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I agree with you on that point lowe, the biomarker is not a validated one; it hasn't gone through years of rigorous confirmation or approval yet.
What they are using is an exploratory biomarker assay that was developed following a retrospective analysis. The company believes that the "validation cohort" study (remember, they developed a testable hypothesis based on an earlier inductive review of exhausted TIL phenotypes in a 20-patient discovery cohort) of 20 patients led by the UCSF supports the discovery cohort findings. The whole point of the biomarker assay developed by the UCSF is to inform future trial designs and inclusion/exclusion criteria.
The facts are:
The validation cohort data confirmed the discovery cohort data. More specifically, 100% of patients with >30% pd-1/CTLA-4-positive TIL phenotype responded to monotherapy Keytruda, while 100% of patients with <20% pd-1/CTLA-4-positive TIL phenotype did not respond to monotherapy Keytruda.
So, why use the exploratory biomarker in the phase II EP IL-12/pembrolizumab study? The answer is it helps with the design and inclusion/exclusion criteria of future studies. It establishes confidence and informs registration trial inclusion/exclusion criteria. This doesn't mean they will necessarily use the biomarker in the registration study.
The FDA recognizes exploratory biomarkers for decision making purposes. They are very useful even if they aren't yet validated.
We'll see if the IO community views the data as a "spin".
Take note of the target population in the keynote-024 trial, the trial for which approval in the first line setting was based - these are NSCLC patients with greater than 50% pdl1 tumor expression. Although they achieved better results than platinum based chemotherapies, they were still only able to achieve a 45% overall response and a 4% complete response. This was a targeted SUBPOPULATION.
So why couldn't even this targeted subpopulation achieve better response rates you ask? After all, the targeted checkpoint was found at a high level of expression in all of these patients. The answer, I believe, is actually related to TIL phenotype expression and quantity. In simpler terms, there just ain't enough pd-1 positive TIL.
Looking at keynote-010 for second line monotherapy keytruda, take note of the overall response rates for pdl1 expression greater than 1% - that is right, only 19%! And of course this does not include patients who don't have any pdl1 expression in their tumors.
Hey Dia, yep, shelf life for disposable parts is certainly important to know about before trials commence. No trial investigator wants to be surprised by a degraded applicator.
When we look at current metastatic melanoma competition, e.g. epacadostat (IDO1-inhibitor) plus pembrolizumab (anti-pd1), T-vec plus pembrolizumab, yervoy (anti-ctla4) plus opdivo (anti-pd1), PV-10 (rose bengal - now plus pembrolizumab), you'll notice several things:
First, these are all-comers trials and they aren't exceeding 58% response rates even in some subpopulations of stage III & IV metastatic melanoma. Moreover, complete responses rarely approach 25% in combinations. PV-10 has demonstrated good complete response efficacy in only cutaneous melanoma patients, and they have to treat lesions individually.
Second, most of these treatments aren't doing much for visceral lesions, which are a HUGE deal in advanced metastatic melanoma. Yervoy plus opdivo does appear to be reducing these lesions, but safety is a significant concern.
Third, many combination therapies are attempting to drive immune responses through the experimentation with multiple novel monoclonal antibodies. The problem is that most of these monoclonal antibodies, i.e. checkpoint inhibitors, simply reduce the number of suppressor cell cytokines. In other words, they aren't actually functioning to increase the number of activated and differentiated CD8 tcells, they simply reduce the percentage of cytokines that would otherwise prevent EXISTING cells from attacking tumor cells. To be clear, these mabs do have a positive effect on responses - see anti-CTLA-4 as an example - but they don't have the punch that would be found in an agent that actively recruits antigen presenting cells, stimulates t-cell expansion, and upregulates pd-1 positive phenotypes in TIL - see EP IL-12. Moreover, mab combinations appear to be causing many serious adverse events, and in some cases up to 40% of patients drop out of treatment (see combination yervoy and opdivo).
