Razelle Kurzrock, MD
@Dr_R_Kurzrock
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Momx7 (4 children; 3 dogs); wife; Precision/Rare diseases; MCW AD; CMO WIN; physician, not provider; Board CureMetrix/CureMatch (cofounder); opinions mine
San Diego, CA
Joined November 2016
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Important editorial by Mark Lewis in Journal of Immunotherapy and Precision Oncology. JIPO.
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I’m not a religious person— but I have to say that watching this— well, it looks engineered.
DNA to RNA real-time speed. Gene Transcription at real-time speed. Transcription is the first step in gene expression.
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Tumor-agnostic FDA approval
#8
When we submitted 1st tissue-agnostic clinical trial (investigator initiated) (MD Anderson ~2007), they said we were nuts—-not those words, but close—with persistence, we were able to do trial
And kudos to V Subbiah for pushing field forward
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Finally got a paper accepted in
Cancer Discovery! 😎
Will atezolizumab be next tumor agnostic approval?
Robust pan-cancer responses with TMB >= 16
MyPath trial— one of the best basket studies that I have had privilege to be involved in
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Predicting immunotherapy
Response
1. TMB =>10
2. MSI-H leads to TMB high
3. PDL1 IHC pos
Newer
1. PDL1 amp
2. ARID1a mut
3. SMARCA4 mut
4. LRP1b mut
6. High immune cell PD1
Other considerations
1. MHC
2. TCR
Resistance/hyperprogression
1. EGFR alt
2. MDM2 amp
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Hot off the press. Pancreatic cancer with SWI/SNF chromatin remodelling gene alterations respond to immune checkpoint blockade
Alterations in
SMARCA4
SMARB1
ARID1A
PBRM1
8 of 9 pts with PR/CR
Longest responses 33+ & 36+ months
Responders include MSS, TMB <10, PDL1 neg
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I am not a provider.
Patients are not consumers.
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Amazing!
Nine approved anti-PD1/Anti-PDL1 inhibitors
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Immunotherapy response predictors (checkpoint blockade)
1. High TMB
2. MSI-H
3. PDL1 IHC
Investigational examples
A. ARID1A
B. SMARCA4
C. MHC
D. PD1 on TIL
E. TCR repertoire
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I get on Twitter and find this really nice tweet. Thank you. My family, my patients and my mentees are the most important aspects of my life. I have been blessed
@Dr_R_Kurzrock
would never toot her own horn so as a proud mentee I will! I am so honored & grateful to work with and be mentored by her! She now has 900 peer-reviewed papers contributing so much to cancer care research & continues helping countless patients! Here’s to 900 more!
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Incredibly honoured to be giving a talk at the Nobel Symposium at Karolinska Institute, Stockholm
It’s in the Wallenberg Auditorium where Nobel prizes are announced.
The talks are so far phenomenal. Learning about precision medicine breakthroughs in many medical fields 🔥🎯👏
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EGFR exon 20ins
1. Classic EGFR inh resistance
2. In silico—>small kinase domain: most EGFRi too big; small poziotinib fits
3. Egfr exon 20ins causes dimerisation: EGFR Ab separates dimers
4. Amivantamab (now FDA approved)& cetuximab active
4. NSCLC on cetuximab: 4+ yrs PR
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2021 NCI Director Award
Very proud to be a recipient
DART clinical trial: THE national trial for IO of Rare Cancers
Open at almost 1000 sites
Almost 800 patients accrued
Serving unmet need of rare
Special thanks to SWOG, NCI team, Drs Sandip Patel, Young Chae, Elad Sharon
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Found in garage. Submitted this grant >10 yrs ago— bold new “transformative” ideas—bad score: —“world-class PI but inexperienced in targeted drug development; not innovative.” Funny, not funny. I was leading the world’s largest early phase dept and we focused on targeted agents
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I really enjoyed writing this piece with David Hong. The MD Anderson Cancer Center phase I dept that I founded/built is one of the largest and best in the world. Kudos to Funda and David for continuing to grow/strengthen it. The principles for success are counterintuitive.
Learn "How to Build a Successful Phase I Clinical Trials Unit", with customized tips from Drs Razelle Kurzrock and David Hong.
