Why Personalized Cancer Treatment Is Hard — and How to Get It

“The Personalization Conundrum” (Brad Power) [#16] July 6, 2022 Brad Power How can physicians be convinced to overcome concerns of safety, reimbursement, and liability to prescribe novel regimens (personalized drug combinations, dosing, and sequences), without randomized clinical trial evidence?

Meeting Summary In this meeting we had a lively dialogue on the "personalization conundrum" for advanced cancer patients – on the one hand, we can identify highly personalized treatments, such as drug combinations, but … on the other hand, high levels of personalization mean that it is unlikely there will be evidence from randomized clinical trials to support the uniquely targeted treatment.

So clinicians may lack confidence to prescribe them and payers to cover them. Treating physicians have concerns about safety, reimbursement, and liability, which are heightened when there isn’t randomized clinical trial evidence. We have learned about personalized treatment strategy thanks to insights from some amazing experts.

Personalized drug combinations (Ally Perlina), dosing, and a strategic sequence of therapies based on evolutionary and game theory (Bob Gatenby) can provide better outcomes for advanced cancer patients. However, access to personalized treatments is often hard.

There are “ expanded access” or “compassionate use” processes for patients to get access to drugs where they would not otherwise be eligible. But there are still other barriers and incentives to getting access to drugs or drug combinations that are “ off label” (unapproved use of approved drugs).

For example, if a patient gets access to a drug off label, providers are not able to mark up the drugs via the typical “buy and bill” paradigm, which is 6% to 600% for infused anticancer drugs. Physicians lose revenue, while also spending more time managing the process and the patient, including potential adverse side effects. Clinicians make treatment decisions outside the guidelines, e.g.

, off-label uses of drugs, for individual patients all the time. When they do, they are guided by their own experience, and the experience of their colleagues. What are those dynamics, and can we encourage more of it?

Testing, mathematical simulation models that predict response, and real world experience from longitudinal studies are three approaches that could give physicians, payers, and patients more confidence to prescribe more personalized therapies. ●Testing: We have heard from Tony Letai and Payel Chatterjee of SEngine about functional testing .

Blood-based liquid biopsy using ctDNA and surrogate markers of efficacy can be used in cases where fresh tumor tissue is unavailable. (Peter Kuhn is scheduled to discuss.) Blood and other novel tests (Karin Rodland) can enable more frequent monitoring of disease progression, enabling fine-tuning of treatment and personalization.

“The Personalization Conundrum” (Brad Power) [#16] ●Predictive Models : There is a lot of investment and e

Kuhn is scheduled to discuss.) Blood and other novel tests (Karin Rodland) can enable more frequent monitoring of disease progression, enabling fine-tuning of treatment and personalization.

“The Personalization Conundrum” (Brad Power) [#16] ●Predictive Models : There is a lot of investment and effort in developing models that will predict drug response by large pharmaceutical companies and academics that can be repurposed. ●Real World Evidence : Every patient should be tracked in an observational trial to share results of their unique, personalized, N-of-1 experiments.

GCTA (XCELSIOR) is one such unique registry (Jeff Schrager): It allows you to create "n-of-1" arms, does not drop the patients on the floor ever, has no exclusion criteria, and understands "arm" in a dynamic way not available to any other trial model.

Several other ideas were raised to address the personalization conundrum: ●Glenn Sabin proposed that the patient could consent to hold the clinician harmless, lowering liability concerns.

●An anonymous caregiver suggested that the job of patients is not to be a grateful consumer of an industry that serves itself, but rather a person with needs, and that you are seeking people who can help you, where your needs and your wishes are primary. ●Ally Perlina recommended having patients raise specific treatment options with their doctor and listen to the specific feedback.

●Saed Sayad pointed to creating a logical process that leverages existing public data.

The information and opinions expressed on this website or platform, or during discussions and presentations (both verbal and written) are not intended as health care recommendations or medical advice by Cancer Patient Lab/Prostate Cancer Lab, its principals, presenters, participants, or representatives for any medical treatment, product, or course of action.

