ALKtALK with Dr. Ross Camidge

Editor’s Note: A special thanks to Marc Rosenzweig for creating and scheduling the ALKtALK programs. Alice Chou graciously committed her time to transcribe the January ALKtALK with Dr. Camidge so that it would be available here on our blog for other ALK patients.. Thank you so much Alice Chou for your hard work and generosity!! . . and a big thank you to Dr. Camidge for spending his Sunday evening with our group answering these questions.

Dr. Ross Camidge, Professor, Medical Oncology, Aurora, CO

GENERAL QUESTIONS:

Q: Should we get the Covid-19 vaccine if available to us?

You should get it as long as you have not had severe allergic reactions to other vaccines. Every state has its own policies that dictate who can get it and when. Please follow your state’s guidelines.

Q: Would you recommend radiation/chemotherapy before TKI treatment? Does that help one to get a better response?

If you are one of the good responders, you will get good response with all treatments.  Evidence with EGFR patients has indicated that if you have chemotherapy or radiation treatment before TKIs, there’s no overall survival benefit, however you do get slower progression.  There was a small study in India that indicated a small overall survival benefit. However, this could also be due to location, healthcare, and other regional differences.  A study (randomized trial) is being done in EGFR patients right now. What is next is unknown.

Q: Explain differences between PET/CT vs PET? Which one is better? Frequency of CT/PET/brain MRI? Lung only? Abdomen? Pelvis?

Current technology is that a PET scan is on a PET/CT machine, so you cannot just order a PET scan on its own now.  All are PET/CT. PET is a CT from the base of brain to the lower body. Glucose is labeled to be visualized in a PET. It will show inflammation areas as well. Other times, I use CT with contrast and the exam should go through areas of disease such as the abdomen or chest when appropriate.  Pelvis CT contains higher dose of radiation because of its location/structure.  So, unless there is progression near the pelvis regions, I do not order a CT of the pelvis. MRI with contrast for the brain is usually done once per year if there was no prior progression.  If there are known brain mets, I would follow every 3 months and eventually every 6 months to monitor.

Q: After starting a TKI, what is the “maximum” time for reduction of lesions?

The time frame we are looking at is usually about 6 weeks after starting a TKI. Some patients may not react to TKIs (about 10-20%). If the lesion looks better, the next examination should be 3 months after that.  If two of the scans looks similar in lesion size, then that is your maximum response time.

Q: Does immunotherapy hold good promise for ALK patients?

One class of drugs such as PDL-1 inhibitors (Opdivo and Keytruda) holds a big promise for lung cancer. However, there have only been 2 known ALK cases out of many that I have researched to have shown any positive outcome. PDL-1 is a gene that is downstream of ALK and ALK’s effectors.  So, the high level of PDL-1 found in ALK patients is not a reliable indicator of good prognosis if using immunotherapy of this class.  No immune cells are found going in/near ALK tumors.  The ALK-positive type of cancers is not very immunogenic to begin with. Another class of immunotherapy may hold better promise.

Q: Alectinib was found in Japan and there were clinical trials in China. How much cooperation is there between international researchers? Who are the top researchers/doctors?

Thoracic oncology is a specialized field. The history of lung cancer has been depressing for a long time. Just 20 years ago, people motivated to make a difference went into this field, kind of a Cinderella specialty.  This is a very collaborative field, in all locations.  There is some healthy competition.  However, a line is drawn when a patient becomes the most important thing.

As to who is the top researcher/doctor? It is in the eye of the beholder.  Each country is very different. There are various metrics in healthcare.  Australia, Japan, Germany and China all have very good results. Some very promising research has come out of Japan and Germany.

Q: Do you do serial NGS (next generation sequencing) biopsy at each progression? Can you just use tumor markers? Or only biopsy?

 Tumor markers can give you similar types of information.  NGS is like a shiny new toy. The goal is the correct interpretation of your situation. You can still use scans or tumor markers and they are cheaper.

Q:  When you are on a standard dose of a drug and have responded well and have side effects that are manageable but could be better, can you/should you reduce the dose? Or should you stay on the full dose even with the side effects?

People are afraid of reducing their dose. It is the mentality of “No pain no gain”. However, if you look at the dose reduction rate, you will realize that dose reduction may still be okay.