#phase1
#oncology
@MDAndersonNews
@Dr_R_Kurzrock
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Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial | Nature Medicine
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Ishwaria Subbiah, MD Joins SCRI as Executive Director for Cancer Care Equity and Professional Wellness | Business Wire
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Setting up KurzrockLab at McW.
With Raul Urrutia and Gustavo Leone.
Planning to decipher/uncover new matched therapies for our patients.
Precision medicine and rare cancers.
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First pediatric CAR T for ALL: 2012
Refractory
Supposed to go to hospice
Father had “whispered dream” she would be treated in Philadelphia and recover
Had severe cytokine release syndrome
IL6 high; given arthritis anti-ILR tocilizumab (repurposed, off label)
Just look at her!!
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Precision Immunotherapy
We’ve come a long way!
Nine checkpoint inhibitors now approved
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I hear criticism re FDA approval of high TMB for Pembro. I disagree. Our experience ~30% response rate. Some responses phenomenal— sixth line next stop hospice and now in CR for 2-4 years (micro-satellite stable). Life saving
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Hear ye hear ye!
FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors | FDA
Her2 3+
👉🔥🎯If it’s a marker, it’s a pan cancer marker: Tissue is not the issue
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Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity: Cancer Cell
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Mutation hot spots may not be targets because
1. They are passengers
2. They are produced repeatedly because of specific signatures such as APOBEC, rather than by selection
3. They are silenced at the RNA level
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Ahem. How about getting rid of the 100 eligibility criteria —only Olympic athletes with cancer need apply
Since the drugs will be used, if approved, in patients with co-morbidities, maybe such patients should be eligible for the clinical trials.
We need to identify barriers to clinical trial enrollment:
- Make trials less burdensome for participants
- Increase access for clinical trials by moving them closer to patients.
- Reimburse participant for direct and indirect costs for participating in studies.
#pancchat
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This is very important paper -Cell
It shows that combination therapy across a pt population usually has higher RRs because different subgroups are targeted by each drug— not synergy or additive effects
This supports our belief that combinations need to be individually tailored
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Trial types in the precision era
1. Basket: one gene, many tumor types
2. Umbrella: one tumor, many genes
3. 1 plus 2 combined
4. Octopus: backbone drug with combos, A+B, A+C, etc
5. Real world: computer download
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Many factors impact immune response: Jardim, KurzrockLab
1. TMB
2. Gene signature: UV, smoking, MSI-H, APOBEC, Aging..
3. MHC
4. TCR repertoire
5. Checkpoints used by tumor
6. Neoantigen processing
7. Genomic alterations-PDL1 amp, POLE, Etc
8. Immune infiltrate
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Pleased to share our analysis of MUTYH
MUTYH germline and somatic alterations are important for gene- and immune- targeted therapy 🎯🎯
International collaboration 🇹🇷🇹🇷
@UmutDisel
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👉How to Build a Successful Phase I Clinical Trials Unit: Lessons Based on the MD Anderson Cancer Center Experience | Journal of Immunotherapy and Precision Oncology
🫵Many of our points are not intuitive.
💥☄️Conventional wisdom not always correct.
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More whack-a-mole
@VivekSubbiah
68 yo man with GIST
Braf v600E mutation treated with dabrafenib and trametinib.
Response and then progression
Molecular profile showed BRAF and cdkn2a mutation.
Palbociclib added to regimen: triplet tolerated well
Response for near one year
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Homologous repair defect genes
Increase sensitivity to PARP inh and platinums
1. ATM
2. BRCA, BARD, BRIP
3. CHEK
4. FANC
5. PALB2
6. PP2R2A
7. RAD
Others???
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Cedar Sinai symposium on Personalized medicine
Who is that (thin) man in a suit giving terrific lecture on heme malignancies?
—-Aaron Goodman, MD.
Great talk!!!
Very happy he accepted invite to be featured speaker at conference.
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Triple negative breast cancer. S/p six therapies; next stop hospice; High TMB, MSS. Nivolumab, 4+ years CR (ongoing). MSI-H not needed with high TMB
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Clinical trials are being transformed. Here is our take on this (r)evolution
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Papa Heme-thanks for the recognition. I saw 2 sisters in their 20s with this previously unreported syndrome; we published it. Apoptosis had not yet been described, so the term used was myelokathexis. In reality, the PMNs were apoptotic because they couldn’t exit the marrow.