You should always consult a doctor about your specific situation before pursuing any health care program, treatment, product or other course of action that might affect your health.

“The Personalization Conundrum” (Brad Power) [#16] Meeting Notes Brad Power: Today we're going to have a conversation about some of the things we've learned about various aspects of making complex testing and treatment decisions for advanced cancer patients, and to get your input on some countermeasures to the “personalization conundrum”.

A lot of the things that we have been talking about, such as drug combinations, have been generally accepted by most people that we've spoken to as a better option. If you can hit multiple biomarkers at the same time, that’s better, but there's a concern around toxicity when you have drug combinations.

How can we balance this conundrum of, on the one hand having what appears to be better, more effective treatments, e.g., through drug combinations, and on the other hand, a concern around toxicity? This is the Prostate Cancer Lab organization.

ns. How can we balance this conundrum of, on the one hand having what appears to be better, more effective treatments, e.g., through drug combinations, and on the other hand, a concern around toxicity? This is the Prostate Cancer Lab organization. We launched in March, so we're about four months in. This is a checkpoint for reflection.

This picture has changed almost every couple weeks because we've added another diagnostic company, another presenter (we have had 15 meetings with a variety of discussion leaders), or another patient, molecular biologist, bioinformatician, or physician. This is our 16th meeting, and each time we've had various people lead discussions, many of whom have raised new ideas.

We have a calendar going forward of meetings, about 10 or so scheduling into September. The discussion leaders are providing insights on this decision process of identifying treatment options, targeting them based on diagnostics and analysis, and then trying to reflect those and prioritize them.

“The Personalization Conundrum” (Brad Power) [#16] This slide summarizes what we've learned and what I'm calling “the personalization conundrum”. Treatment Strategy : Ally Perlina of CureMatch has presented their recommendations for matching approved drugs indicated by the patient’s biomarkers. CureMatch’s distinctive contribution is drug combinations.

Their premise is that hitting multiple biomarkers is better than hitting one at a time. Saed Sayad has also made the point that more drugs at lower dosage is better than fewer drugs at higher dosages. Bob Gatenby has been an influential, theoretical strategic guide for us with his ideas. Cancer is a heterogeneous population.

Any drug or treatment is going to have an effect on that population and generate a resistant strain. If you administer drugs at maximum tolerable dose until resistance, you will breed resistant strains. Rather, we should think about knocking down the population using game theory, evolutionary theory, and adaptive therapy.

Emma Shtivelman has been a leader in giving us principles for choosing among treatment options and ideas about treatment. For example, a targeted CAR-T therapy may be in Brian’s future. It could target PSMA or a couple of other antigens. Therefore, if you have a drug that reduces the PSMA-presenting cancer cells in the population, then it might make the efficacy of that eventual CAR-T less.

She also had ideas about choosing different pathways. A lot of the prostate cancer therapies are targeting androgen deprivation and androgen receptors.

“The Personalization Conundrum” (Brad Power) [#16] find drugs and treatments that would be targeting different pathways, and see what they can do, rather than continuing to pound the same pathway and get increasingly diminishing returns. Treatment Options : Brian has submitted his data to Cancer Commons, xCures, CureMatch, and Massive Bio. CureMatch focuses on combinations of approved drugs.

eting androgen deprivation and androgen receptors. Can we

“The Personalization Conundrum” (Brad Power) [#16] find drugs and treatments that would be targeting different pathways, and see what they can do, rather than continuing to pound the same pathway and get increasingly diminishing returns. Treatment Options : Brian has submitted his data to Cancer Commons, xCures, CureMatch, and Massive Bio. CureMatch focuses on combinations of approved drugs.

Massive Bio focuses on clinical trials. Cancer Commons is mostly Emma Shtivelman. xCures is the software engine that's running Cancer Commons, and they have come up with yet another set of options. Brian reviewed the treatment options they recommended for him last week. He had 18 options, of which four seemed to be on the top.