As far as Immunopulse going into deep or visceral tumors, we have no idea how well the new device and approach works. But, like you said, we should know more next month. I am very curious myself, because it could turn a one trick pony into a team of galloping ponies if they are able to safely apply the new device and plasmid payload as efficiently as they do with melanoma. There is a clear abscopal effect with EP IL-12 treatment; if they can get to those deep and visceral tumors, then I'm serious when I say the sky is the limit. Anti-pd-1 agents appear to be working in every single solid tumor indication thus far investigated (with the exception of BMY who allowed NSCLC patients with low PDL1 tumor phenotype - duh, of course an anti pd-1 won't work on those patients!). Therefore, all of these tested solid tumor types have PDL1-positive cells that can be treated using an anti-pd-1 or anti-pdL1 checkpoint inhibitor agent. All that's needed is an immune boost to drive more pd-1-positive TIL, and there probably isn't anything better than intratumoral IL-12 to accomplish that task.
Aside from the technology, which I'm obviously excited about, we do need clarity on future funding like you said, especially considering the runway is now shortened to Q3 2017. I have been trying really hard to resist the temptation to say "this company is so undervalued", but I think the threat of dilution to advance through clinical trials is keeping folks at bay.
Also, we may have some idea how well Immunopulse EP IL-12/pembro will work in metastatic melanoma, but efficacy was based on a retrospective study. The interim phase II combination data being presented next month will certainly either support or refute the retrospective study data.
Nearly every company that is using checkpoint inhibitors - and it's a lot of them! - would benefit from a therapy that would hypothetically extend use into a much larger patient population. The refractory patient population is a combination of non-responders, partial responders, and recurrent complete responders. With less than 20% of all patients showing durable complete responses with any combination of therapy, what you're left with is a large refractory population in a second-line setting for advanced metastatic melanoma. There is simply way too much incentive to ignore Immunopulse, but again, everyone needs to see the data first.
Yep, there is absolutely no indication of inflammation with Bavi. I would bet my house on that point. There are no significant changes in IL12 production with Bavi either.
It is all about reducing the immune suppressor cytokines, that is all it is with Bavi. I am 100% certain of this MOA.
Just a little more refinement...
Reducing suppressor cells in combination with an anti-pd-1 agent is synergistic to a degree. In fact, I have read and heard that anti-CTLA-4 agents harbor the same MOA, i.e. they don't actually improve the number of TIL, but they reduce the number of suppressor cells.
Therefore, I think Bavi would be akin to using an anti-CTLA-4 agent with an anti-pd-1. If true, efficacy and safety with a Bavi and anti-pd-1 or anti-pdl1 combination should look similar to an anti-pd1 and anti-CTLA-4 combination. Mixing all three together though would not only be very expensive, but would theoretically be very toxic with negligible added benefit.
Here is something else I just noticed in the immune profiling for PPHM's preclinical data presented at this year's AACR (I think this is what sets EP IL-12 apart from Bavi and other IO agents):
First and most importantly, the mouse equivalent Bavi does not demonstrate an inflamed immune profile. You will note that macrophages, Th1 cells, total tcells, DC cells, PD-1 positive tcells, and interferon gamma do not change much if at all after administration with Bavi.
So what is Bavi's MOA in my opinion? It is capable of reducing immune suppressing cytokines. While this benefits responses, I don't think it is going to add much long term survival benefit over anti-pd-1 agents used alone or in combination with an anti-CTLA-4 agent.
In short, I don't think Bavi is actually improving immunity and driving more TIL, it is simply reducing the number of suppressor cells.
Just so I don't divert much from an ONCS discussion, I will say this: both PPHM and ONCS hope to achieve similar goals, i.e. expanding the number of TIL to allow for a more robust response to checkpoint inhibitor therapies.
PPHM has what appears to be some good things going for it judging by response data in preclinical trials.
I do believe their combinations with chemotherapy agents are going to be hindrances in terms of duration of responses though, and there are a lot of these investigator-led trials with chemo agents. Most chemo agents suppress the adaptive immune system, thus giving rise to recurrences and only partial responses. You can see that in the phase 1 bavi-plus-pacli her2-negative breast cancer study: response durations drop like a rock.
It is also starting to look like combination monoclonal antibodies, i.e. checkpoint inhibitors, may give rise to decent partial responses, e.g see yervoy and opdivo, but their systemic application is leading to terrible SAEs. That would be my primary concern with bavi use in combination with other mabs. You see some good preclinical responses, but will they prove to be risky relative to another treatment accomplishing similar efficacy? Because they are administered systemically, that means they could be releasing the brakes throughout the body wherever the checkpoints exist, not just in tumor microenvironments.