When you progress on the drug, the cancer’s sensitivity to the drug reduces about 1000X fold. Tumor growth is not because you reduced the dose. It is because resistance was already present in the tumor.  To go back to a higher dose will no longer affect the tumor the same way.  Resistance has already occurred.  One exception is in the brain. For the majority of the TKIs, only a portion of the drug gets into the brain. Loraltinib may be one of the exceptions. Don’t worry about reducing the dose in the body if you have hard side effects.  If you have progression, it is not because you reduced the dose. But, if you are on a reduced dose and have progression in the brain, then go back on the higher dose.

Q: Where is the current research on pregnancy on a TKI?

This is a sector of research that we are still working on. Not surprisingly, it has not been well explored. There are two school of thoughts: 1) we don’t know much so the safe thing to do is: do not try; Or 2) we don’t know so you can go ahead. If you are a female ALK patient, using TKIs may interfere with embryogenesis.  An early enough embryo may just be aborted even before you take notice (in theory).  For a male patient, it might be okay.  But, there’s a lot of paperwork that needs to be completed if something like that happens. I know a few patients who have managed to have an ALK baby!  Details of those cases need to be the written up as case studies. I know male patients who have had kids. Do not try though because that’s a lot of paperwork for me. Female patients have started a family with egg donation (surrogate) or adopted. More needs to be studied on this aspect of ALK treatment.

Q: I have an oncologist without expertise in ALK. Should I consult with ALK expert? What is a good time: when all is well or when we hit a bad situation?

I would recommend doing it later. I would like to allow someone to gain experience in ALK. This way, we can empower local oncologists!  I believe when you consult with me as a 2nd opinion, I work for the patient.  If you like, I can work with your local oncologist. My preference for 2nd opinions is to work with the patient or the patient plus the oncologist.  I do not like to have the consult behind the back of the local oncologist.

Q: What about TPX0131, a next generation ALK inhibitor by Turning Point Therapeutics?

This is a niche area of resistance because it works on compound mutations where two mutations are next to each other.  It is not very common. It occurs more often now because we have sequential TKI administration. When we have better inhibitors such as Alectinib or Loraltinib up front, it will become even less common. This therapy may not be as useful as time progresses. You have to start thinking: do I have a second driver? You need to chase down what is actually driving the cancer.

Q: I have been on Crizotinib for 6 years. I just had some radiation last April. What should be my next treatment option?

If you have progression in brain? No change. It is awesome for you! If progression is in the body and is isolated, zap it! If there’s too much or coming too frequently? Go on Brigatinib because it provides longer progression-free time after Crizotinib.

Q: What is some ongoing research on what causes ALK cancer?

ALK cancers are due to a fusion. There are two competing theories right now. Theory 1: Radiation/radon exposure smashed a chromosome and just smashed the wrong one up accidentally.  When the DNA’s mechanism tried to join the broken-up pieces, they did it wrong. Theory 2: A virus can integrate into the DNA and when the viral DNA pops in/pops out of the DNA, it carries the DNA with them, fusing various pieces of DNA together.  Why would there be viral DNA? There are viral DNA pieces in our genome that that could be a legacy of something that happened way in the past. How do you prove the theory? The viral theory is not provable. Some researchers have tried to prove/or disprove the radon theory.  A group in France has tried to look at radon gas vs. frequency of lung cancer retrospectively. They found it may be more likely but not statistically significant. It is NOT the radon in your house. It could be where you could have been!  I have a better suggestion. In Colorado, there is a collection of lung cancer samples coming from uranium miners.  I have been trying to obtain these samples and use modern molecular techniques on them. Since this population is often smokers, I am assuming it will be a low incidence of ALK lung cancer. If there’s a high ALK lung cancer, it may be proof positive that radon can be a cause. Ask me again later.

Q: Could using X-ray for healthcare professionals have something to do with developing ALK lung cancer?

There are many possibilities for healthcare professions.  Did they walk the wrong way and pass the X-ray machine? Or it could be because medical professionals know what kind of questions to ask and seek second opinions more often. I do not know.

Q: Is there any progress on the treatment of bone mets?

If you have ALK positive and bone mets, the oncologist will put you on a TKI plus a medication such as Zometa or Xgeva. You don’t need it. Bones will heal themselves. I have been treating lots of patients and no one has had bone fractures in 10 years.  I do not give Zometa or Xgeva.  You have to treat the cancer, and the bone will heal itself.   We have a study of testing for markers of bone repair in people on TKIs vs. people on the TKI plus medication on bone healing.  Study to come.

