The outcome of Immunicum's previously completed kidney cancer study in Phase I / II regarding median survival, survival rate after 18 months and tumor-specific CD8 + T-cell infiltration in tumors and early interim data for the latter in MERECA together promise very well for the larger Phase II study MERECA'S outcome in metastatic kidney cancer to be presented the first week of September 2019
It is stated on page 12 that there were 3 of 11 patients in the Phase I / II study in metastatic renal cancer who did not achieve 3 different studies' comparative reference data with median survival of 14-16 months ( Heng 2009; Ko 2014; Mejean 2018) , while the other 8 patients did by a huge margin, and thus the median survival for the entire group of 11 patients was as high as 48 months, which corresponds to a powerful median survival effect of approximately 2.7-2.8 years.
However, random factors etc. can affect such a small study relatively much, but even if you correct for an assumed enormous luck in the outcome and therefore remove all the 4 patients with longest survival in Immunicum's Phase I / II study in metastatic kidney cancer, the median survival for the the remaining 7 patients would still be about 24 months, ie about 8-10 months longer than the comparison data, which would still be a very good outcome as if it had been achieved in a large controlled Phase III study, it would have been sufficient for the market approval regarding efficacy.
A block buster for many years, the angiogenesis inhibitor Avastin was market-approved with a much worse safety profile despite a median survival effect of only about 1-3 months in some different cancer indications.
So, assuming that the outcome for the 7 remaining patients with the worst outcome according to the reasoning above, which outcome in itself would be good, in fact was a more normal outcome in terms of expected value, then the probability is extremely small that the 4 additional outcomes are all highly favorable, but as they really were.
For example, suppose that ilixadencel treatment resulted in, for example, 20-40% probability of a sufficiently clinically relevant improved outcome for an individual patient compared to standard therapy alone, which should be estimated to be compatible with the sufficiently good outcome for the 7 patients where it should be most likely correspond to that 1-3 patients responded adequately to the treatment.
Then it would also occur for all 4 other patients with a probability of ((20 to 40)%) ^ 4 = 0.16% - 2.56%.
This simple calculation shows that the Phase I / II outcome in kidney cancer must be best interpreted as ilixadencel more likely than the opposite to have had at least a good effect on the median survival.
In the Phase I / II study, 3 of 11 patients, in addition to ilixadencel, also received the tyrosine kinase inhibitor sunitinib and 3 other patients who instead received the tyrosine kinase inhibitor pazopanib after ilixadencel treatment. These two drugs have at least 3 common receptors to which they both bind (VEGFR, PDGFR, c-Kit). All of these 6 patients passed expected survival by a very high margin, probably caused by a synergistic effect of the combination with ilixadencel.
For those 3 who died quickly within about 3-7.5 months, the outcome was perhaps already fairly given due to sarcomatoid kidney cancer. Ilixadencel's effect is likely to take some time to become fully effective.
The 2 other patients who received ilixadencel alone passed the expected median survival, in fact even though one had sarcomatoid kidney cancer.
provides an explanation for how sunitinib, (as well as checkpoint inhibitors), can "pave the way" for tumor-specific CD8 + T cells activated by ilixadencel. Sunitinib acts in kidney cancer with several different mechanisms, but what is probably most relevant in this context is that sunitinib reduces myeloid-derived suppressor cells (MDSCs) that otherwise counteract the ability of cytotoxic CD8 + T cells to attack tumor cells. Furthermore, sunitinib also down-regulates tumor-infiltrating regulatory T cells (Treg) which otherwise down-regulate cytotoxic CD8 + T cells.
Synergy effects between ilixadencel and sunitinib and pazopanib, respectively, are probably the main explanation for the Phase I / II study's high median survival effect of approximately 2.7-2.8 years.