Also, the way we should probably view immunopulse EP IL-12 is as an in-situ vaccine that is capable of driving a significant immune response primarily through the production of interferon gamma. Triggering interferon gamma in the tumor microenvironment draws the attention of antigen presenting cells to tumor-specific antigens. Once APC take these antigens to naive t cells, the tcells become activated as CD8 killer tcells. This is the basic mechanism that leads to innate immune responses and the abscopal effect.
Because the primary function of IL-12 is to stimulate the immune system indirectly through interferon gamma production, it makes a lot of sense to electroporate it within the tumor prior to using checkpoint inhibitors. As a corrolary to the innate immune response with neoantigen matching, there should theoretically be significant response durations observed with EP IL-12. In addition, because PD-1 positive immune cells are by far the most common checkpoints in exhausted TIL, it makes more sense to target just that checkpoint over others if adding additional mabs leads to systemic toxicities. Lets see what they can accomplish by just combining EP IL-12 with an anti-PD-1.
That is right, there is an unprecedented push to expand checkpoint inhibitor use. In fact, over two hundred combination trials to be exact, and every large pharma is getting into it. Merck isn't the only company with a good incentive to expand usage; it is practically every major biopharma company.
If a company is capable of improving TIL, specifically pd-1 and ctla-4 phenotypes, then they are setting the stage for improved responses in virtually every solid tumor indication.
I tend to think melanoma is a low hanging fruit for electroporation. Device improvements would need to be made to reach visceral tumors. Proof of principle in applying EP IL-12 with other potential gene combinations in deeper tissues and organs needs to be addressed before anyone can become confident in indications outside melanoma. We have not seen any data yet, not even on a preclinical level, for applications in visceral tumors. I think the company needs to demonstrate that electroporation can work in these other disease indications.
If the current phase 2 combination melanoma trial demonstrates success in the non-responder population AND they can demonstrate success in getting to deeper solid tumors, then the sky is the limit in terms of treatment opportunity with checkpoint inhibitors. I am obviously very curious how successful they can be in electroporating deeper solid tumors.
According to the new investor presentation, the cash runway is now through 3Q 2017. It had been 1Q 2018.
Yeah, I'm also in agreement with Chickpea. A response rate of 64%-75% in the retrospective study is unheard of in metastatic melanoma. Even the toxic yervoy and opdivo combination couldn't reach that level in a SUB-POPULATION of metastatic melanoma patients.
I think it would be hard to get to that level-equivalent (approximately 50% like you mentioned) in the current combination trial, but if it does approach that level of response, then we may be setting a VERY HIGH BAR. The epacadostat and pembrolizumab ECHO 202 phase 1 trial demonstrates the clinical significance and market excitement for successful small trials with widely-applicable treatment platforms. A 50% response rate (in non-responders) is completely unheard of for metastatic melanoma, and on top of that the EP IL-12 platform may work in other indications (e.g. merkel cell, head and neck).
Hi Chick, just to clarify, that retrospective study was not specific to monotherapy pembrolizumab non-responders. The patient population was refractory to various prior therapies. In fact, only 2 out of 14 evaluable refractory patients were previously treated with pembrolizumab. A biomarker was not used to select or exclude patients.
The current combination trial that will report out next month with interim results, is selecting a non-responder (to monotherapy pembrolizumab) population. The trial design makes it much more difficult to obtain responses, i.e. because it is specifically selecting patients who will not respond to monotherapy pembrolizumab. Thus the 30% goal that PD threw out there is not comparable to the 64%-75% responses observed in the retrospective trial. Obtaining 30% in a NON-RESPONDER population is quite good and compares favorably to the best combinations observed in any other combination metastatic melanoma trial.
On September 28, 2016, Incyte and Merck announced updated results of their phase 1 ECHO 202 trial evaluating Incyte's epacadostat (an IDO1 inhibitor) in combination with Merck's pembrolizumab for metastatic melanoma. This all-comers trial evaluated safety and efficacy in 21 patients. The overall response rate was 58%, on par with combination T-vec plus pembrolizumab and Yervoy plus Opdivo. Again, this was not a non-responder (to monotherapy pembrolizumab) population, but was inclusive of patients who could theoretically respond to pembrolizumab alone.