WHIM Syndrome (Wharts, Hypogammaglobulinemia, Infections, and Myelokathexis)
[Short PapaTorial]
#RareDisease
First described by Wetzler and
@Dr_R_Kurzrock
in 1990 [Wetzler. AJM. 1990]
Characterized by myelokathexis = mature PMNs retained in bone marrow and die (apoptosis)
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I made the list. Finally. :) Recipients - Highly Cited | Researcher Recognition:
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Reasons for missing the target
1. Tumor lacks target
2. Drug action different than presumed
3. Gene co-alterations drive the tumor
4. RNA silencing
5. Rescue mechanisms activated
Nature Cancer
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My Beautiful Boy | Journal of Clinical Oncology
Please everyone read this story. We must put an end to this illness.
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Molecular profiling enables personalized combination therapy: the I-PREDICT study, Nature Medicine:
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Honored to hold the Linda T. And John A. Mellowes Endowed Chair in Precision Oncology
Wonderful gift to move the precision medicine field forward.
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Gene of the day!
SMARCA4
ATPase for SWI/SNF chromatin remodeling
~6% of Ca
Hallmark of small cell ca ovary hypercalcemic type
Germline: RTPS2 (rhabdoid ca) (LOF); Coffin-Siris
Possible Rx: IO and BET, EZH2, HDaC, CDK4/6, FGFR inh, DNA damage repair, MOP and Aurora K inh
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Go killer T cell!!
A killer T cell of the immune system destroying a monstrous ovarian cancer cell.
#cancer
#science
#AACR23
Credit:
@RitterLab
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All patients had complete response. Treat early. Repeat. Treat early. It’s CML all over again. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer | NEJM:
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Another rare cancer success. 🦓🦄
Congratulations to Dr Michael Wagner, and our PIs Sandip Patel & Young Chae and our entire Early Therapeutics and Rare Cancers Committee/ NCI and SWOG teams
NCCN updates guidelines to include ipi and nivo immunotherapy for angiosarcoma 🔥🔥
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What Happens When All the Great Doctors Are Gone?
Nice tribute to Eli Estey, MD
He was a mentor when I came to MD Anderson
Very quirky. So many stories.
He also changed our family.
We adopted our youngest daughter inspired by his family.
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Hear Ye hear Ye! Wake up!! This is important! FDA Approves Pembrolizumab for TMB-High Solid Tumors
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Hyperprogression after immunotherapy: Hype or progress. Adashek, KurzrockLab Oncologist 2020 —> it’s real
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Precision Medicine World Congress
I am walking the hallways through the precision medicine world congress and I feel like I traveled from another galaxy and found my home planet. Everywhere are the words precision medicine, personalized medicine, patient care, multi-omics
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Hot off the press!!
I-PREDICT treatment-naive study
N-of-1 combinations for lethal metastatic cancers
Treat EARLIER
Multivariate OS, HR 0.42; p=0.02 for matching score (reflects degree of matching)
PFS and rate of SD>=6 mos/PR/CR linearly related to degree of matching
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Cholangiocarcinoma is the NSCLC of GI oncology
Multiple druggable targets
Another rare tumor that we hope soon bites the dust — not there yet, but moving in the right direction
🌟HOT OFF THE PRESS🌟in time for the weekend‼️ By the incredible
@OslerResidency
Amol Gupta,
@MCWCancerCenter
@Dr_R_Kurzrock
in
@Cancers_MDPI
our review on🎯targeted🧬therapies in cholangiocarcinoma‼️
'Is Cholangiocarcinoma the🫁‘NSCLC’ of GI Oncology'⁉️
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Tumor Infiltrating Lymphocyte Expression of PD-1 Predicts Response to Anti-PD-1/PD-L1 Immunotherapy | Journal of Immunotherapy & Precision Oncology
Our data: PD1 is better IO response predictor than PDL1.
Need validation.
We have one in the works
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I am seeing tweets re response being over rated; want quality of life. Agree if response is at toxicity cost.
But mantra taught me by my mentor, Dr Robert Benjamin at MD Anderson. “The worst toxicity is progressive cancer”.
