CNS Metastasis - Is There a TKI?

We strongly recommend you listen to our previous episodes metastatic lung cancer (Episodes 0032 and 0033) to better be able to follow along with this conversation. Key trials mentioned in this episode include:

CHECKMATE 227

KEYNOTE 024

Q:Do you send molecular testing (PDL1 and NGS) on the biopsy, peripheral blood or both?

* Yield is highest from the tissue sample

* Peripheral blood (circulating DNA) samples are dependent on the burden of disease and so often the yield is lower

** One of the benefits is that it can be sent quickly and having a fast turn-around; Tissue samples are dependent on being able to schedule a biopsy

* Dr. West says he definitely sends this on a non-smoker with non-squamous lung cancer, as they are more likely to have molecular targets

* Dr. West has not personally adopted the idea of sending peripheral and tissue samples for NGS testing for everyone

Q: Do you ever use Ipi/Nivo in patients with PDL1 <50% (ref: CHECKMATE 227)?

* There are a lot of other options so he does not use this, as it is harder to predict the side effects with therapy like this

* “Chemo-free does not mean side-effect free”

Q: We understand there is a lack of randomized trial data on the use of consolidative radiation after IO based treatment in the metastatic setting. If patients have a good response to systemic treatment, when do you consider using consolidative radiation for cure?

* A systemic therapy that is effective that leaves you with oligo-residual disease, radiation can be considered for the right patient

** We need to balance what a radiation oncologist says he/she can radiate vs. what is actually the right thing to do

** Sometimes, it’s best to give the cancer some time to “declare itself”.

* A nuanced discussed, but it may be worth considering especially in patients who have disease that is

** (a) growing at a clinically meaningful rate

** (b) in patients with a few sites of disease, but otherwise great control

* This is much more effective in patients with driver mutations being treated with TKIs with oligo-residual disease

Q: Do you ever give chemo along with IO in patients with PDL1 >50%?

* KEYNOTE 024: First study to show that IO was superior to chemo in high PDL1 patients lead to an instant change in our approach

* More recent data suggests that there are differences between patients with PDL1 90% vs. someone at like 50, 60, or 70% (not all PDL1 >50% is created equal!)

* If there is a patient with a lot of cancer burden, a lot of symptoms, and rapid progression of disease, you don’t want to miss an opportunity to do what is best for the patient. There is always a chance that IO may not work as monotherapy. This is a case-by-case discussion, but in cases like this, he discusses with his patient about using chemo + IO

** Essentially attacking the cancer from multiple angles

Q: In patients with positive driver mutations who are initially stable on treatment, but then progress, do you repeat molecular testing at the time of progression? Do you ever treat with two TKIs at the same time?

* Dr. West referenced recent abstract at ESMO 2022 by Dr. Julien Mazieres from CHU de Toulouse in France who presented data regarding the use of MET inhibitor tepotinib with osimertinib:

** In the study, when screening for MET amplification, about 36% of patients were positive; at 9 months, the response rate was 54%

** One limitation of this study is that every company that tests for MET amplification has a different definition of what constitutes “amplification”

* Otherwise, there is mixed data about this

* Molecular testing is often done on repeat biopsies in many academic centers, but that is not universally true and not the standard of care

Q: TKIs have great CNS penetration. Let’s say a patient achieved a CR of CNS metastasis, but has progression of disease elsewhere. Do you continue the TKI?

* He prefers, in general, to continue TKI given great CNS penetration while adding chemotherapy for other systemic metastatic sites

** This is more expert opinion, not well-studied

* Flare phenomenon can happen, meaning that abruptly stopping TKI may allow a clone of the cancer to begin rapidly growing if this subset of disease is responsive of treatment

* Remember: Not all mutations are created equally

** You DO NOT want to give EGFR and/or ALK IO even if they have a high PDL1

** On the other hand, patients with KRAS and BRAFV600E do respond to IO treatment

About our guest:

Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women’s Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD

References:

https://www.nejm.org/doi/full/10.1056/nejmoa1606774 - KEYNOTE024

https://www.nejm.org/doi/full/10.1056/nejmoa1910231 - CHECKMATE227

https://oncology.medicinematters.com/esmo-2022/non-small-cell-lung-cancer/insight-2-tepotinib-osimertinib-advanced-nsclc/23480600 - ESMO 2022 abstract on tepotinib with osimertinib

https://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy - Episode 032

https://www.thefellowoncall.com/tfocpodcast/jt7mmp342rn85wy-stczg - Episode 033

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