Precision Cancer Drug Combinations: Targeting Multiple Pathways at Once

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] April 20, 2022 Brad Power Meeting Summary Ally Perlina, Chief Science Officer at CureMatch, presented combinations of approved drugs that are the best fit for advanced prostate cancer patient Brian McCloskey based on his cancer’s unique molecular profile.

CureMatch is a San Diego-based company which takes biomarkers identified by most any diagnostic sequencing test and matches them with approved drugs in combinations. Their distinctive value is using multiple drugs in combination to achieve a better fit with the unique characteristics of a patient’s cancer, and therefore better patient outcomes.

The CureMatch system starts with input from a patient’s molecular profile, derived from DNA and/or RNA sequencing of a patient’s tumor tissue or liquid biopsy sample. The test will identify biomarkers or variants of interest (variants from normal cells, potential drivers of the cancer), usually 4 to 6. Not all biomarkers or variants go into the algorithm.

Some may be rejected because they are not pathogenic (don’t drive the disease), and some because there are no therapies targeting that biomarker. The physician has latitude to include or exclude biomarkers or treatment options due to any reason, such as medical history. For example, Brian had pembrolizumab, so he might decide to remove it as a treatment option.

Then CureMatch analyzes the patient’s selected biomarkers against the roughly 300 drugs that the FDA has approved in combinations of 3, 2, or 1 drugs. They do not include clinical trials in their recommendations.

For example, Brian has a variant (B7-H3/CD276) which has several clinical trials targeting this pathway, but it would not be included in a CureMatch recommendation because there are no approved drugs for it yet. Off-label uses of drugs (drugs that have been approved but for a different indication) are included in the treatment combinations. The roughly 4.

5 million possible combinations of the roughly 300 approved drugs are then scored on the extent to which they address the patient’s selected biomarkers. If a drug combination addresses 4 of 6 biomarkers, the score is 67%, 3 of 6 would be 50%, and 2 of 6 would be 33%. The drug combinations are ranked on their scores, with explanations and links to support the choices.

For example, Brian had 6 actionable markers, 16 on compendia drugs, 54 matching drugs, and 24,857 relevant combinations. CureMatch’s top option, with a score of 32%, was a 3-drug combination of apalutamide (FDA approved, AR target), olaparib (FDA approved, FANCA target via PARP-1, PARP-2), and trametinib (off-label, BRAF target via MAP2K1, MAP2K2, and MAP2K2 target).

As Emma Shtivelman, an experienced PhD molecular biologist and Chief Scientist at Cancer Commons summed up, “... someone like me looks more for clinical trials rather than off-label treatment options.

2K1, MAP2K2, and MAP2K2 target). As Emma Shtivelman, an experienced PhD molecular biologist and Chief Scientist at Cancer Commons summed up, “... someone like me looks more for clinical trials rather than off-label treatment options. And when I look for clinical trials, I keep in mind the previous treatments...

CureMatch has this assumption that a physician will be able to prescribe off-label combinations of two or three drugs. This happens rarely, even with the best specification.

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] the recommendations, and it worked great. But it's an exception... It's unfortunate and very frustrating.” Advanced Prostate Cancer Patient Panel Report Brian McCloskey shared highlights from a meeting of advanced prostate cancer patients who have registered with the Prostate Cancer Lab community.

Four themes emerged that they would like to see if they could change one thing about their care: ●Better physician-patient communication : Providing patients with simple language they can use to understand their disease and treatment options. ●Better diagnostics for personalizing treatments : Tailoring treatments uniquely to the profile of each individual.

●Medical guide partner : Finding a trusted medical advisor who will be an expert partner on the journey. ●Access to experts : Achieving a high quality of care in rural locations. Requests ●Do you have any feedback on the CureMatch presentation? Would you recommend their approach to a friend or family member?

●Do you know anyone who would be a good candidate to serve on our Prostate Cancer Lab patient board? The candidate should be very active in wanting to learn more about his advanced prostate cancer and treatment options.

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.

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] — 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.

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. Meeting Transcript CureMatch Recommendations for Treatment Combinations for Brian McCloskey Brad Power: To set up Ally's CureMatch analysis, we're going to have Brian briefly set the stage with his medical history.

Brian McCloskey: I was diagnosed in 2016. I had a prostatectomy. Unfortunately, it came back, and then I went on this wild ride. I went on first line hormone therapy, then Lupron, then radiation, and then we saw an uptick in my PSA. Then I went to a second line hormone therapy with apalutamide, and saw an immediate response to that, which was great.

I took a bit of a holiday in December of 2019, you can see at step 5 there. Unfortunately, I had a biochemical recurrence at that juncture, but it became visible as soon as I went off of all hormone therapy. In August of 2020, point 6 on this graph, we discovered I had six metastatic lesions in my peritoneum. We did surgery, and then I started a combination of chemo and pembro.

You can see my PSA began to drop during all of that. I took six rounds of chemo and stayed on pembro for about 12 months. I began to see a bit of an uptick in September of last year. We did some more imaging and found I had 3 metastatic lesions in the peritoneum. Prior to that there were no visible mets after the surgery and after chemo. I am now on abiraterone. I have had a PSA decline from .

