The goal of treatment in AML is to reduce the blasts in the bone marrow to below 5% and return the blood cell counts to normal levels. This is considered a complete remission, or CR. A hematopoietic stem cell transplantation (HSCT), or bone marrow transplant, is generally recognized as the only curative treatment option. Typically, patients who are able to achieve a reduction in bone marrow blasts below 5% are more suitable candidates for an HSCT and have an improved projected outcome following an HSCT
As you may know Cabozantinib inhibits FLT3
NCT01961765---Under the radar and currently enrolling patients. This trial may sneak up and show some interesting data.
Here is a brief on Quizartinib FLT3 inhibitor
Quizartinib Phase 2 Clinical Trial
A Phase 2 clinical trial of quizartinib in relapsed/refractory AML patients was initiated in November 2009 and completed enrollment in November 2011. Data from our single-arm, 333 patient clinical trial was reported at the American Society of Hematology meeting in December 2012. In the trial, quizartinib demonstrated the ability to significantly reduce the number of blasts in the bone marrow of a substantial number of patients.
Our Phase 2 clinical trial demonstrated the following three key clinical outcomes:
1.Quizartinib, as a monotherapy, demonstrated approximately a 50% CRc response rate in relapsed/refractory FLT3-ITD positive patients;
2.A substantial number of patients treated with quizartinib were bridged to a potentially curative hematopoietic stem cell transplantation, or an HSCT (commonly referred to as a bone marrow transplant); and
3.Overall survival in FLT3-ITD positive patients treated with quizartinib compared favorably to historical survival data reported for both FLT3-ITD positive and negative AML patients.
In addition, nearly one of every five patients treated with quizartinib (irrespective of FLT3-ITD status) remained alive for more than 12 months and such patients are referred to as long term survivors.
"I can't verify until the new HOPPS 2014 schedule comes out, but I would be very surprised if the switch to lymphoseek would not result in positive financial impact for facilities."
FYI this is the new 2014 CMS HOPPS final rule. Has an A code
A9520 NEW 2014
Tc99 Tilmanocept Diag 0.5MCI TECHNETIUM TC-99M TILMANOCEPT, DIAGNOSTIC, UP TO 0.5 MILLICURIES
LymphoSeek™ Replaces Deleted C1204 NDC # 52579-1600-05
I asked other nuclear tech's within sister facility alliance. Out of the 3 hospitals I am in touch with frequently, only one has made the switch to lymphoseek.
Here is a twitter quote from David Miller
David Miller @AlpineBV_Miller 2h
The $EXEL news doesn't change theirshare of cobi sales, but does allow them to get an oncology sales force for free.
U.S. marketing and commercialization costs are shared equally regardless of who is promoting. Genentech already has a salesforce size in mind already. Now Genentech will supply 75% of that number.
I think this was a no brainer for Exelixis to opt in. Financial obligations were fixed regardless of whether they opted in or not.
" A combination of a BCL-XL inhibitor which unbinds apoptosis inducing proteins proves to be very effective in-vivo. Specifically ABT-263 was mentioned which is a BCL-XL inhibitor co-developed by Abbot and Genentech / Roche. This was discovered through an exhaustive search."
Regarding KRAS mutant lung cancer line
Note at 37:10 into the presentation how ABT-263/MEK combination is more sensitive on Epethelial cell lines and not so much on Mesenchymal cell lines in KRAS lung cancer.
From pooled shRNA-drug screen approach they hope to identify other combinations
Exploration of other RAS effector pathways (PI3K)
Novel RAS targets (TBK1,TAK1,GATA2)
" The study "A Study of MEHD7945A and Cobimetinib (GDC-0973) in Patients With Locally Advanced or Metastatic Cancers With Mutant KRAS" makes sense in light of this talk. It was said that EGFR enables cell survival due to BRAF inhibition and a triple combo of MEK + BRAF + EGFR inhibition was suggested in the talk. MEHD7945A + Cobimetinib addresses a part of this combo, with MEK being down stream of both BRAF and EGFR in MAPK. It's possible that adding something like Vemurafinib might result in too much toxicity."
The first part of the 47 minute 45 second video concentrated on BRAF resistant colon cancer. So the talk I listened to doesn't really relate to the Mutant KRAS GDC-0973 study you describe. The theory in BRAF colon cancer is triple combo MEK + BRAF + EGFR or dual combo MEK + BRAF in low EGFR expressor cancer cells and EGFR + BRAF in high EGFR expressor cancer cells. Ideally a triple combo treatment would close the loop of resistance in both EGFR or MEK if the combination is tolerable. If not, targeting immediate resistor of either EGFR or MEK would be the most important first potential dual target.------- Interestingly the real target here is RAS, and the speaker identified EGFR inhibition as the best way to knock down this target. Hence, why I mentioned RAS knockdown from Cabo in EXAM MTC trial. Here is the the relevant piece regarding RAS in MTC EXAM trial
"For those without an RET mutation but with an RAS mutation, the drug conferred significantly greater benefits on PFS than placebo (47 weeks versus 8 weeks, HR 0.15, 95% CI 0.02-1.10, P=0.03) -- though the confidence interval straddled 1 here.