How did the market react to the news? Incyte's market cap increased $776 million, and at one point had exceeded $1 billion during the day on more than twice their daily volume.
This begs the question: what happens to a company's market cap when they demonstrate responses in a NON-RESPONDER population for the same indication with similar enrollment numbers?
Yes, converting 30% of non-responders (to monotherapy Keytruda) would be outstanding. I have been estimating that T-vec in combination with Pembrolizumab may be similar to having somewhere between a 28%-38% BORR with non-responders. Therefore, converting 30% is potentially in line with the top metastatic melanoma stage III/IV data reported to date. If EP IL-12 was not demonstrating efficacy, we shouldn't see responses in the trial, obviously because they are dealing with a non-responder population.
Combination Yervoy (anti-CTLA4) and Opdivo (anti-PD1) demonstrate response rates on par with T-vec and Pembrolizumab, but the side effects are horrendous, most likely due to their systemic applications. Combination T-Vec and Pembrolizumab also don't appear to be eliminating visceral metastatic tumors in stage III/IV melanoma.
I would be very happy with a 30% BORR as well. We'll see what happens though.
It might very well be, but I think there is probably a little more to the rationale. I do get the sense that the company and collaborators are genuinely excited to share more information with investors AND THE SCIENTIFIC COMMUNITY. They are stacking up conference appearances, not just to present, but also I think, to gauge how significant their data are relative to current breakthroughs. They seem to be keenly aware of all combination trials.
I think dilution is always a strong possibility for companies at this stage of development, but at what price would the offering(s) be in the case of ONCS?
Titan,
I disagree slightly with the commercialization timeline suggested by McCarthy, primarily because I think ONCS WILL secure Accelerated Approval with the upcoming phase II combination EP IL-12 and Pembrolizumab trial (i.e. the trial that has not started yet - the "registration" trial). I try to run the math on even the most conservative outlooks, which in my view is exemplified by McCarthy's review. I prefer to be pleasantly surprised than to be caught off guard and disappointed. I don't think McCarthy makes assumptions about Accelerated Approval, therefore his 2022 commercialization estimate reflects a reasonable perspective.
Here is another possible timeline:
Oncosec will secure a Breakthrough Therapy designation sometime in 2017 based on the currently-enrolled Phase II metastatic melanoma trial combination data. This trial, as you know, will have interim data out next month, and should be wrapping up in the first half of 2017. Per PD, enrollment should be complete by the end of the 2016 calendar year. Assuming ONCS submits for Breakthrough Therapy designation, it will take the FDA up to 60 days to respond with an approval or denial.
The Phase II metastatic melanoma combination "registration" trial will commence in 2017. The FDA will work closely with ONCS on expediting enrollment and trial completion, owing to the Breakthrough Therapy designation.
Sometime in late 2018, we will know whether or not the "registration" trial met primary and secondary endpoints.
In early 2019, ONCS will submit a NDA for Accelerated Approval in the indication of advanced metastatic melanoma using EP IL-12 combined with Pembrolizumab.
In late 2019, ONCS receives Accelerated Approval based on the submitted NDA.
Commercialization begins in 2020, thus shaving off two years relative to McCarthy's estimate.
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To answer your questions...
The phase 2 proposed AA-design trial mentioned in slide 20 is the "registration" trial for refractory patients. In other words, ONCS thinks they can secure an Accelerated Approval based on the trial design - obviously this is dependent on positive efficacy and safety. Per NIH definition, refractory is "cancer that does not respond to treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment." I interpret this to include all non-responders (resistant at the beginning of treatment), partial responders (become resistant - they still have metastases), or recurrent complete responders (become resistant - disease returns due to residual disease). Therefore, it includes the vast majority of metastatic melanoma patients. I look at "non-responders" as more of a specific sub-category of "refractory".
I agree with you about the post-approval trial stipulation required after AA.
Maxim Group Says OncoSec Still a “Buy” (ONCS) by James Garrett Baldwin, dated 10.17.2016.
http://www.investopedia.com/news/maxim-group-says-oncosec-still-buy-oncs/
Excerpts:
"The analyst slashed his price target from $17 to $5 and delayed expectations for the commercialization of a key cancer immune therapy.
McCarthy’s analysis on OncoSec centers on changes to his firm’s model to reflect new assumptions in the pricing and competitiveness of Immunopulse and the timing and commercialization of its immunotherapy products.
