TDM1 for HER2+ brain mets reocurrence?

[karina14]

Has anyone tried TDM1 after brain mets reocurrence? My initial treatment was WBR 9 months ago, the number of mets is large, currently I am only controlling the extracranial disease with Herceptin & Perjeta. I have not done Lapatinib + Capecitabine yet and have not looked into IT Herceptin yet (as I see it is only for lepto-meningeal mets). Thank you for all the guidance and help!

[Lani]

Clin Breast Cancer. 2014 Oct 19. pii: S1526-8209(14)00223-7. doi: 10.1016/j.clbc.2014.10.003. [Epub ahead of print]

Brain Metastasis and Response to Ado-Trastuzumab Emtansine: A Case Report and Literature Review.
Kalsi R1, Feigenberg S2, Kwok Y2, Tkaczuk K1, Mehta M2, Chumsri S3.
Author information

KEYWORDS:
Ado-trastuzumab emtansine; CNS metastasis; HER2; Lapatinib; Radiation
PMID: 25454740

[rhondalea]

You can rent that article for 24 hours for $9.50 or 3 days for $14.50 through RightsLink. You'll have to create an account first if you do not already have one.

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If that link gives you trouble, go here:

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Then choose the little link below and to the right of the purchase box that says "Get Rights and Content." It will take you to the correct page, and you can make your selections. Many times, you can get these articles free through RightsLink, but in this case, if you decide to purchase it ($39.95), just go through the main page, because the RightsLink purchase price is higher ($55.20).

[Lani]

thanks rhondalea

I have always been particularly lousy @ providing links (although I have improved a bit over the past 9+yrs I have been posting)--thank goodness you are there to make up for my lapses

[rhondalea]

You just keep doing what you're doing, Lani. Slogging through all those papers is the hard part. Finding clicky links afterward is a walk in the park. This site would be much diminished without your input, and we are privileged to have it. Thank you for all that you add to the experience.

[sassy]

Thanks to both of you for your invaluable sharing of information and assistance to all our members.

[karina14]

Thank you for the link and info how to get to it. I have found it earlier but with the empty abstract. I hope I will get to the trial, looks to have very new info re-TDM1 and brain mets

[waterdreamer]

While on TDM-1 I had two brain mets on two separate occasions. I did Novalis radiation at UCLA and it has now been 1 1/2 plus years with clear brain scans. I would suggest a low carb and sugar free diet (including the sugary fruits - if you can do that) Lots of vegetables. That is just my experience.

[Rolepaul]

Univ of Southern California might have IT Perjeta available soon. Word is IT Herceptin is also going to get deep brain lesion approval soon. I will try to see who to contact for these and get back to you. Two to four deep brain IT Herceptin success stories are available, but steroids are an absolute need due to brain swelling from the cancer cells dying.

[karina14]

Thank you, Rolepaul. IT Herceptin or Perjeta to go to deep lesions is probably what I need. My tumors are not in lepto area but cerebellum and deep. The bad is that there are too many, so wbr was the only alternative both times. I finished second round radiation and next step in plan before is to start TDM1 in March as there are few success stories (they want to wait for the follow up brain MRI). But if IT Herceptin is probably a better solution if they can get it beyond the lepto area. The probably have a different device?

[Rolepaul]

Same device. The drug will make it to the tumor areas. IT is just convincing doctors to try. Steroids are very important as the Herceptin activates the white blood cells to go after the cancer cells. TDM-1 systemically will penetrate the BBB at maybe 5% of what is in the systemic, but that might be enough to slow things down.

[vqtilley]

Thanks to everyone and especially Rhondalea for your kind advice on accessing the 2015 Kalsi review article on Kadcyla and brain mets. Prowling around Google I was able to access it free via Research Gate (RG). You have to be a published scholar to get on RG -- any academic field, apparently, because mine isn't medical -- but once you're there, Kalsi et al have posted their article on their RG page and it's downloadable. I wish I could provide a link but it's firewalled. Here are some highlights. Note: This article is based on a single case study of a 28-year old woman with BM who progressed on everything until she took TDM-1, but includes a short background summary of research to date including EMILIA. One important bit here is the possibility of avoiding WBRT and the very low incidence of new brain mets while on TDM-1. Another is the suggestion that TDM-1 without the more toxic lapatinib and capecetibine, although that combo is powerful, appears to be efficacious: only 2% of patients on TDM-1 with BM at baseline developed CNS disease. BTW, I've gone back on letrozole due to its relatively strong BBB penetration and unclear early MRI signals of leptomeningeal spinal disease - hope the combo works.