Brose noted that in the RET mutation-negative population, the PFS benefit was largely attributable to RAS mutations, and responses in this population may be due to anti-VEGFR2/MET activity."
Very nice find Wildbiftek!!!
Is CMET the one acting on RAS in the Cabozantinib MTC EXAM trial? You make recall Peter Lamb's excitement regarding RAS mutant responses in Cabo treated MTC EXAM trial. Cabozantinib currently in trial with Vemurafenib in metastatic melanoma.
Makes me wonder if that is why Onartuzumab is being used in combination with Cobimetinib and Vemurafenib in KRAS-mutant, Stage IV colorectal adenocarcinoma, or KRAS-mutant metastatic non-small-cell lung carcinoma. OR Patients with histologically confirmed BRAFV600-mutant unresectable Stage IIIC or Stage IV metastatic melanoma.
"I'm guessing if COMET-1 fails and our share price corrects, we'll very likely see an enthusiastic low bid from Roche."
I'm guessing a positive COMET-1 rekindles Asian partnership talks. Good randomized statsig OS data may provide an opportunity to get some decent upfront money to lessen possible secondary dillution.
A Study of MEHD7945A and Cobimetinib (GDC-0973) in Patients With Locally Advanced or Metastatic Cancers With Mutant KRAS
A Study of the Safety and Pharmacology of MPDL3280A Given With Cobimetinib in Patients With Locally Advanced or Metastatic Cancer
1 Swiss Franc = approx 1.1 U.S. dollar
Looks like run rate is close to $400 million on yearly worldwide basis (in U.S. dollars) EU and International market still growing, but U.S. market had a hiccup in 3rd quarter. It will be interesting to follow going forward. I don't know where the competition stands at this point. Is the GSK BRAF/MEK combo close to market?
CD47 is an interesting target I have been google searching of late. I stumbled across this in my CD47 google search.
"Three molecules characterize the metastasis stem cell
In a systematic screening process, Baccelli first isolated cells carrying a typical protein of breast cancer stem cells (CD44) on their surface from the CTCs. This protein helps the cell to settle in bone marrow. Next, the researchers screened this cell population for specific surface markers which help the cells to survive in foreign tissue. These include, for example, a signaling molecule that protects from attacks by the immune system (CD47) and a surface receptor that enhances the cells' migratory and invasive capabilities (MET).
Using a cell sorter, the researchers were then able to isolate those CTCs which exhibit all three characteristics (CD44, CD47, MET) at once. Another round of transplantation tests showed that these really were the cells from which the metastases originated.
Depending on the patient, cells exhibiting all three surface molecules ("triple-positive" cells) made up between 0.6 and 33 percent of all CTCs. "It is interesting that only cells with the stem cell marker CD44 carry the combination of the other two surface molecules," said Irène Baccelli. "It looks like the triple-positive cells are a specialized subtype of breast cancer stem cells circulating in the blood."
This Cowen survey recently appeared on twitter yesterday.--Could not copy and paste the text
"Our most recent poll showed a noticeable shift in physician sentiment, in particular, those viewing Cabo as a promising drug decreased from 44% to 10%."
"50% of medical specialists assigned approx. 25% probability for Cabo OS benefit in COMET 1
40% of medical specialists assigned approx. 50% probability for Cabo OS benefit in COMET 1
Category of doctors who believe Cabo is poorly tolerated and not particularly promising changed from 11% to 30%"
"Irrespective of all the above, within a matter of months, perception and guessing will be replaced with some hard data and the stock price will break one way or the other."
Assuming positive COMET 1 results, do you see a compendium listing preceding approval?
Assuming negative COMET 1 results, and a stock decline aftermath, would you consider it a buying opportunity on pivotal Renal and HCC indications?
"I know that Cabo demonstrates large effect on CD44+ cells"
FYI, I did find an article on CD44V6 that talked about an antibody that failed do to toxicity. The article postulated that VEFGR2/CMET would be and interesting way to target CD44V6. I posted about MET/VEGFR2 crosstalk on cell surface CD44V6 before. Anyways, I may be done posting for awhile as I have a lot of work related stuff to get done. prep for committee meetings etc.