In his analysis, McCarthy said he pushed back the timing of commercialization from 2020 to 2022. “While the phase II data in melanoma as a monotherapy is positive, it is clear that a combination study with a checkpoint modulator makes sense and would be consistent with the direction in which we see immune-oncology heading,” McCarthy wrote. “So while a small investigator-sponsored phase II study in combination with Keytruda is ongoing, it is still early in the complex development process of cancer immune therapy.”"
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Here's looking forward to 2022 - cheers! If that's the case, we are looking at significant capital raises to get to that point. Obviously, there are other options besides dilution, but right now we have no reason to believe funding will come from anywhere else but stock offerings/warrants.
If McCarthy is correct, six years is a long runway to reach commercialization. If there is no partnership through the registration trial, and assuming the trial enrollment mirrors the Masterkey 265 phase III trial, then we could be looking at registration trial costs around $39.6 million ($60,000 per patient x 660 patients, assumptions mine only). This is on top of the day-to-day operational, research, etc and filing costs. I estimate it will cost around $250 million to reach commercialization, and this assumes Merck will cover the cost of pembrolizumab throughout the registration trial. Per the conference call from last week, it looks like this will be a classical registration study. I'm obviously not an expert on finance - so take my assumptions with a grain of salt - but it sure looks like we are going to need some substantial cash to make it through to commercialization if McCarthy's estimate is correct. Where is that money coming from?
I doubt ONCS has intentions of selling at this point, or maybe that is just wishful thinking.
Just some background, Biovex was purchased in 2011 while they had monotherapy t-vec in a phase 3 melanoma trial.
The drug was ultimately approved last year as a monotherapy.
From the FDA release, posted October 27,2015..
"Imlygic has not been shown to improve overall survival or to have an effect on melanoma that has spread to the brain, bone, liver, lungs, or other internal organs."
In other words, the systemic visceral effect with t-vec is quite limited. Early data with EP IL-12 demonstrates a strong abscopal effect, although we have to wait on more substantial data to determine how well that systemic response is in combination with pembrolizumab. I think I have a good idea, but robust data verification is needed.
After reviewing countless published articles written by numerous researchers - both inside and out of the US - I tend to believe that EP IL-12 is capable of substantially priming the requisite TIL phenotypes, i.e. pd-1 and ctla-4-positive t-cells, that lead to responses with anti-pd-1 checkpoint inhibitors. To put a pricetag on a therapy that may substantially expand responses to checkpoint inhibitor use in solid tumors is like placing peak sales figures on anti pd-1 drugs during their testing infancy. I think metastatic melanoma is just the tip of the iceberg for EP IL-12/anti-pd-1 therapy, and I certainly hope they don't sell out now.
When it is time for phase 2 interim data release, I will be paying close attention to ORR as an indicator of clinical effectiveness. Combination t-vec - which hasn't shown a systemic immune effect - and pembrolizumab demonstrated a 56% response rate in a phase 1 advanced metastatic melanoma trial. That trial, which enrolled something like 20 patients, was enough to convince Merck and Amgen to advance into their registration phase 3 trial. In addition, that combination is now being tested in other indications by both companies.
The 56% response rate suggests to me that t-vec can turn monotherapy pembrolizumab nonresponders into responders. Duration of response and complete responses are a whole other matter. If my math is correct, a 56% ORR is equivalent to a 28%-38% ORR in the UCSF/Oncosec/pembrolizumab phase 2 metastatic melanoma trial. This is based on a 30%-40% response rate for pembrolizumab monotherapy.
If we see ORR exceed 28%-38% in the UCSF/Oncosec/pembrolizumab phase 2 interim data, I think it would be safe to say that we are onto something enormous in melanoma and solid cancer therapy in general. We are just one month away.
Yes, these patients should theoretically not respond to keytruda monotherapy based on the published retrospective studies, therefore any response suggests EP il-12 is elevating the number of pd-1 and ctla-4 exhausted TIL phenotypes.
CAR-T cell therapies work remarkably well in blood cancers, not so much in solid tumors. Some researchers are going to great lengths to engineer autologous CAR-T cell therapies while the same goal can be accomplished through a simpler in-situ mechanism.
