BIG news: the decades-long paradigm of leveraging the highest and most toxic dose of a cancer drug, called the Maximum Tolerated Dose (MTD), may be coming to an end!
Shortly after the Patient-Centered Dosing Initiative's presentation about MBC patients’ treatment-related side effects at ASCO’s 2021 worldwide conference, Richard Pazdur, Director of the FDA’s Oncology Center of Excellence, stated that the FDA will start requiring drug companies to test the efficacy of multiple drug doses during clinical trials instead of identifying and moving forward with the MTD.
This is a game-changer because the MTD, which is identified in Phase 1 clinical trials that focus solely on toxicity, is the dose that generally causes the most severe side effects. In today’s world, whenever patients with MBC begin a new treatment, they are generally prescribed the MTD unless there’s a medical contraindication. But in tomorrow’s world, at least two doses will be identified in Phase 1 clinical trials for further study so that ultimately the optimal dose - based upon a balance of efficacy and toxicity - will be given to patients.
Please join a webinar hosted by Friends of Cancer Research on Wednesday, Nov. 10th at 12PM ET. Panelists including the FDA, pharmaceutical companies, Friends of Cancer Research, and myself, will be discussing the transformation of MTD-based oncology studies.
That is awesome news! I never understood why the doses would be the same for everyone, no matter their weight or other issues. It would seem like the lowest dose should be tried first to see if it works or if it needs to be tweaked. I think people would have a lot less side effects that way. Can I register for the conference and watch it at another time? Thanks.
love2golfwell, Although in some instances lower doses can be as effective as higher doses, that is not always the case. A balance needs to be struck between efficacy and tolerability, which is the FDA's new direction and which the Patient-Centered Dosing Initiative supports. I'm not sure whether the webinar will be available for viewing after 11/10. I hope it will be!
Thank you Bestbird! I am hoping if they start doing trials at different dose levels that there can be a good balance for patients. I see so many women on this site who have had to reduce their dosage because of mouth sores, pain or really low white blood counts. I am hoping they are still getting a good benefit from the medications. I have been on the highest Ibrance dose since I started a year ago and luckily have not had those issues, just a lot of hair thinning. And I have had 2 good scans. If I could do that well on a lower dose, though, I would be happy to do that. I am going to register for the webinar and hope they will send out something saying that it is available for viewing after. Hugs to you.
Yes! I had heard about this and am registered. This is exactly what I have been thinking and talking for awhile. I can’t wait to see what may be available going forward!
Sandra, I'm delighted that you registered for the conference! Interestingly, in some cases we're seeing that a lower dose of an FDA-approved drug is as (and sometimes even more) effective than the MTD (let me know if you'd like to receive this information). The FDA's new direction will help ensure that the best dose in terms of efficacy and toxicity is selected.
You raise an excellent point regarding the paucity of reporting the efficacy of lower doses in clinical trials. The Patient-Centered Dosing Initiative (PCDI) plans to approach pharma companies next year in an effort to obtain more data, both from clinical trials and in the real-world setting.
Even with the FDA's new direction, the PCDI's mission of encouraging dosage-related discussions between oncologists and patients will still be needed because:
1) Patients' responses in the real-world differ from those of patients in clinical trials because they are not subject to rigid inclusion/exclusion criteria
2) It will take a while for new drugs being developed to leverage the new paradigm, and drugs currently on the market will still be prescribed based upon the MTD.
3) Patients will always have unique personal attributes (co-morbidities, drug sensitivities, etc.)
I knew it was unwise to go on with the maximum dosage when I started Ibrance. 75 mg does me fine. Why put more toxic substances into my body when it doesn't need all that?
SMPG, it is wonderful news indeed! Yet we need to be aware that although in some instances lower doses can be as effective as higher doses, that is not always the case. A balance needs to be struck between efficacy and tolerability, which is the FDA's new direction and which the Patient-Centered Dosing Initiative supports. Wishing you the best!
Thank you for all your work on our behalf, Anne! It must be good to know that you are having a useful impact in this field!
I, too, have registered for the conference. From the agenda, it doesn't look like there will be time to discuss many of the various patient characteristics that may well have an impact on whether or not an individual patient will benefit from a particular drug (regardless of the dosing administered).
Given, for example, that, according to the MONALESSA-2 trial, ribociclib only had a clinical response in 43% of the patients, it seems to me that we need to know how closely we resemble the patients who responded, before we agree to tolerate the extensive side effects of ribociclib. This is especially true for patients like me with heart conditions since more than one of ribociclib's side effects impacts the heart.
None of this is to say that I think dosing is a less important issue. On the contrary, it seems to me only logical that different bodies may well respond differently to different doses of such powerful medications. Surely, physicians have been trained to modify the dosages of many medicines to suit the needs of individual patients. Why should oncologists not use the same training with their cancer patients??
Thank you for the info on the conference. I registered. Another subject I have however, is on markers. I have not seen anyone with markers as high as mine. It seems most onc's in this forum dismiss them or don't even take them. My onc seems to have no clue why they keep rising. Personally, I think they're trying to tell me something. On 10/30/21 my CM 15-3 were 1983 compared to 6/30/21 of 1126. My C27-29 were 3404 compared to 1866. I have MBC primarily to the bones (2016) and this year three lesions to the liver. I just had SBRC (radiation) to one of my liver lesions, by my suggestion, not my onc, but confirmed maybe helpful by radiologist. I presently take Xeloda (Capecitabine) 3000mg/day. My last Pet Scan impressions were as follows: 1) L Liver metastases are stable although a third metastatic lesion has recurred. 2) Persistent hypermetabolism in a stable small sized left and new small sized right pleural effusion. The persistence of metabolic activity within this fluid raises the possibility of indolent pleural carcinomatosis. 3) Widespread bone metastases with diffuse bone marrow activation and heterogeneous areas of marrow activity. A few discrete lesions are identified similar to prior exam. Any thoughts? Thanks, Elaine
SoCalLady, markers involve testing, which is a separate issue from dosing. From what I've read, a change in treatment be based upon scans in lieu of markers, although a trend in rising markers may suggest progression but may not always be definitive. If you have further questions, discussions with your oncologist and potentially a second opinion may be considered.
Sandra, Very true! Yours is one of the three reasons below why the Patient-Centered Dosing Initiative is still needed:
Dosage-related discussions between oncologists and patients remain vitally important because:
1) Patients' responses in the real-world differ from those of patients in clinical trials because they are not subject to rigid inclusion/exclusion criteria
2) It will take a while for new drugs being developed to leverage the new paradigm, and drugs currently on the market will still be prescribed based upon the MTD.
3) Patients will always have unique personal attributes (co-morbidities, drug sensitivities, etc.)
Sandra, when I was diagnosed with MBC I was hoping to survive for a year. I truly am grateful to still be here, and perhaps that is one of my main motivations in trying to improve the lives of people living with MBC.
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Just received this email about previously named ERSO.... now ERX-315
Sad update about ErSO 
