spike to 4.48 this morning confirms by premise that the trading range is ratcheting upwards. Beyond that its hard to say without seeing the outcome of various issues. CaboSun, the Apolo tral, first quarter sales, etc.
Closed out most of my position at $4.41. Have a buy in at 4.32. More small ball, but I will not apologize for taking a quick profit. Still plan to build a longer term position, but we are at the top of the trading range here and taking a profit seems to be the right move.
"It's the system of/by/for rich and power, can't fight it, we just have to get there to join with them."
I agree with you. It is disheartening though. I truly believe capitalism is a great system, it just needs some tweaking to make I better.
Hey Mack, I don't like giving advice, but your situation is compelling. If you don't have anyone depending on you, then fine, take a stab at day trading. If that's not the case, then you will need your savings and simply can't afford to risk it. When you are playing with money you can't afford to lose, maintaining a detached perspective is really difficult. I suggest polishing up the CV and buying a new interview suit. Day trading is not a good answer for you.
"Per latest SEC filing, CEO MMM got a 87% raise, and Dr Gisela,CMO, got a whopping 94% raise in salary/compensation."
Our corporate governance laws are due for a serious overhaul. The system of accountability is messed up. CEO's answer to the BoD's they nominate and shareholders are kept at arms length from the process.
Interesting to listen to. Viewpoints from MD Anderson and MSK. Their perspectives may be a bit different than most community practices. The Anderson guy was pushing L/E, but that may ignore the reality of the reimbursement agencies pressuring practices away from expensive doublets when cheaper alternatives are available. The MSK guy always has an eye on putting patients into cutting edge clinical trials, a perspective that may be unique to the opportunities his institution offers, options that may not be available in Peoria. Both had favorable opinions of Cabo and interestingly both favored Pazo over Sunitinib.
"It is open label. On 4/9/2015, the trial protocol was amended to reflect overall survival as a primary objective - in addition to PFS."
The most logical way to do this is the same way Meteor was done, have a first look at PFS and then continue the trial to future date with another analysis for survival. The outcome on this one is not an automatic win for Cabo. Sunitinib is a good frontline drug. It's outcome in CRPC was very similar to the Comet results.
Back in at 4.32.
"Building position for RCC approval.'
That's still the plan. I was/am hoping to get a nice fill in the lower $4's and in the meantime I've been distracted playing smallball with 7-10 cent spreads. Time to hit a double or triple and pony up in the next few days. The trading range seems to have ratcheted up to 4.20 to 4.40. Three's may be in the rearview mirror. We'll see. On a 1 to 10 scale, having a successful topline result from a pivotal trial is a 9 or 10. Receiving an anticipated approval is more like a 4 or 5. Statsig PFS from CaboSun would be more exciting to me than the RCC approval.