The fact that the AA trial is selecting refractory patients rather than just predicted nonresponders based on a biomarker, suggests to me that enrollment will be much quicker than the current combo trial.
Refractory is more inclusive. I think the phase 2 trial described on slide 21 is a registration study, i.e. one for which a NDA will be based.
Refractory includes initial nonresponders or patients who become nonresponsive, e.g. partial responders, to pembrolizumab. I estimate that the refractory population is approximately 90% of all unresectable stage III/IV metastatic melanoma patients who are treated with monotherapy pembrolizumab. I believe only approximately 10% of patients experience durable complete responses with monotherapy Keytruda in metastatic melanoma.
Breakthrough Therapy designations have been bestowed on companies with fewer numbers. I don't see how any anti pd-1/pd-l1 company would not see value in extending use to an otherwise refractory population - right now, even with ctla-4 combination, they achieve no more than 22% complete remission in a metastatic melanoma SUBPOPULATION WITH BRAF WILD TYPE MUTATION. If ONCS is effective in turning refractory/ non-responding patients into responders, it would hypothetically more than double estimated peak revenues for the checkpoint inhibitor companies if they were to partner; that is a lot of incentive, and this "puny" phase 2 trial is a value creator in my book.
Some random thoughts...
If I'm not mistaken, the positive predictive value for >30% PD-1/CTLA-4-positive TIL was also 100%. Relative frequencies that approach 20% from the higher end demonstrate significantly less predictability. ONCS is specifically selecting patients with a <25% PD-1/CTLA-4-positive TIL profile.
I tend to think that EP IL-12 is augmenting these exhausted TIL phenotypes, thus leading to responses in otherwise non-responders treated with monotherapy checkpoint inhibitors.
It looks like combination checkpoint inhibitors, e.g. Opdivo and Yervoy, are able to achieve significantly more responses in metastatic melanoma than either treatment used alone. I find this to be intriguing, because there must be patients with lower relative PD-1/CTLA-4-positive exhausted cells who are responding to dual checkpoint inhibitor combination therapy. Perhaps the combination of checkpoint inhibitors is simply allowing existing TIL to mount a stronger attack due to the release of more brakes. In other words, they aren't necessarily increasing the number of TIL, they are simply allowing more existing TIL to mount an attack. For example, despite the relatively lower frequencies of CTLA-4 positive TIL in most tumors, the inhibition of the checkpoint might drive just enough CTLA-4-expressing TIL to control disease progression, thus leading to a response. Alternatively, the addition of Yervoy to supplement Opdivo might also be leading to a reduction in the number of Tregs rather than just significantly altering the number of TIL available to mount an attack on tumor cells.
I continue to believe that the gold standard for metastatic melanoma and potentially other solid tumors will eventually include combinations of mAbs (e.g. anti-PD-1 and anti-CTLA-4), immunoregulatory cytokine (e.g. EP IL-12), and antigen-specific T cell activators (e.g. Gp-96lg/OX40L).
I also think EP IL-12 is going to be integral to a lot of solid tumor combination treatments due to its ability to induce interferon gamma production, and consequently, differentiation of naive cells into Th1 activated cells. Th1 cells also produce interferon gamma, thus contributing to a positive feedback loop that allows for expanded T cell activation. Interferon gamma induction also leads to increased macrophage production, which stimulates antigen processing.
Moreover, if you combine an antigen chaperone like Heat Biologics' Gp-96lg and you allow it to be electroporated in the tumor microenvironment, you would theoretically have 1) chaperones that carry tumor-specific neoantigens to 2) a significant population of antigen presenting cells, which 3) were expanded by IL-12 and prior T-cell activation through interferon gamma production, 4) compounded differentiation of naive T-cells to antigen specific Th1 cells, leading to 5) a robust expansion of exhausted TIL. Those exhausted TIL will generate higher frequencies of PD-1 and CTLA-4 expression, thus establishing the requisite phenotypes for anti-PD-1 and anti-CTLA-4 combination therapies.
Because they aren't selecting patients in the phase 2 study based on a positive predictive value.
Anyone would agree that it is a small number, but the point is that the exploratory data along with the developed biomarker hypothesis was not invalidated by the subsequent study. Therefore, the negative predictive value still holds at 100% until proven otherwise.