Brain Metastasis and Response to Ado-Trastuzumab Emtansine: A Case Report and Literature Review
Richa Kalsi,1 Steven Feigenberg,2 Young Kwok,2 Katherine Tkaczuk,1
Minesh Mehta,2 Saranya Chumsri3

... "Preclinical studies showed that lapatinib can penetrate the BBB and significantly decreased phosphorylation of HER2 in metastatic CNS lesions.10 Based on these results, a number of prospective clinical trials were conducted to evaluate the efficacy of
lapatinib in controlling BM (summarized in Table 1).11-17 Despite the promising preclinical studies, lapatinib monotherapy seems to have only modest CNS activity. In a large multicenter phase II study,12 there was only a 6% CNS objective response rate (ORR) with single-agent lapatinib. In the extension part of this study, the
addition of capecitabine to lapatinib increased the CNS ORR to 20%. Subsequent studies confirmed the CNS activity of this regimen with the CNS ORR ranging from 18% to 66% (Table 1). Based on the promising activity of this combination and the fact that WBRT is associated with the risk of neurocognitive dysfunction, in the LANDSCAPE trial upfront treatment with lapatinib and capecitabine before WBRT was evaluated.16 Interestingly, almost two thirds (65.9%) of patients had a CNS objective response to lapatinib
and capecitabine without WBRT. The median time to progression was 5.5 months for systemic and CNS progression.

... "More recently, the retrospective analysis of the EMILIA trial, a phase III trial comparing T-DM1 with lapatinib and capecitabine, showed that the incidence of BM was
quite low in both treatment arms (1.8% in T-DM1 and 0.6% in lapatinib and capecitabine). Furthermore, among 95 patients with BM at baseline, only 2% who received T-DM1 and 1.6% who received lapatinib and capecitabine developed CNS progressive disease during the study. The median PFS in patients with BM at baseline was similar in both groups (5.9 months in the T-DM1 and 5.7 months in the lapatinib group; hazard ratio [HR], 1.0; P ¼ .9998). Similar to the result of the whole trial,5 the median OS was also significantly longer in patients with baseline BM treated with T-DM1 compared with lapatinib and capecitabine (26.8 vs. 12.9 months; HR, 0.382; P ¼ .0081).26

"Despite disease progression during multiple lines of systemic therapies including trastuzumab, pertuzumab, and lapatinib, our patient had a striking CNS response with T-DM1. A similar phenomenon has been reported in another case that described a patient who also showed significant CNS response to single-agent T-DM1.27 Based on the striking CNS response seen in these patients and the retrospective analysis from the EMILIA trial, it seems that T-DM1 might have the ability to cross the BBB and effectively target BM." ...

CONCLUSION

"Although targeted therapies such as combinations of lapatinib or trastuzumab have demonstrated some efficacy in the treatment of BM, the options available for these patients remain limited. This further emphasizes the immediate need to explore other options and conduct further preclinical and clinical research in this field. In addition, patients with progressive CNS metastases face diminished quality of life due to neurocognitive and/or neurologic decline. T-DM1 appears to show CNS and non-CNS activity and has demonstrated better tolerability. With its favorable side effect profile5
and known efficacy in the treatment of systemic metastasis of HER2þ breast cancer, a more rigorous investigation of its activity in the CNS is necessary. Moreover, the combination of these systemic therapies with stereotactic radiosurgery as a way to safely defer WBRT should also be further evaluated as a way to potentially improve quality of life by minimizing neurocognitive dysfunction. Finally, even in patients who require WBRT, combination approaches using these BBB-penetrating anti-HER2 therapies need to be investigated further."

[Rolepaul]

Short term studies that do not look at long term resolutions. TDM-1 systemic did slightly improve the Brain MRI haze, so there is some penetration, but prior to IT Herceptin there was steady progression in Nina. She had survived two years from the initial discovery of a 6 cm diameter by 0.5 cm thick spot. By this study, she was a success. But she would be dead three years ago. Same with many of the women that have had their brain mets not resolved by surgery or Gamma Knife. Tykerb and Xeloda do help, but the side effects are severe and they are not permanent. IT Herceptin may not be permanent either, but it appears to be giving tens of months to years of survival versus five or six months. The number of patients in high dose studies is limited, but the results are pretty promising. And a Traumazamab/Pertuzumab combination IT may be the long term resolution to put the disease into remission.
Right now, I would not change Nina's healthcare treatment from what we did. Excision, then stereotactic radiation, Xeloda/tykerb, and now IT Herceptin. She is not the $6 Million Woman, but she is at least $2 Million Woman. But I wish the oncologist would have done the brain MRI in 2006 or 2007 like we asked, as it may have allowed attacking the lesion when it was smaller.

