Overall Response Rate; ORR is a Game Changer
Here late, but better late than never, I guess.
So, we all know what happened this week with the 8/12/24 Press Release disclosing that CytoDyn Announces Completion of FDA Meeting on Phase II Study of Leronlimab in Patients with Relapsed/Refractory Microsatellite Stable Colorectal Cancer.
"...leronlimab in combination with trifluridine plus tipiracil (TAS-102) and bevacizumab in participants with CCR5+, microsatellite stable (MSS), relapsed or refractory metastatic colorectal cancer (mCRC).
The Company intends to proceed with a submission of its final study protocol to the FDA, formal engagement of a clinical research organization (CRO), and related preparatory work towards initiating the proposed trial.
This open label randomized (1:1), multicenter trial will evaluate the anti-tumor activity (via overall response rate, ORR) of leronlimab at doses of 350 mg and 700 mg in combination TAS-102 and bevacizumab in approximately 60 patients with CCR5+, microsatellite stable metastatic CRC (mCRC).
Patients enrolled in the trial must have measurable disease per RECIST v1.1 and have received prior treatment with fluoropyrimidine‐, oxaliplatin‐, and irinotecan‐based chemotherapy, an anti‐VEGF therapy, and, if RAS wild‐type and medically appropriate, an anti-EGFR therapy. CCR5 tumor expression will be determined by immunohistochemistry assay (IHC) and diagnosis of MSS CRC will be confirmed by IHC or next-generation sequencing (NGS).
TAS-102 and bevacizumab will be administered for three of four weeks in a four-week cycle, and leronlimab (at doses of 350 mg or 700 mg) will be administered weekly. The study will include a safety lead-in treating five patients in the 350 mg leronlimab arm prior to beginning enrollment to the 700 mg leronlimab arm."
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Pitt followed up with a few good posts:
"So here is what I found.
The Swiss drug company Roche has applied to have its drug bevacizumab (marketed as Avastin) taken off the World Health Organization’s list of essential medicines as an ophthalmic treatment.
And Taiho pharmaceuticals is owned by Otsuka Pharmaceutical is a wholly owned subsidiary of Otsuka Holdings Co., Ltd. Please see the Investor relations information of our parent company Otsuka Holdings for financial statements from the Otsuka Group.
So, the trifluridine plus tipiracil (TAS-102) is owned by Otuska and bevacizumab is owned by Roche which is the 2nd highest market value of 221 billion behind only J&J in the world.
So, after researching Roche's drugs we align and very possibly could be a takeover target to strengthen their portfolio of the already approved meds. Remember all these patents expire but if combined with leronlimab which could make them even better, would lengthen the patent.
Herceptin (trastuzumab). Herceptin was the first HER2-targeted therapy for breast cancer. It is a monoclonal antibody. We know leronlimab is in the breast cancer arena.
Herceptin® (trastuzumab) Treatment of HER2-positive early and metastatic breasts.
Erivedge® (vismodegib). Uses of Erivedge ® (vismodegib):. Treatment of advanced (metastatic) basal cell carcinoma
CellCept is used in the prevention of organ rejection in patients receiving kidney, heart, or liver transplants. It is an oral. We know leronlimab is in Graph versus Host disease.
Avastin is used for the treatment of advanced stages of breast, colorectal, non-small cell lung, kidney, ovarian and cervical cancers. This is the combo we are doing.
Lastly:
Genetech originally made the drug, but Roche bought out Genentech for $46.3 billion in 2009. So even though Genentech is in California, Roche owns the drug. Again, Roche is the second largest pharma in net worth in the world behind J&J."
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Here is a cool post by i_Observer:
"I love Roche/Genentech's website. Their AI/ML and manufacturing programs are solid. It's also noteworthy that their headquarters are just a few miles from Dr. Jay's home, and their pipeline layout reminds me of the recent update to CytoDyn’s website. As I mentioned in a post back on December 26, 2022, keep an eye on this company. Here we are in August 2024, and they continue to impress.
...
Now Jesse is coming through with some pretty interesting finds:
Jesse might be thinking that CytoDyn transferred their manufacturing technology to Genentech.