100% negative predictive value for TIL containing less than 20% PD-1 and CTLA-4 phenotype- validated and peer reviewed. This is not a fabrication, it can be easily accessed online in the Journal of Clinical Investigation. Also, all patients who exceeded a 30% TIL threshold were responders.
The UCSF validation study confirmed that 100% of patients with TIL containing less than 20% PD-1/CTLA-4 phenotype will not respond to anti-PD-1 monotherapy. Their inductive post hoc analysis was the exploratory study that established the TIL biomarker hypothesis, and the validation study produced confirmation of the biomarker cutoffs and predictive values. This was all reported in August.
Thanks for the link Twiz; it's nice to see that the UCSF biomarker study is garnering some attention considering they have identified a biomarker with 100% predictability for non-response in monotherapy anti-PD-1.
The metastatic melanoma patients enrolled in ONCS's investigator-sponsored (UCSF) phase II combination trial are selected - if my memory serves me correct - based on a less-than-25% PD-1/CTLA-4 TIL phenotype. What this means is that a patient has a 0% chance of responding with a <20% PD-1/CTLA-4-positive TIL phenotype and a 5% chance of responding with a 20%-25% PD-1/CTLA-4-positive TIL phenotype, if using pembrolizumab alone. Patients enrolled in the phase II combination trial would not - for all intents and purposes - theoretically respond if given pembrolizumab alone. Therefore, any responses in this phase II combination trial are quite significant.
Just a side note, the combination of Yervoy (anti-CTLA-4) and Opdivo (anti-PD-1) are one of the immunotherapy combinations nearly reaching 60% (59% ORR in metastatic melanoma) - see CheckMate-069. This suggests that the addition of an anti-CTLA-4 checkpoint inhibitor to an anti-PD-1 mAb is turning non-responders into responders - they are essentially doubling the response rates. The complete response rate was 22% - again, slightly more than double the rate with Opdivo used alone. I tend to think that combination EP IL-12 and pembrolizumab will observe slightly better ORR and complete responses based on IL-12's ability to drive an increase in "exhausted" phenotype TIL. In addition, 78% of advanced metastatic melanoma patients treated with combination Yervoy and Opdivo would be considered refractory, because they are either partial responders or non-responders. In other words, sustained 22% complete responses (remissions) observed in the Yervoy/Opdivo combination trial still leaves the door wide open to ONCS, because ONCS is going for the refractory population that is currently around 78% based on available information.
One important point on the patient population for the registration trial - refractory patients include partial responders. Thus far, the highest complete response rates in metastatic melanoma observed and reported have been with combination Yervoy and Opdivo (22%) for BRAF wild-type. Partial responses are around 39%, for a total 61% BORR. Therefore, we are looking at a patient pool that is relatively large due to the fact that the highest treatment bar (Yervoy plus Opdivo) is unable to produce complete responses or any response in approximately 78% of metastatic melanoma patients with BRAF wild-type. This is a smart move and a major unmet need.
I think you are exactly right Titan. ONCS obviously has confidence to proceed with a phase 2 AA trial design that would theoretically support a NDA filing, with the stipulation of a future phase 3 confirmation trial.
However, the current phase 2 combination metastatic melanoma trial has Breakthrough Therapy written all over it, assuming data are as good as I think they will be. If they receive BT designation based on current trial data, it is even possible that a phase 3 confirmation trial wouldn't be necessary.
In any case, they appear to be very confident in the current phase 2 metastatic melanoma trial results. I think they are indeed elevating the relative percentages of PD-1 and CTLA-4-expressing TIL in predicted non-responders. If the patients are reaching that magic 30% threshold in TIL, then ONCS will be converting folks into responders. This is a very significant unmet need in metastatic melanoma. There are a majority who will not respond to checkpoint inhibitors alone or in combination, and among those who do respond, about 75%-90% of them are partial responders, which means there is still measurable residual disease. Those partial responders would, therefore, by definition become "refractory".
No news on Monday folks, it is all about the Blue Ribbon Panel recommendations for achieving the Cancer Moonshot goals.
The Blue Ribbon Panel's 10 recommendations for achieving the Cancer Moonshot's ambitious goals are out... if you aren't into immunotherapy yet, you will be soon!
See recommendation B on establishing a national immunotherapy network. Pay close attention to the second paragraph on page 15 - this is exactly the reason why immunotherapy companies turned course today.