[vqtilley]

Thanks, Rolepaul, and yes, longer term outcomes are vital & often omitted. But are you saying that Nina was the case in the Kalsi article? Not sure but she doesn't sound like the same case, reading the article - this case had WBRT, for example. Certainly resectable BMs appear statistically to respond best to treating first with resection/radiation, which for me was gamma knife, followed by systemic therapy, but the question is which meds and when. I'm aiming for IT Herceptin when my leptomeningeal disease kicks off: there's a clinical trial at Northwestern and friendly med oncs and radiation oncs ready to help me. But postponing that step is highly desirable presently, as I'm seeking hip replacement surgery in May for my sometimes debilitating femur lesion, which the IT treatment would preclude, while still working and trying to have a functioning brain, so any info on BBB penetration and BM efficacy by Kadcyla & letrozole is important at this stage. Very interesting about IT Trastuzumab combined with Pertuzumab: will follow up.

Below is an extract from the Kalsi article profiling the case study:

Case Report
A 28-year-old female presented for treatment of unresectable inflammatory
breast cancer that was positive for estrogen (90%)
and progesterone receptor (40%) with high Ki-67 (> 90%), and
HER2þ. She initially received 6 cycles of TCH (docetaxel, carboplatin,
and trastuzumab) and progressed during this therapy.
Subsequently, she was referred to our institute and was treated with
multiple lines of therapies, including the combination of a panhistone
deacetylase inhibitor, vorinostat, and lapatinib in a phase II
trial followed by ixabepilone, trastuzumab, and lapatinib. She had an
excellent response and was considered for surgery. However, the
patient was lost to follow-up and presented several months later with
lymphedema due to lymph node progression. At that time, she was
found to have multiple asymptomatic BM and received whole-brain radiation (WBRT), palliative right breast, and ablative ovarian radiation
to a total dose of 20 Gy (in 8 fractions of 2.5 Gy per fraction)
because of transportation limitations for a longer treatment course.
Three months after completion of WBRT and during fulvestrant,
trastuzumab, and lapatinib treatment, she developed progressive BM,
andWBRTwas repeated to a total dose of 20 Gy, also in 8 fractions of
at 2.5 Gy per fraction. She subsequently received multiple lines of
trastuzumab-containing regimens, including gemcitabine, eribulin,
and vinorelbine. Approximately 5 months after the second course of
WBRT, she developed further intracranial progression and underwent
frameless stereotactic radiotherapy to the 2 symptomatic lesions
in her brainstem and left cerebellum, and received 18 Gy in 3 fractions.
After approval of pertuzumab, her treatment was switched to
pegylated liposomal doxorubicin, trastuzumab, and pertuzumab
during which her disease progressed systemically after 3 cycles. The
treatment was switched to T-DM1 and after 3 cycles, her follow-up
brain magnetic resonance imaging (MRI) scan showed a striking
central nervous system (CNS) improvement, including several lesions
that did not receive radiosurgical treatment (Figure 1). The superficial
and deep enhancing metastatic lesions in cerebral and cerebellar
hemispheres, and the brainstem all decreased in size. The largest cerebral
lesion in the thalamus decreased from 20 mm to 9 mm and the
largest cerebellar lesion diminished from 25 mm to 20 mm. The
edema and original midline shift associated with these lesions also
almost entirely resolved."

[Rolepaul]

That case was actually run under Dr. Slamon. I contacted her mother in October of 2011. The woman has some short term memory issues, with the need to make a list of everything she needs to do for the day and a good outlook calendar. WBRT has a wide range of cognitive effects that we chose not to risk. Some are minimal and it seems there is no impact. Others are no longer able to work or even look after children due to inability to remember and focus. I am fairly aware of the cases and progress that have been done at this point.
Northwestern was running a lower dose than we wanted to do. Dr. Razier was not willing to change the dose, so we made our own compassionate care mini clinical trial. Not many could make that happen three years ago, but we had the right educational background to make it work.
Nina's case is still in discussion. It had two papers published referencing the work as a sidebar. It has gone to San Antonio Breast Cancer Conference twice for discussion that we are aware of. It will always be the MD Anderson Cancer Center case by Nina's choice.