" I remember a presentation by Logothetis where claims that PC doesn't increase cell diversity as the disease progresses."
I was very disappointed by his presentation---he vaguely talked about epithelial to mesenchymal transitions, and related stem cell niche. Dasatinib was the big focus and I can see why. The presentation was sponsored by Bristol Myers Squibb. I wasn't really impressed with Dasatinib early data they presented in combination with Docetaxel. Well maybe the RECIST responses were interesting, but markers of metastatic disease were on weaker side and mainly solely on osteoclast side of things.
It was a long presentation and I skipped through most of it, so I may be missing something interesting. I kind of doubt it though.
What's your theory about what happens to PC cells when they exhibit Cabo resistance?
If you look at the pancreatic model targeting nodal/activin in this article titled
"Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy" a Cabo cocktail inclusion may look interesting.
Interesting quote from article "Mechanistically, we could show that despite a marked decrease in CD133 content following 4 days of treatment with SB431542 alone, the CD133+ population replenished within 48 hr after withdrawal of treatment. When cells were treated with SB431542 and gemcitabine, however, the CD133+ population was irreversibly eliminated "
"Further mechanistic studies revealed that SB431542 alone (reversibly) drives CSCs into a more differentiated state, as evidenced by loss of CD133, but cells still retain the ability to revert to the CSC phenotype. Intriguingly, although gemcitabine alone led to a relative enrichment of CSCs, the combination of SB431542 and gemcitabine resulted in their irreversible and complete elimination. Indeed, in vitro combination therapy resulted in complete abrogation of the in vivo tumorigenic potential of the remaining cells."
I think cell surface marker CD133 could be one interesting key in epethelial to mesenchymal transition. I can't find specific CD133 knockout information on Cabozantinib, but know that VEGFR2 is a coreceptor. I know that Cabo demonstrates large effect on CD44+ cells and may have some activity on CD133 populations.
I would fathom to guess that adding Cabo to SB431542+gemcitabine could introduce some redundancy, but may be some crosstalk. I've been looking at some other interesting articles, but this one stuck out when you asked about the resistance with Cabo. I will reserve more thoughts until I can look at some of these articles I have been looking over. I thought you might like this one in particular--out of space
"So the cross talk we see between the c-Met and AR pathways might be caused by different cells with different sets of characteristics taking over when one path way is suppressed instead of one type of cell changing receptor pathways as the cancer progresses."
To survive cell death through androgen deprivation these cells need to seek out alternative sources to fuel growth. To compensate, these cells seek host cell interactions that don't depend exclusively on androgen . (hence mixed androgen and androgen independent cell lines) I imagine through host cell interactions, these cells can change and take on characteristics of host cell. This leads to the cancer cell's ability to rely on sources that are not exclusive to androgen. More of an adaptation to survive imo.
Very good read here. I've had trouble citing a direct quotation with non association of PSA and androgen independent cell lines. Here is a direct quote regarding lack of PSA expression with androgen independent cell lines.-----Cell lines targeted by Cabozantinib.
"Cultured PrCa cells and orthotopically-induced in vivo cancers lacked PSA expression. We report here the propagation of Cancer Initiating Cells (CIC) directly from Stage I human PrCa tissue without selection or genetic manipulation. The propagation of stem/progenitor-like CR-PrCa cells derived from early human prostate carcinomas suggests the existence of a subpopulation of cells resistant to androgen-deprivation therapy and which may drive the subsequent emergence of disseminated CR-PrCa."
"The market entry of multiple agents that have prolonged overall survival in pivotal Phase III studies has created an urgent need to understand the optimal sequence in which these therapies should be given," said Decision Resources Group Senior Business Insights Analyst Khurram Nawaz, M.Sc. "When considering the sequence of therapies for mCRPC, the majority of surveyed physicians agreed that they would switch to an agent with a different mechanism of action upon disease progression, use novel hormonal agents before chemotherapy and delay use of chemotherapy for as long as possible."
"according to oncologists surveyed in Q3 2013, Johnson & Johnson/Janssen Biotech/Janssen-Cilag's Zytiga is the patient-share leader in the first-line asymptomatic and symptomatic metastatic castrate-resistant prostate cancer (mCRPC) settings; respondents in Q1 2013 cited conventional hormone therapy and docetaxel as lead therapies in these respective settings. Surveyed oncologists in Q3 2013 reported that Medivation/Astellas Pharma's Xtandi holds the most patient shares in the second- and third-line mCRPC settings. The findings are from the TreatmentTrends® Prostate Cancer (US) Q3 2013 report, in which 50 urologists and 51 medical oncologists were surveyed about their current and expected treatment practices for prostate cancer."