We need to give a shout out to our inspiration Bryce Olson, who has been through nine lines of treatment, though it could be more. He's currently on bipolar androgen therapy, which is an extreme version of adaptive therapy. It's being very effective. Rick Stanton has presented previously that he's identified 10 options for his treatment.

Rick's treatment options have largely come from his clinical team, which includes Tanya Dorff, Rana McKay, and doctors at UCLA.

“The Personalization Conundrum” (Brad Power) [#16] There are two little thumbnails of slides that you can't quite see off to the right. One is Rick's analysis of the NCCN guidelines. I included it to make the important point that we are beyond the standard of care.

The discussion and decisions we're talking about are for patients who've exhausted the standard of care, and they've exhausted the obvious choices for drugs or treatments. Most have had a prostatectomy, radiation, and androgen deprivation, and they've failed all of those.

They are in the zone of discretion, where there might be a dozen or 20 options, and a patient and his medical team needs to choose amongst them. The second thumbnail slide is called “the Stacey matrix”, which says that we're in the zone of complex decisions, not straightforward and easy decisions.

Treatment Selection : The essence of this conversation is how we can make physicians and patients more confident in making personalized decisions, particularly drug combinations, but also dosing and sequencing. When Bob Gatenby reviewed Brian's case, he said that since Brian has a very low PSA, he is a candidate for an “extinction event''.

He recommended that Brian choose a ladder of three drugs in rapid succession or in a cocktail, and see if he could get an extinction event, to use the evolutionary terminology. But we run into the question of toxicity when we have combinations, because we're in uncharted territory, because there aren't clinical trials that have run that personalized combination at personalized dosing.

Personalization Confidence? : There are three tools that we could use to give patients and clinicians more confidence.

ing different pathways, and see what they can do, rather than continuing to pound the same pathway and get increasingly diminishing returns. Treatment Options : Brian has submitted his data to Cancer Commons, xCures, CureMatch, and Massive Bio. CureMatch focuses on combinations of approved drugs. Massive Bio focuses on clinical trials. Cancer Commons is mostly Emma Shtivelman.

xCures is the software engine that's running Cancer Commons, and they have come up with yet another set of options. Brian reviewed the treatment options they recommended for him last week. He had 18 options, of which four seemed to be on the top. We need to give a shout out to our inspiration Bryce Olson, who has been through nine lines of treatment, though it could be more.

He's currently on bipolar androgen therapy, which is an extreme version of adaptive therapy. It's being very effective. Rick Stanton has presented previously that he's identified 10 options for his treatment. Rick's treatment options have largely come from his clinical team, which includes Tanya Dorff, Rana McKay, and doctors at UCLA.

“The Personalization Conundrum” (Brad Power) [#16] There are two little thumbnails of slides that you can't quite see off to the right. One is Rick's analysis of the NCCN guidelines. I included it to make the important point that we are beyond the standard of care.

The discussion and decisions we're talking about are for patients who've exhausted the standard of care, and they've exhausted the obvious choices for drugs or treatments. Most have had a prostatectomy, radiation, and androgen deprivation, and they've failed all of those.

They are in the zone of discretion, where there might be a dozen or 20 options, and a patient and his medical team needs to choose amongst them. The second thumbnail slide is called “the Stacey matrix”, which says that we're in the zone of complex decisions, not straightforward and easy decisions.

Treatment Selection : The essence of this conversation is how we can make physicians and patients more confident in making personalized decisions, particularly drug combinations, but also dosing and sequencing. When Bob Gatenby reviewed Brian's case, he said that since Brian has a very low PSA, he is a candidate for an “extinction event''.

He recommended that Brian choose a ladder of three drugs in rapid succession or in a cocktail, and see if he could get an extinction event, to use the evolutionary terminology. But we run into the question of toxicity when we have combinations, because we're in uncharted territory, because there aren't clinical trials that have run that personalized combination at personalized dosing.

Personalization Confidence? : There are three tools that we could use to give patients and clinicians more confidence. ●Testing: We've had a discussion led by Tony Letai of Dana Farber about functional testing and what it can do.