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Missing the target in cancer therapy. Nature Cancer. Adashek’s great writing and title— play on words. KurzrockLab
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Hear ye hear ye! It’s not yet Friday, but here we go. FDA Approves Ivosidenib for Patients with IDH1-Positive Cholangiocarcinoma
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Our paper was reviewed from someone stuck in the year 1990.
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STK11 alterations in the pan-cancer setting: prognostic and therapeutic implications - KurzrockLab: HINT STK11 is prognostic not predictive
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Wheelchair/near hospice high TMB and PDL1 amp, now CR ongoing at four years. Metastatic basal cell carcinoma with exceptional response to anti-PD1 therapy | npj Genomic Medicine:
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CUP
Cancer of Unknown Primary
Multi-omics to “know the unknown”
Majority of patients have actionable biomarker
Customized combinations with high degree of matching of drugs to biomarkers correlate with best outcomes
Multi-omics is the diagnosis
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A successful marriage is all about the best match. Whether in life or in cancer therapy— targeted therapy, immunotherapy, hormonal therapy and chemotherapy.
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RAS was always “undruggable”
But the reality is that MEK inhibitors have activity, in particular with certain forms of RAS that have high functional MEK activity.
And in particular as part of combinations.
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Gripe. Plagiarism checkers should not include Methods sections. To reproduce results, Methods must be the same. Yet we are forced to perform verbal acrobatics to evade the plagiarism checkers
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The Marriage between Immunotherapy and Genomics.
Sung to the tune of
Matchmaker, Matchmaker
Look through your book
And find me the perfect Match
(Credit to Fiddler on the Roof)
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Basic principle. Find what each person is good at and passionate about and let them build it
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Hot off the press. Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy | 429 pts. Kato
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Hot off the press.
Featured gene: ARID1A
Chromatin remodelling regulates transcription
~20% of Ca have SWI/SNF chromatin remodelling mutations
~ARID1A is SWI/SNF DNA binding subunit
~6% of Ca have ARID1A loss-of-function mut
ARID1A mut —> immune checkpoint inh responsiveness
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The Nobel family.
Marie Curie: 2 Nobel Prizes (Physics and chemistry)
Pierre Curie (Nobel in physics)
Irene Curie (young daughter in pic would grow up to receive Nobel in chemistry)
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Another use for liquid biopsies!🔥🔥
When liquid and tissue biopsies have concordance t alterations, the outlook (survival) is worse.
This result is independent of %ctDNA.
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Look who I found at the TargetCancer meeting for rare cancers in Boston. Vivek Subbiah gave a powerful talk on clinical trials. He is leading the field forward.
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Most TMB high tumors are MSS
TMB high MSS respond to IO
Analysis of 148,803 samples
@AaronGoodman33
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Hear ye! Hear ye!
So is this the first tissue-agnostic, genomic based approval for hematologic malignancies?
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Vivek Subbiah, MD, Joins SCRI to Advance Early-Phase Clinical Research | Business Wire
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Microsatellite-Stable Tumors with High Mutational Burden Benefit from Immunotherapy | Cancer Immunology Research
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Randomized Clinical Trials Vs Database Analyses: JAMA Network
Shows they are comparable
Question. Which would you believe if they differ — real world database or RCT?
Also is it important to be able to source verify the database ??
I think so.
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Multi-Cancer Screening Tests: Communicating About Risks
Important Prasad commentary: must distinguish
1. Indolent Ca where screening makes no difference
2. Aggressive Ca where screening makes no difference
3. Ca where screening important
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Important. Increase response rates with combinations in unselected populations is almost always due to targeting different subgroups, not synergy. Cell
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Update. Time to retweet.
Patient still in CR at 6+ years.
Was end-stage triple negative breast cancer.
High TMB, MSS; treated with nivo
On our I-PREDICT study (Nature Medicine, 2019)
Example of under-utilisation of hospice.,
Thanks Dr Kato and Sicklick
Our protocol patient with triple negative breast cancer. S/p 6 therapies. Very advanced, end of life. Found very high mutational burden. Given nivolumab. Now in CR 2+ years later. Example of underutilisation of hospice :)
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ALK as another tumor agnostic marker? MyPath pilot for alectinib. Disease control rate = 60% in ALK rearranged including PRs in colon and pancreatic and uterine leiomyosarcoma. No responses in ALK mutated or amplified
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TMB is prognostic. Low & highest TMBs do best, regardless of therapy.