Oncosec and Heat Biologics will no doubt be targeted; the former inflames the tumor microenvironment through EP IL-12, which in turn drives a local immunologic response, while the latter maximizes immune activation through the chaperoning of neoantigens to antigen presenting cells, like dendritic cells.
I have mentioned this several times, and I will say it again here - if you improve neoantigen presentation and you also increase the number of available t-cells, what you get are swarms of activated CD8 positive t-cells that match up with tumor cells carrying the same antigens. The end result is a significant increase in tumor infiltrating lymphocytes, or TIL, that contain pd-1 and ctla-4-positive expression. Adding a co-stimulatory molecule like FC-OX40L found in Heat Biologic's COMPACT therapy, adds an additional layer of long term efficacy by greatly expanding the numbers of memory precursor cells. Once checkpoint inhibitors like keytruda are unleashed to block immune suppression, you are essentially staring down a cure for many solid tumors.
Obama has requested just under $700M in his FY2017 budget for implementation of the Blue Ribbon Panel's Cancer Moonshot recommendations, and if passed by Congress - which has overwhelming support from both sides of the aisle - will potentially bring a lot of attention and monetary resources to both Oncosec and Heat Biologics.
Everyone, just watch what happens when you electroporate and combine Heat Biologics' COMPACT therapy with IL-12 and add checkpoint inhibitors to the mix... heck, watch what happens when you simply combine EP IL-12 with Keytruda in metastatic melanoma. This is exactly what is being recommended as an initial immunotherapy target in the Blue Ribbon Panel's list of recommendations for achieving the Cancer Moonshot. To steal VP Biden's words to Obama, "This is a big f'n deal."
The Blue Ribbon Panel's 10 recommendations for achieving the Cancer Moonshot's ambitious goals are out... if you aren't into immunotherapy yet, you will be soon!
See recommendation B on establishing a national immunotherapy network. Pay close attention to the second paragraph on page 15 - this is exactly the reason why immunotherapy companies turned course today.
Oncosec and Heat Biologics will no doubt be targeted; the former inflames the tumor microenvironment through EP IL-12, which in turn drives a local immunologic response, while the latter maximizes immune activation through the chaperoning of neoantigens to antigen presenting cells, like dendritic cells.
I have mentioned this several times, and I will say it again here - if you improve neoantigen presentation and you also increase the number of available t-cells, what you get are swarms of activated CD8 positive t-cells that match up with tumor cells carrying the same antigens. The end result is a significant increase in tumor infiltrating lymphocytes, or TIL, that contain pd-1 and ctla-4-positive expression. Adding a co-stimulatory molecule like FC-OX40L found in Heat Biologic's COMPACT therapy, adds an additional layer of long term efficacy by greatly expanding the numbers of memory precursor cells. Once checkpoint inhibitors like keytruda are unleashed to block immune suppression, you are essentially staring down a cure for many solid tumors.
Obama has requested just under $700M in his FY2017 budget for implementation of the Blue Ribbon Panel's Cancer Moonshot recommendations, and if passed by Congress - which has overwhelming support from both sides of the aisle - will potentially bring a lot of attention and monetary resources to both Oncosec and Heat Biologics.
Everyone, just watch what happens when you electroporate and combine Heat Biologics' COMPACT therapy with IL-12 and add checkpoint inhibitors to the mix... heck, watch what happens when you simply combine EP IL-12 with Keytruda in metastatic melanoma. This is exactly what is being recommended as an initial immunotherapy target in the Blue Ribbon Panel's list of recommendations for achieving the Cancer Moonshot. To steal VP Biden's words to Obama, "This is a big f'n deal."
I definitely agree. They seem to be 'priming' themselves.
Doc, I think there will be a major preclinical catalyst hitting the streets sooner than the fourth quarter; it has to do with combination preclinical studies. The company seems to be tapping into their ATM a bit, but I don't think they will continue much longer at these prices.
Electroporated Compact/fc-ox40l with il-12 and anti-pd-1 would be a combination dream team. Compact fc-ox40l is no joke - look at those activated cd8 t cell and memory responses!
Paid subscribers had initial access through Sage Journals on June 30, and the rest of us who are nonsubscribers now have an opportunity to read it.