A lot of his other posts point to good reasons why Genentech and Roche could become CytoDyn's partner in the coming mCRC trial. Given this weeks Press Release, I definitely agree. We have been fooled by the Keytruda / Merck into thinking mCRC would be with a PD-1 blocker, but this week's PR tells us that leronlimab is effective in mCRC, but not necessarily with the PD-1 blocker.
Bevacizumab, a VEGF inhibitor, originally made by Genentech as Avastin, is now owned by Roche. We are aware that although leronlimab primarily functions as a CCR5 blockade, it also functions to inhibit VEGF indirectly. CytoDyn is looking for Synergy in this combination trial. It is not looking for monotherapy.
So, we can clearly see by this recent Press Release, that CytoDyn must be in discussions with Genentech and/or Roche. The simple fact that these medications were mentioned in the PR and given the similarity of the proposed CytoDyn trial to last year's Trifluridine/Tipiracil Combined with Bevacizumab Receives FDA Approval in Metastatic CRC trial, it becomes rather clear that the companies are seeking an improvement over and above the SUNLIGHT linked trial performed last year. That medication combination currently competes with Regorafenib by Bayer in the treatment of mCRC. Certainly, Genentech/Roche are interested in the treatment of the MSS MicroSatellite Stable tumors, which are those cancer types which represent about 85% of the cancer tumors. With the addition of leronlimab, this vast slice of the oncology pie becomes available. Without leronlimab, they are limited to treating only 15% of the oncology pie which are the MSI MicroSatellite Instability tumors.
On May 16, 2024, in the May 2024 Letter to Shareholders, Dr. Lalezari made the decision to drop the Inflammation, Immune Activation trial as Priority #1 and to replace that with this proposed mCRC trial in combination with Trifluridine/Tipiracil and Bevacizumab. Please re-read the following posts which I had written immediately following Lalezari's change, but on this re-read, replace Merck and Keytruda with Genentech/Roche and bevacizumab/Avastin: Changing Gears and its Part 2 complement A Means To An End.
There was a murine study in mCRC conducted by MD Anderson. The results were shared with CytoDyn, but not actually given to CytoDyn. CytoDyn is aware that leronlimab is definitively effective against mCRC and therefore, CytoDyn had shared those murine results with Genentech/Roche. There are sufficient peer reviewed research journal articles regarding CCR5 in mCRC which augment those communicated murine results and that likely helped in Genentech/Roche's decision-making process to participate in this combination trial. Take notice, there is NO leronlimab only arm. This is combination trial only. There is no intention on getting leronlimab approved as monotherapy for mCRC at this time. The intention is for combination therapy and combination therapy points to future partnership.
"“We are pleased to have received the FDA’s feedback on our Phase II study of leronlimab in patients with relapsed/refractory microsatellite stable colorectal cancer and remain on track to commence our oncology trial in the coming months. Advancing leronlimab in the oncology indication has been an important priority for our team as we progress CytoDyn’s clinical pipeline,” said Dr. Jacob Lalezari, CEO."
So, what does that mean? It means, so far, CytoDyn shall execute and pay for the proposed mCRC trial. If the trial proves to be successful and significantly improves the OS, PFS and ORR, then, the partnership for a Phase III materializes where Genentech/Roche takes over the show of getting leronlimab approved for this indication. It takes several months to get the trial going and over a year for the OS and PFS results to show a significant improvement given that the current OS is 10.8 months and current PFS is 5.6 months. However, ORR, Overall Response Rate is another animal.
Let's refresh our understanding on leronlimab and cancer. 12/7/22 R&D Update: Leronlimab in Oncology - Clinical Data
52:24: So when we look at the changes in tumor growth by PET/CT, we see some very encouraging results here. So this is patients who received -- 12 patients who did receive scans that were then qualified using RECIST criteria. And what we can see is that all the patients had either stable disease or at least a partial response over the course of the study*. And so those are very encouraging results. You can see from the waterfall on the right that the vast majority of the patients stayed within the stable disease range.*
53:00: Within oncology, this is a positive indicator that disease is not getting worse than with the subset of patients, the tumors were certainly getting smaller*.*
53:15: When we look at the patients from just the Phase Ib/II study and then break them out by the dose they received, again, you can see that the majority of patients actually did see reductions in their tumors*. Some of the* patients actually discontinued carboplatin and remained on leronlimab as a single agent for some time*. Interestingly,* those patients did have the largest reductions in the MAX change in their tumor size*.*
53:51: And then finally, what I'll present here before showing the colorectal cancer data is data from a poster presentation at the AACR conference earlier this year. So this looked at changes in circulating tumor cells that have been associated -- or can be looked at as a surrogate for progression of disease. And what you can see here is that the progression-free survival for patients who received at least 1 dose of leronlimab*, they had --* and those that had an absence or a decrease in circulating tumor cells, (both), had a trend for better survival than those that had an increase in CTCs. And similarly, we saw a similar sort of trend on the overall survival curve.