1. Low TMB, maybe because not too many drivers.
2. Highest TMB may do well because
A. Provokes innate immune response
B. Multiple mutations decrease cell viability
Riviere, KurzrockLab
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It’s out! Our work with liquid biopsy for car T cell response
Assessing CAR T-cell therapy response using genome-wide sequencing of cell-free DNA in patients with B-cell lymphomas - Transplantation and Cellular Therapy,
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Precision Medicine World Conference 2023
Honored to be recognized
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What is the diagnosis?
What are common molecular findings?
62 y.o. man with growing mass
Surgeon deemed it unresectable.
PET suspicious for internal disease
CR on nivolumab-based Rx; stopped for liver toxicity at 5 mos;
CR since 2017
Nikanjam. Annals of Oncology, 2018
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STK11 altered is prognostic, not IO resistance predictive
1. STK11=LKB1=serine/threonine kinase11
2. Tumor suppressor
3. May sensitize to PI3K/mtor inh
4. STK11 mut—>worse outcome regardless of Rx
4. Germline StK11= Peutz Jeghers = GI polyps & cancer & pigmented lips/skin
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Rare pic!
My daughter Rena and I at Chicago Field museum. 💕
We just finished the “what happens after death” exhibit.
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PD1 stronger predictor of IO response than PDL1. Our work was published in JIPO— incredible up and coming journal with editor Naing at its helm. Big thanks to Jacob Adashek for bringing this work over the finish line
OUT IN
@JIPOEditors
w/
@Dr_R_Kurzrock
@AaronGoodman33
, PD-1 TILs PREDICT RESPONSE TO ICB‼️ PD-1+ TILs in tumors associated w/ ⬆️mPFS (7 v 1.9 m;p=0.006) & ⬆️OS (18.1 v 8 m;p=0.04) post-ICB. Time to stop staining for PD-L1 and start staining for PD-1 TILs❓
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Hear he hear ye. It’s Friday so the FDA must have approved something... drum roll— drugging the undruggable Sotorasib Earns Accelerated Approval for KRAS G12C+ NSCLC
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The DART immunotherapy trial for rare cancers strikes again
CCR most cited 2020
Ipilimumab and nivolumab
44 percent response rate in high grade neuroendocrine
No responses in low grade
NCI SWOG
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Homologous DNA repair genes
ATM
BRCA1/2
BARD1
BRIP1
CDK12
CHEK1/2
FANCL
PALB2
PPP2R2a
RAD
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Sometimes I have to agree
Twenty years of randomized trials did almost nothing for pancreatic cancer.
Just published in
@TheLancetOncol
! In this essay, Chris Booth and I discuss how 25 years of “innovation” in the treatment of metastatic pancreatic cancer has barely budged the survival rates for this still lethal disease. Just moving the goalposts doesn’t mean patient outcomes…
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Treatment-related adverse events, including fatal toxicities, in pts with solid tumours receiving neoadjuvant and adjuvant immune checkpoint blockade: a systematic review and meta-analysis of randomised controlled trials - The Lancet Oncology. Fujiwara
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Hot of the press!!
Subbiah
@VivekSubbiah
and I share our view.
Universal germline and tumor genomic testing needed to win the war against cancer: Genomics IS the diagnosis.
JCO 2023
🚨HOT off the press
@ASCO
@JCO_ASCO
👉 Delighted to share our Opinion in COMMENTS & CONTROVERSIES section
✅Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: "Genomics Is the Diagnosis" 🎯🧬
@Dr_R_Kurzrock
@oncoalert
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FDA Grants Multiple Breakthrough Therapy Designations to Trastuzumab Deruxtecan— will this be tissue agnostic — hitting the Her2 target and with a payload 🎯🎯
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Fascinating!!
New type of “hereditary” cancer (NEJM)
Maternal to fetal transmission from cervical ca (including without overt cancer in mom in one case)
Children showed cancer at age 2 and age 6— huge delay
Sequencing shows it is mom’s cervical cancer
Nivo for CR in one case
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