Q: How do you see tell the difference between a scar tissue or no evidence of disease?

PET scan or biopsy.

Q: Do you believe a certain diet, such as plant diet, can fight cancer?

I believe a diet changes how you feel and how you cope with your situation. Data that shows diet can change your outcome is controversial.  It is an area that is very hard to study.  Many of the data can be circumstantial. It might be very hard to remember what you just ate last night. We are also very bad at changing our diet. If you have more fresh fruit or vegetables, you generally tend to feel better.

Q: Do you recommend chemotherapy between TKIs before going onto another TKI?

Only do chemotherapy when you do not have a personalized medicine approach.  If you do not have any more TKIs to try or if you have a 2nd driver and there’s nothing to use for that. Then I will use chemotherapy. Now, there is a group in Cedar’s Sinai that uses chemotherapy to drive the cancer cells down just like the way we use radiotherapy.  But that is the exception. 

If you are a super sensitive responder, you will do well. If you do well, you will do well!  It is probably not due to adding chemotherapy in the middle of the treatment.

Q: Right now, the reference is about 6.8 years of survival. What do you think we should research to increase that length of survival? Do you recommend TKI+LCT for someone newly diagnosed?

If you are on a TKI and it is controlling the cancer well, then the survival number is just a number. Resistance is just more than treating at the primary location.  MD Anderson had a study where they treated locally after the TKI had reached its maximum response.  It seems to be beneficial.  So, yes, please do LCT (local consolidative treatment) if possible after TKI, by radiation.

ALECTINIB QUESTIONS

Q: If taking Alescensa at 1200mg, there’s some scarring and volume loss but cancer has been stable for 2 years, is it possible to reduce Alescenca at this point? Should we go in for a consult or wait until progression? How do you use tumor markers?

Serum tumor markers are different than mutations in the gene. The best known serum tumor marker is PSA for prostate cancer.  I usually order: CEA, CA125, CA199, and CA2729.  Those are markers known for colon cancer, ovarian, pancreatic, and breast cancer.  However, having a high value of these serum markers does not necessarily mean you have that cancer.  They can be put out by many cells. I monitor CT scans and tumor markers.  If the CT scan is clean but the markers are increasing, I will look more closely by ordering a PET scan.  If you have oligo-progression, it is easier to pick up by using tumor markers.

Q: If I was on Alectinib 1200mg but reduced to 960mg. I saw an increase in SUV but no increase in the size of my tumor. Would you think the same thing would have happened if I did not change dose?

There would have been no difference! The change has already happened.

LORLATINIB QUESTIONS

Q: If Lorlatinib becomes first line, what happens when you progress on it?

When Loraltinib becomes a first line treatment drug, it does not mean the oncologist has to use it as a first line drug. We know its side effects are stronger than those of other TKIs. It is up to the oncologist to determine what is best for you.

What if you progress on Loraltinib? We really do not know at this point. A potential second oncogene driver can be the culprit, like MET. How you find the other secondary driver? There’s more that needs to be researched to find secondary drivers.

Q: If a patient progresses in the brain and is currently on Lorlatinib and no more brain radiation can be given, what’s next?

Lorlatinib has good brain penetrance, however sometimes brain mets will still arise and you have to continue to scan the brain even on Loraltinib. In the future, we can initiate a lumber puncture to look for any mutations in the fluid.  However, at present, you can see what dose of Lorlatinib you’re on. Do you Increase the dose? If you can tolerate the dose, go up to 125mg to increase drug penetrance.  Perhaps add in another drug such as Avastin to help. Oral chemo for brain tumors such as Temodar is okay to use with Lorlatinib, however it can cause some blood count issues.  

ALTERNATIVE RESISTANCE QUESTIONS

Q: How frequently do you see MET as a resistance mutation? What is the difference between MET amplification vs MET mutation?