With checkpoint inhibitors, another synergy effect arises through several different downstream mechanisms that directly counteract the tumor's own immune suppression of activated CD8 + T cells by the fact that checkpoint inhibitors are monoclonal antibodies that can block receptor PD-1 on the surface of these T cells or block receptor ligand PD-L1 and therefore both inhibit the tumor's immune supression with its high expression of the ligand PD-L1 which can activate the PD-1 receptor of the T cells, but qualitatively the end result is similar, ie, by ilixadencel-activated tumor-specific CD8 + T cells, in both cases, get an increased opportunity to attack and kill tumor cells .
In this context, it can be mentioned that Immunicum's liver cancer study in Phase I / II and in vitro studies showed that a combination with sorafenib, on the other hand, was not suitable because at least two different mechanisms of sorafenib instead both counteracted ilixadencel's own mechanism of action. But even in liver cancer, there is now a better combination option for ilixadencel since a checkpoint inhibitor in 2018 has also been approved in that indication.
In MERECA, an exclusion criterion was expected survival less than 4 months, versus 3 months in the Phase I / II study, so the probability should decrease somewhat that a given patient in MERECA died so early that ilixadencel failed to produce full effect, and sunitinib treatment with its expected synergistic effect (since it can counteract the tumor's own immune suppression) also did not occur.
Furthermore, sunitinib was given to each patient (5-8 weeks after surgery) in MERECA and not, as for several patients, not at all in the Phase I / II study. Overall, therefore, the probability for a synergy effect should increase somewhat in MERECA compared to the Phase I / II study, which would increase the chance of success somewhat relative to the already very promising Phase I / II outcome.
Both studies included renal cancer patients with MSKCC high risk and intermediate risk but not low risk.
Futhermore 6 patients of 11 had sarcomatoid kidney cancer which according to a big study affects only about 5 % of kidney cancer patients and is associated with just 8 months expected median overall survival. If this risk factor to some degree is independant of the MSKCC criteria, then the exspected MOS in reference studies regarding the Fas I/II-study could have been even lower than 14-16 months. All things being equal this implies that the probability for success in MERECA could be slightly higher.
A case study in the Phase I / II study in metastatic renal cancer can be done on the basis of a published external study of 16 renal cancer patients with brain metastases treated with sunitinib. Not in a single case did they receive adequate response and the median survival was only 6.3 months.
One patient included in Immunicum's Phase I / II study had a total of 4 brain metastases (and in addition 3 other metastases) but in that case, the patient first got ilixadencel and later sunitinib and all the metastases disappeared and the patient had in October 2018 survived about 10 times as long as the MOS in the study linked above where the patients only received sunitinib.
This case study clearly shows what can happen if a primer such as ilixadencel that activates tumor-specific CD8 + T cells is combined with another drug (in this case sunitinib) which can pave the way for CD8 + T cells 'attack on tumors including metastases by counteracting tumors' own suppression of CD8+ T cells.
Since Immunicum has also shown that a significant proportion of renal cancer patients, partly in the Phase I / II study and partly in MERECA according to early interim data in PM 29 Jan 2016 and in the latter case compared with the control group have received a large infiltration of tumor-specific CD8 + T cells in cancer tumors that shows the desired mechanism of action of ilixadencel in practice, it greatly reduces the risk that the very positive outcome of the MOS in the Phase I / II study could have been entirely due to chance and therefore also reduces the risk that the MERECA study would fail.
I therefore consider it very likely that ilixadencel in a large proportion of renal cancer patients can activate a tumor-specific CD8 + T cell response, but partly because the immune system and tumors of different individuals may have varying characteristics, the expected survival effect of ilixadencel also varies between different patients within a treated large group of cancer patients.
If the Phase I / II study nevertheless yielded a "too good" outcome, for example, due to too favorable random or bias-influenced selection of patients, then MERECA's outcome could more likely than otherwise be weaker than my own expectation, for example mechanistically explained that cancer tumors may sometimes fail to present neoantigen on the tumor cell surface, which would probably make them impossible to be recognized by tumor-specific CD8 + T cells already activated by ilixadencel.