54:46: Now this is not surprising. Other agents that would look at a similar breakdown in terms of CTCs would see a similar effect. When we also look at tumor-associated cells, we see a similar trend towards better survival when the tumor-associated cells drop in the peripheral blood measures.
56:12: I now want to show just a little bit of data on -- from the CRC patients from the basket study, where we had a total of 6.
55:22: So when we look again at their tumor growth through the spyre grams and through the waterfall plots, that we only had 6 patients here. But as you can see, all of them remain within the stable disease and many actually achieve partial responses over the course of the short study. And one of them actually had no measurable lesions on the PET scan at follow-up*. And the remainder saw either stable disease or partial responses.*
How is the Overall Response Rate ORR Measured?
"RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) is a standardized set of criteria used to measure tumor response to treatment in clinical trials. It helps determine how well a treatment is working by providing a consistent way to evaluate changes in tumor size and the appearance of new lesions.
Key Aspects of RECIST v1.1:
- Target Lesions: Tumors selected for measurement, typically up to five total, with no more than two per organ.
- Complete Response (CR): Disappearance of all target lesions.
- Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions.
- Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, or the appearance of new lesions.
- Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
- Non-Target Lesions: All other lesions not selected as target lesions, assessed qualitatively.
- Evaluated for CR, non-CR/non-PD (stable disease), or PD based on changes in size or the appearance of new lesions.
- New Lesions: Appearance of new lesions indicates disease progression.
Application of RECIST v1.1 in the SUNLIGHT Trial:
In the SUNLIGHT trial, RECIST v1.1 was used to measure the effectiveness of the combination of Trifluridine/Tipiracil with Bevacizumab in patients with metastatic colorectal cancer. The criteria were employed to:
- Assess Tumor Response: The trial measured changes in tumor size over time to classify patients' responses into categories like CR, PR, SD, or PD.
- Determine Overall Response Rate (ORR): The ORR, a key outcome of the trial, was based on the percentage of patients who achieved either a CR or PR according to RECIST v1.1.
The use of RECIST v1.1 allowed for a standardized evaluation of tumor response, facilitating comparisons between treatment groups and contributing to the trial's overall assessment of the combination therapy's efficacy.
In clinical trials using RECIST v1.1 criteria, the diameter of tumors is measured using imaging techniques such as CT (Computed Tomography) scans or MRI (Magnetic Resonance Imaging). Here's how the process works:
1. Selection of Target Lesions:
- Baseline Scans: Before starting treatment, baseline scans are performed to identify and measure target lesions. These are the largest and most measurable tumors, up to a maximum of five total lesions, with no more than two per organ.
- Measurement: The longest diameter (LD) of each selected target lesion is measured on axial images (cross-sectional) from the CT or MRI scans. The sum of these diameters across all target lesions is recorded as the baseline sum.
2. Follow-Up Scans:
- Subsequent Imaging: During and after treatment, follow-up scans are taken at regular intervals to measure the same target lesions.
- Comparison: The diameters measured during follow-up are compared to the baseline measurements. The sum of the diameters from each follow-up scan is compared to the baseline sum to assess the tumor's response to treatment.
3. Response Assessment:
- Complete Response (CR): If all target lesions disappear, the response is classified as CR.
- Partial Response (PR): If there is at least a 30% decrease in the sum of the diameters compared to baseline, it's classified as PR.
- Stable Disease (SD): If the change in sum of diameters does not meet the criteria for PR or PD (progressive disease), the response is considered SD.
- Progressive Disease (PD): If there is at least a 20% increase in the sum of the diameters, or new lesions appear, the disease is classified as PD.
Tools and Techniques:
- Precision: Modern imaging software helps to measure the tumor diameters with high precision, and these measurements are typically verified by radiologists or oncologists.