The trouble with MET is because the MET signaling cascade can turn on EGFR or ROS1 and can be turned on in a number of ways. There are MET fusions (rare).  MET mutation skip14 (5%) is seen as well.  MET amplification means that multiple copies of MET are seen. The problem is that it is a continuous variable, not a simple on or off.  It depends on where you draw the line - the frequency of when a MET mutation (that matters) occurs in a cancer is about 5%. It may be overcalling it.  One interesting thing was when a cell line was derived by a patient who was on Brigatinib. They had no MET amp, no MET mutation, or any MET fusion.  Yet, when we grew these cells, MET turned out to be the mechanism that the cell line grew. There is a way that MET can be turned on, but we do not know how it is turned on! There are unknown ways to turn on things and we do not know the method to detect it yet. NGS is for MET fusion or MET skip mutations. But you need a FISH test for MET amplification, and not everyone can do this test.

FURTHER RESEARCH QUESTIONS

Q: What about CRISPR gene editing in ALK?

CRISPR is a gene editing technology. It is very useful in a laboratory setting. Can you do it in a person? NO. There are cases where you can use it outside of a person, then put the edited cells back into a person. Then, yes, it is the essence of gene therapy, however we are just starting to do that.  For single gene disorders, such as sickle cell disease, they are trying it in young kids. No one is trying something like that for a complex disease like cancer, yet.

Q: What kind of therapy modality would you like to see further studied for ALK? Ideas such as protein degraders? Vaccines?

There’s always something new to talk about. Skill is needed to be able to sort everything down to a more manageable short list of things to try. I think of it like three buckets.  One bucket for crap. One bucket for very promising items. And there is a third bucket of undetermined items to keep an eye on. Filtering everything down to only three things to do and try to get it done.

For protein degraders, you bind something to the protein so you tag it and throw it out like the garbage.  I like the idea of it. This technology can allow targets that are hard to target in the first place. However, can you degrade enough of it so it matters? If you have 500 million proteins in the cells and you drop it down to 480 million, does it help?  So, how to achieve therapeutic levels is interesting. Maybe you can use this technology in conjunction with another method.

Natural killer (NK) cells is a kind of an immune-based method.  It is kind of in its infancy. What will allow cells to be detected and dragged to these cells?

There was a reason why Pemetrexed and chemotherapy was very useful.  However, the main team in the pharmaceutical group was dismantled years ago.  This class of anti-folates is very useful.

Antibody conjugates, where chemotherapy can be directed to the cancer cells. It is a very interesting option because you can give less chemotherapy drug but it will be more at the tumor cells locally, making it easier to tolerate.  Anti-folate class chemotherapy to be used with an antibody conjugate is an area that might be interesting to be explored.

I would also like to see some radio-pharmaceuticals be explored where you would take these things instead of being radiated. Radiation targeted to the tumor sites instead of radiation from the outside.  These are all interesting ideas to be explored.

Q: From all research right now, what do you think would provide a cure? Or turn ALK into a chronic disease?

Right now, cancer is considered a chronic disease.  It was an insane goal 15 years ago. Hold on to that. TKIs have an amazing response right now. But we know if there’s no TKI, then the cancer will start to grow again. If you go back on the TKI, the cells will go back to sleep. Cancer seems to be like in three states: cancer dead, cancer growing, or cancer dormant. What we need is to target dormant cancer for a cure! That is where progression occurs. A group in UCSF and partly by us, are doing early re-biopsy to see what’s left. About 20-30 patients did it. What is that dormancy survival pathway. If they can find something that can target it. The treatment does not have to be well tolerated.  You can go through hell for one day but be cured. You can go from 99% cell kill to 100% cell kill, awesome! Cure!

Q: What about clinical trials with combination projects of two or more drugs?

The right people are looking into it.

Q: How do you accelerate research from big pharma past phase 2? Is there some biotech company that we should be watching?

Sounds like an investment strategy!  Right now, our system may be broken.  If you look at 10-20 years ago, a lot of research was driven by cooperative groups. Government funding was there.  Now, most cooperative groups are underfunded.  Instead of competing with pharma, they are better at addressing fundamental questions that is not being addressed by big pharma.  The big pharma is capturing the narratives and its direction of study is being pulled by big pharma.  Some really good academic oncologists are being lost to big pharma.  Something is fundamentally wrong.  Even if you are in a lab, about 90% of the time you will not be funded.  If you are lucky and it is funded, you are underfunded. 

If you want to watch the entire video, this is the YouTube link. The questions have been organized and are not in the same order as on the video.

 Compiled and transcribed by: Alice Chou