[Rolepaul]

That case was actually run under Dr. Slamon. I contacted her mother in October of 2011. The woman has some short term memory issues, with the need to make a list of everything she needs to do for the day and a good outlook calendar. WBRT has a wide range of cognitive effects that we chose not to risk. Some are minimal and it seems there is no impact. Others are no longer able to work or even look after children due to inability to remember and focus. I am fairly aware of the cases and progress that have been done at this point.
Northwestern was running a lower dose than we wanted to do. Dr. Razier was not willing to change the dose, so we made our own compassionate care mini clinical trial. Not many could make that happen three years ago, but we had the right educational background to make it work.
Nina's case is still in discussion. It had two papers published referencing the work as a sidebar. It has gone to San Antonio Breast Cancer Conference twice for discussion that we are aware of. It will always be the MD Anderson Cancer Center case by Nina's choice.

[vqtilley]

The current Northwestern study is presently described as a dosage study. Is this dose range (below) lower than the the one you chose? May I ask what dosage you did choose?

"The initial phase of this study will be a dose escalation trial of 3-6 patients per each dose level. Dose escalation will occur until the MTD or the maximal defined dose (MDD) (40 mg) is reached. The starting dose will be 10 mg for cohort 1, 20 mg for cohort 2, 30 mg for cohort 3 and 40 mg for cohort 4. Patients will be treated twice a week for 4 weeks, then once a week for 4 weeks, and then every 2 weeks. The starting dose is based on the safety of this dose and higher doses as reported in the literature. The MTD or MDD will be used for phase II."

Certainly my priority is to avoid WBRT as long as possible.

[Rolepaul]

Nina and others started at 40 mg weekly for a four week period. This lets the easy to kill cells die and causes less of need for steroids. Then bump it to 1.6 mg/kg to get the rest of the cells. For Nina at 60 kg, 142 lbs, we went to 80 mg and then 100 mgs. Every week from February 4 2012 to July 1 2012 at 80 mg, then 100 mg every two weeks for six months, then 100 mgs every four weeks for past 28 months. So quite a bit different. The cost of the treatment is dependent upon the hospital being able to use the remaining amount of Herceptin in the vial on another patient. This can also be used for the systemic in some settings. With Nina, we went to systemic Herceptin and navelbine from March 2012 to August 2012. Then just herceptin from August 2012 to August 2014. Switched to TDM-1 August 2015 because of a hot lymph node, which then went cold by October 2014.
I have a good relationship with the treating physicians and they will run outside the lines for me.
There are people that stay inside the box, there are people that go outside the box, and there are a few of us that found if you stand on the box you get a better view. But it means that you sometimes have people throw more rocks at you.

[vqtilley]

This is fascinating. I hope you don't mind a few questions. Do I understand correctly that for the past 28 months you are combining 100 mgs of IT Herceptin every four weeks with systemic TDM-1 since August 2014, which I'd guess is administered every 3 weeks? If so, how is she doing on that combination? Is she using an Omayya reservoir for the IT? If so, can you share anything about how is that going for her? It seems like a lot of accessing - she must be worn out with it, no?

I appreciate the box analogy. I'm the stand-on-the-box type, myself, but fortunately I feel I have an excellent neuro-surgery and radiology team at the Sideman Center/Barnes-Jewish in St Louis who also seem to like standing on boxes.

[Rolepaul]

I get a can of Coke Zero or Diet Coke for every question I answer.
She does get accessed a lot, which means we train nurses how to access her at one of the Cancer Centers. Only three medical people access the Ommaya, and we are really careful that no other people do. She could have local people do the Ommaya and access the port, but we do not have comfort with the local crew for that. Let's just say that Nina being a RN with a BS in Nursing means she teaches people how to perform access in a specific manner. I help make sterile therapeutic injectables, so I may be harder on nurses than she is.
Nina does great. She did not drive a car great before the disease and is not doing any different now. She walks five miles per day (me too when home), flies to Houston when she needs IT treatments and I am not along, and otherwise is no different than before the disease. She was not as limber after they radiated her spine, but now is doing great. She does yoga four times per week and water aerobics on Friday mornings.
Nina is doing better than some because she is 55 and was pretty healthy before the disease. She had balance issues before and they might be slightly worse. She is at 144 pounds as of Sunday. She has some problems with constipation as it is likely that she had damage to the muscles that help with the digestion of food.
You are smart to be on the box. Your treatment facility is one of the best in the business. let me know if you want to talk more. chemengmba@aol.com