- Reproducibility: The use of standardized imaging protocols ensures that measurements are consistent and reproducible across different time points and trial sites.
The use of these precise measurements is crucial for accurately determining how well a treatment is working, and for making decisions about continuing, adjusting, or stopping a therapy based on the tumor's response.
The use of RECIST v1.1 allowed for a standardized evaluation of tumor response, facilitating comparisons between treatment groups and contributing to the trial's overall assessment of the combination therapy's efficacy.
The SUNLIGHT Phase 3 trial, which evaluated the combination of Trifluridine/Tipiracil with Bevacizumab in patients with metastatic colorectal cancer, reported an overall response rate (ORR) of 6.9% for the combination therapy. This response rate includes partial responses observed in patients, and although it was modest, the combination therapy still demonstrated significant improvements in overall survival and progression-free survival compared to Trifluridine/Tipiracil alone (Cancer Network) (OncData).
This finding indicates that the current Trifluridine/Tipiracil with Bevacizumab therapy does not drastically increase tumor shrinkage (as measured by the low ORR of only 6.9%), it still does offer a survival benefit of 10.8 months OS and 5.6 months PFS for patients with advanced, treatment-refractory colorectal cancer. How much higher shall the addition of leronlimab raise the ORR? Certainly, we know from the above graphs that leronlimab shrinks tumors. We know that it does this both in MSI and MSS type tumors. That is MicroSatellite Instability and MicroSatellite Stable tumors. That is Hot tumors and Cold tumors. What I'm saying is that leronlimab shall raise the ORR tremendously. But how quickly? Looking at the graphs above, it appears that it reduces tumor size within 3 months, and it maintains that smaller size and on some, it might reduce tumors completely. So, that translates into that by 7 months from now, March/April 2025, we could have an outcome of the new ORR.
It was a great idea that Dr. Lalezari decided to measure ORR and not OS or PFS, because by measuring ORR, the outcome of the Phase II trial can be known so much sooner. If all leronlimab needs to do is to improve the ORR, overall response rate of the SUNLIGHT trial from 6.9% to likely over 33% (is my guess, but I may be undershooting if anything), then a Phase III study and future partnership are in the bag. From there, leronlimab would be developed unto approval by Genentech/Roche for this mCRC indication. I think, that if Genentech/Roche see that the ORR is improved by such a staggering improvement, they should want to earnestly pursue the subsequent Phase III trial.
This is how I see it unfolding. Genentech/Roche has good results when it comes to OS and PFS, but not when it comes to ORR. Leronlimab is a specialist in getting a rapid response, within 3 months. It does shrink tumor size, and it works on CCR5 dependent tumors, and this Phase II trial shall only be conducted on CCR5 dependent tumors. In addition, I suspect the OS and PFS shall also be increased, but it is not necessary to know by how much to advance to Phase III.
"...Phase II study that will investigate the preliminary safety and activity of leronlimab in combination with trifluridine plus tipiracil (TAS-102) and bevacizumab in participants with CCR5+**, microsatellite stable (MSS), relapsed or refractory metastatic colorectal cancer (mCRC)."
A few months more, ~early November I would guess, we have the initiation of this proposed Phase II trial. A few months after that, we should know the Overall Response Rate ORR and I'm expecting an outcome in excess of 33%. If that happens, it is only up from there for CytoDyn, mid-Spring 2025. Maybe CytoDyn won't even have a part in the Phase III trial aside from supplying the leronlimab. Maybe that may be handled in the licensing manner. There are many ways to form a partnership.
I think the results are going to be amazing, even compelling. I think this leads to a big contract, but it will be in the hands of companies with deep pockets, Genentech and Roche. Apparently, inhibiting VEGF alone was not enough, but they knew what to do about their problem and so did Dr. Lalezari. All of this has been in progression since that May Shareholder's Letter when the #1 Priority change was made. All of this has been in play, being set up which leads to a big, big contract.
We will keep our eyes on it to see how it continues to unfold. Just wanted to document the recent news as I see it and many thanks to Pitt, i_Observer and Jesse who I quoted. Thanks also to everyone on ST and Investor's Hangout where I glean great tib-bits all around.
Posted Aug 15, 2024, 9:56 PM UTC