Hello everybody, I see there are several knowledgeable people here with complementary biotech skills and I’d like to throw out a few ideas about the IMM (science and markets). I stumbled upon the IMM 2 months ago and I couldn’t stop thinking and reading about the IMM since the moment I scrolled through the investor presentation in which the NSCLC and HNSCC data looks really promising combined with the mechanism of action that enables huge markets if successful. Since then I’ve read all the scientific publications from the IMM team and publications related to the mechanism of action, aPD-1 resistance, FDA fast track process (especially accelerated approvals that 'failed' P3), aPD-1 addressable markets and much more.
My summary of the pros and cons to date of "what have we got".
The negatives:
- The first trial of Efti 30mg + paciltaxel vs paclitaxel was ‘negative’ and too small trial, n= 220, to exclude meaningful benefit. Median OS difference was 2.9m which is more than the average mOS dif among approved cancer drugs in the last decades.
- All novel drugs should be investigated first in the most optimal patient and indication setting (moneywise and ethics wise) due to potential harms without benefits. If the investigators understand the disease and the novel drug candidate, the chances of positive confirmatory trial should decrease after the first failure.
- Efti is only investigated in combination trials, which is in the traditional sense a red flag. In the cytotoxic era, the rule of thumb was that if the drug is effective it should have a standalone effect. I’m not aware of any known synergies among currently approved cancer drugs, say 1+1 >2. Synergism that is not related to drug metabolism is not common in medicine, but e.g. smoking+asbestos exposure -> lung cancer is mentioned in every textbook.
- IMM raised money very closely before 1L HNSCC data announcement. Internally they have known the results for months and the right ball-park for the results >6 months.
- Efti is not a dendritic cell vaccine, but a long history of clinical failures with DC vaccines may suppress the enthusiasm among biotech investors who do 10min due diligence per company.
- Efti is soon 20 years into the development and the company is still investigating the optimal dose even though toxicities has not been the blockade.
- If the next data release comes with good but not sensational results, say PD-L1 >1 ORR 25% vs 35%, p-value litte over 0.05, I’m not sure how the ASX markets will appreciate the results. Volume in IMM has not been big enough for many US institutional investors and may be one reason why it is under-radar.
Then the positives:
+ 1L NSCLC data is extremely good with large differences and inherently logical (ORR->mDoR->mOS) between comparable trials and within different subgroups. Among cancer drugs, there can't be much better counterfactuals than efti+pembro vs pembro-mono / atezolizumab-mono / nivo-ipi. The cytotoxicity done by the same CD8 and NK cells that efti (likely) activates when combined with aPD-1.
+ In 1L NSCLC the sample size n=130 (TACTI-002-A + INSIGHT-003) is big enough to exclude (random error + very small benefit) as a reasonable explanation. If Efti does not enhance the results in P3, it is due to systematic errors in the data, not the random error. Before trial enrollment there are not many available markers to predict who will get response from aPD-1 treatment, especially during 2019-21 when patients were recruited. After trial enrollment, liquid biopsies and peripheral blood analysis helps somewhat in the prediction.
+ 2L HNSCC and 1L HNSCC (PD-L1 <1 cohort) is ~60 patients. Again, compared to pembro-mono data, the difference is 2xORR->mPFS->mOS data which is inherently logical in the benefit of efti+pembro and random error is not a likely explanation.
+ Sarcoma neoadjuvant looks very promising in terms of RT+efti+aPD1 mechanism of action and if succesfull, it enables more indications to aPD-1, as PD-L1 negative patients in 1L NSCLC, 1-2L HNSCC cohorts indicate, too. In this sarcoma trial only 6 patients known to date, but pCR 4/6 is a lot higher than what aPD-1+RT has yielded previously; 10-15% pCR rates in small samples. Chemo+RT has had 30-40% pCR but DoR is likely not good. This trial is single center in Poland and STS is rare so there aren't many to cherry pick from.
+ The first 6 mBC patients with 90mg efti+paclitaxel provided good results compared to my literature search of similar studies, CR is quite rare with paclitaxel alone. However, oncologists have decades of experience in chemo and they know what kind of people have higher likelihood to benefit. To remind, the CR patient was in her thirties who can stomach (in avg) more chemo than the average mBC patient in her seventies. Also, they had in AIPAC-RCT pre-specified subgroups (age, monocytes, luminal) with better results → possibly this CR patient is an outlier if these subgroups are real. However, they should not have many reasons to cherry pick the patients in this trial as they want as soon as possible to know the dose going forward for P3 NSCLC.