Theoretically, if a patient's metastases would not have a single neoantigen in common with a primary tumor injected with ilixadencel, the treatment could not give rise to any neoantigen-based CD8 + T cell activation, which otherwise would lead to tumor cell death, but it should be low even if it may not be ruled out in some cases. The number of neoantigens varies greatly between patients.
However, this study shows that neoantigen produced by a special mechanism is most common in kidney cancer and very immunogenic which is favorable.
Furthermore, despite a slightly modified exclusion criterion, the synergistic effect between ilixadencel and sunitinib may not have occurred in a larger proportion of treated patients in MERECA because they may have died very early before sunitinib was used, as was the case for a few patients in the smaller Phase I / II study in kidney cancer.
Regarding adverse events of ilixadencel, they have so far been few and not serious despite close to 100 treated patients in clinical trials, and it is also natural since ilixadencel's mechanism of action means that only tumor-specific neoantigens cause a by ilixadencel generated immune response against them and not against normal tissue because it "per definition" does not contain neoantigens.The thymus gland has helped to eliminate CD8+ T cells that recognize body-specific proteins in normal tissue, since the immune system should not attack such tissue.
An intuitive conclusion, without attempting to calculate this even more mathematically if possible, should, in my opinion, be that the probability of the MERECA outcome, ie the larger Phase II study in metastatic kidney cancer, for being successful is well above 50%,which is sufficient to imply a very favorable risk / reward to call with an appropriate portfolio share the outcome to be presented in the first week of September 2019, in particular since ilixadencel's mechanism of action is applicable to all cancer indications with injectable solid tumors and the company value is still and probably for a long time only a fraction of what such a success in MERECA should motivate and Big Pharma would then probably be very interested in inlicensing ilixadencel or buying the drug candidate ilixadencel.
Merck KGaA and Pfizer, who have already shown their interest in Ilixadencel by providing Immunicum's ILIAD study with their own checkpoint inhibitor avelumab for combination therapy with ilixadencel at no cost to Immunicum, are some of the possible Big Pharma. The exceptionally favorable safety profile of ilixadencel is a major competitive advantage in such combination therapy.
My own subjective expectancy value for the MERECA outcome is currently around 8 months - 2 years of median survival effect, but it will require longer follow-up to be able to determine a really high median survival effect. Follow-up will take place until the beginning of 2023.
However, the survival rate after 18 months, which is also a primary measure of efficacy in MERECA, will be presented as a definitive outcome where the group of 58 patients who received ilixadencel in this case is also compared with the control group of 30 patients.
In that case, my subjective expectancy value is that the ilixadencel group received an order of magnitude of 10-20% units higher survival rate after 18 months than the control group.
In addition, corresponding outcomes and comparisons for subgroups of patient categories will be presented. Especially for the subgroup with poor prognosis according to the MSKCC criteria, the survival rate with a high probability may show a very significant improvement if it only becomes fairly close to the outcome Phase I / II study in kidney cancer, where a full 67% (4 of 6) lived after 18 months compared to the order of 15-20% according to an estimate from some historical data.
Even the median survival effect of the same subgroup, ie poor prognosis according to MSKCC, can be expected with rather close to final results in the September newsrelease since the expected median survival with sunitinib alone is significantly lower (about 9 months based on historical data) than expected in the entire control group's MERECA on average (14-16 months according to historical data).
An important secondary measure of efficacy is CD8 + T cell infiltration in the evaluable tumors, as it provides a very clear indication of ilixadencel's own desired mechanism of action without the effect of the drug it was then combined with, in MERECA's case sunitinib, since sunitinib treatment began 5-8 weeks after removal of the primary tumor while ilixadencel was given even before surgery. The above analysis indicates that the CD8 + T-cell infiltration in the tumors in MERECA will be reported to be very good and most likely roughly in line with the outcome of the Phase I / II study.
However, no guarantee of success can be given for the MERECA outcome and, in principle, never in such contexts, since there are random variables that affect the interpretation of studies that have already been carried out and also the outcome of the current clinical trial itself (although the latter as in the case of MERECA, for example, tend to be larger and therefore to a lesser extent affected by chance).