9 to 1.45. Saed Sayad: What was the Gleason score?

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] Brian McCloskey: It was a 4 + 3, with grade 5. Ally Perlina: Thanks for having me. I hope what I have will be helpful. I spoke to Brian last year. We met virtually. I know there is a history of his getting a different CureMatch report in 2017. It was different data then, and there was different knowledge out there in the world.

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5]

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] You can think of CureMatch as knowledge representation and reasoning, as opposed to a machine learning kind of AI. We are not trying to make a prediction. It's more like scoring molecular fitness of treatments (therapies, drugs) to the markers of molecular type in each individual patient profile.

As our founder and chief medical advisor Dr. Razelle Kurzrock said, it's like a snowflake, everybody's cancer is unique.

/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.

Meeting Transcript CureMatch Recommendations for Treatment Combinations for Brian McCloskey Brad Power: To set up Ally's CureMatch analysis, we're going to have Brian briefly set the stage with his medical history. Brian McCloskey: I was diagnosed in 2016. I had a prostatectomy. Unfortunately, it came back, and then I went on this wild ride.

I went on first line hormone therapy, then Lupron, then radiation, and then we saw an uptick in my PSA. Then I went to a second line hormone therapy with apalutamide, and saw an immediate response to that, which was great. I took a bit of a holiday in December of 2019, you can see at step 5 there.

Unfortunately, I had a biochemical recurrence at that juncture, but it became visible as soon as I went off of all hormone therapy. In August of 2020, point 6 on this graph, we discovered I had six metastatic lesions in my peritoneum. We did surgery, and then I started a combination of chemo and pembro. You can see my PSA began to drop during all of that.

I took six rounds of chemo and stayed on pembro for about 12 months. I began to see a bit of an uptick in September of last year. We did some more imaging and found I had 3 metastatic lesions in the peritoneum. Prior to that there were no visible mets after the surgery and after chemo. I am now on abiraterone. I have had a PSA decline from .9 to 1.45. Saed Sayad: What was the Gleason score?

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] Brian McCloskey: It was a 4 + 3, with grade 5. Ally Perlina: Thanks for having me. I hope what I have will be helpful. I spoke to Brian last year. We met virtually. I know there is a history of his getting a different CureMatch report in 2017. It was different data then, and there was different knowledge out there in the world.

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5]

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] You can think of CureMatch as knowledge representation and reasoning, as opposed to a machine learning kind of AI. We are not trying to make a prediction. It's more like scoring molecular fitness of treatments (therapies, drugs) to the markers of molecular type in each individual patient profile.

As our founder and chief medical advisor Dr. Razelle Kurzrock said, it's like a snowflake, everybody's cancer is unique.

“Drug Combinations Promise Precision” (Ally Perlina, CureM

e. The idea of her CureMatch brainchild that was born in 2015 was to be able to emulate molecular tumor board reasoning, with all the knowledge at hand, so that for any unique new case, even if some mutations have never been seen before

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] in the arrangement that they align in a give patient, no matter how unique a case is, if there is a way to therapeutically address or drug the target, then the match will be considered by our system. I'm going to tell you how it fits in the therapy-matching space, and then go to the reports.

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5]

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] We don't attempt to call variants or markers as pathogenic or not. We are not trying to assign the initial clinical interpretation and variant curation of significance the way that labs do.

We go next in line after an NGS report, and also consider molecular data on a proteomic or gene expression level from other types of reports. Unlike some companies that do a beautiful job of showing what are the known therapies associated with actionable markers, we also cover novel combinations.

We work with the over 300 or so available cancer drugs to consider the millions of ways to mix and match them into customized two-drug or three-drug combinations, which is what molecular tumor boards often recommend. They take drugs that are available and combine them in ways that have possibly not been tested in clinical trials or approved. But the drugs themselves are available.

The novel combinations cover about 99% of the top molecular matches for each patient. Brad Power: Can you please define some terms? NGS is for Next Generation Sequencing. They are typically looking at an oncopanel of about how many genes? Ally Perlina: We are not limited by the panel or number of genes that the lab looks at.

Larger panels from CLIA-certified labs may be better, but we will take any sample type, liquid biopsy or solid tissue, any company or lab that does NGS analysis, whether they interpret the results or therapies or not. We will take the molecular profile markers that are discovered, from DNA level or RNA level tests, and and will CureMatch that.

Brad Power: To get a sense of scale, one of these companies, like Foundation Medicine, looks at 200 or 300 genes, and then identifies variants in a half dozen or dozen markers that might be useful?

“Drug Combinations Promise Precision” (Ally Perlina, CureMatch) [#5] Ally Perlina: Usually what we see are 5 or 6 markers on average. When patients turn to CureMatch is when the decision is not trivial to choose from among millions of possible combinations to come up with the best combination of two to three drugs. Often this is too late. We hope that NGS will be ordered sooner and more frequently, and CureMatch will become the standard of care. We get quite complex cases. We see