+ Different dosage of aPD-1, treatment duration, “adherence” nor a better supportive care are not likely explanations for better ORR/DoR/OS seen in 1L NSCLC, 2L HNSCC, 1L HNSCC (PD-L1 neg announcement) than in the compared Keynote, Checkmate and other trials. Merck, BMS and Roche have maximized every trick to give the best chance for their drug beat the control arm in their respective 1L NSCLC and 2L HNSCC trials. These comparison trials are not one of those easily beatable 'SoC' therapies chosen from the kid’s menu that one can observe in some of the P2-3 trials, nor are they decades old trials conducted with inferior imaging capabilities and post-progression therapy. For example, see doi:10.1001/jamaoncol.2024.1569
+ If TACTI-002 (1L NSCLC) would have recruited patients with slower growing tumors, they could get better OS without ORR+DoR enhancements. To explain the big mOS difference in the case efti is not effective / only marginally effective, they should at the same time recruit patients with slowly growing tumors and assess many truly SDs as PRs, then hold those those people longer as PRs (large mDoR) even though primary tumor or metastasis are growing in multiple longitudinal CT scans. Radiological assessments do not come without measurement error, however, in P2 they are double-checked and they are not that bad at measuring the tumor sizes. Other possibility is to recruit patients that respond to aPD-1 more likely than the average population which is addressed in above.
+ IMM has 2 FDA Fast Track Designations, in 1L NSCLC (10/2022) and 1L HNSCC (4/2021) for efti+aPD-1. FDA has 30y experience in accelerated approvals, in average ~70-80% of FTD will get approved, accelerated or regular. It is often cited that in average in oncology P2 -> P3 trial the probabilities are like 40-50% of coming up positive are like 40-50%. Then, by the numbers, FTD should provide insight to effectiveness. Two FTDs in closely similar indications with the same drug combination should increase the probabilities of succes, especially as most clinical results have come back quite good after FTD announcements (1L HNSCC PD-L1 neg, INSIGHT-003, sarcoma, atezolizumab+efti, 90mg mBC).
+ If efti+aPD-1 will become approved in metastatic 1L NSCLC across all PD-1 levels, even with little worse results than in TACTI-002, there will be A LOT more aPD-1 to be sold. Currently the median treatment duration is 7-8 months for pembro in TPS 1-50% and >50% (reported in Keynote trials and real-world data) and the maximum is capped at 24 months in many places of the western world. My napkin calculations (it is tricky as the variability is big) resulted in 2-3xpembro usage in NSCLC if Efti+aPD-1 is approved in all PD-L1 levels and the P3 data comes little bit weaker than it is in TACTI-002 and INSIGHT-005. This increase in aPD-1 use comes by higher amount of patients responding with same/better DoR and increased duration of mPFS and therefore increase in duration of treatment (efti+aPD-1) for many: ~40-60% higher ORR and ~50-100% higher mPFS in TPS >1% population with the same/better DoR. Then add the PD-L1 neg cohort (1/3 of population) with 7+mo mPFS and 50-70% ORR (INSIGHT-003), DoR not known yet. This is not highlighted in IMM materials, nor is it obvious to everybody, but it surely is for Merck! In 2023 pembro sold for 9 B$ in NSCLC alone and doubling that wouldn't hurt without acquiring new drugs or conducting trials for new indications, right? One example of the real-world data in 1L advanced NSCLC TPS>50% from US: doi.org/10.3390/cancers14041041
+ Upcoming P3 in NSCLC plans to recruit 750 patients in 18 months or >40/mo. In cancer indications, that is fast recruitment and I doubt it would be possible if IMM would try to organize it alone. Merck has administrative expertise, employees and contacts to conduct such RCTs, otherwise there would be a lot of bills coming from consults and administrative companies to IMM. My only minor worry is that if Efti has to prove effectiveness in all three PD-L1 categories (<1%, 1-50%, >50%) by p<0.05 in ORR/mPFS separately, then the sample size may not be big enough if the effectiveness drops between P2->P3 (N=125vs125 x 3 and subtract loss to follow-up). Due to previous points, Merck has large incentives that Efti is approved as soon as possible, if it does benefit patients as much as in P2 trials.
+ IMM has been lean from total expenses per year point of view. In the last 3 FYs, the expenditures have totaled around 100M A$ and they have recruited over 200 patients across the trials ‘earning’ 2 FTDs among other things. Most comparable oncology biotechs listed in Nasdaq use 40-200M US$ per year and most of them don't recruit 200 patients (I scanned >300 Nasdaq biotechs: m cap, last FY net income, trial phase, target disease category, MoA).
+ Due to MoA, hopefully large benefits at least in immunologically hot cancers (NSCLC, HNSCC, melanoma, RCC etc) and nontoxicity (found to date) Efti will have large off-label potential in the hands of the biggest drug companies, after the first approval, of course. The biggest drug companies have connections to persuade oncologists to start prescribing Efti long before confirmatory trials are published, which would not be the case for many other novel cancer drugs that come with known adverse events. After a decade of spreading usage of aPD-1 and some cured metastatic cancers, if an oncologist is not excited after hearing that it is possible to boost adaptive immunity alongside other cancer drugs without added toxicities, then I don’t know what would do.
The best of luck for all the buyers and sellers. Even as a newcomer in IMM, I wait the results as much as anybody here.
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