Last week the Society for Neuro-oncology (SNO) hosted their second annual brain mets day, and this virtual event was so good that I might have come around on having a brain biopsy. Because it seems like it would be interesting.
We’ll save the brain biopsy for a bit later.
One of the few philosophical things that has really changed since I was diagnosed a decade ago was the opening of trials to patients with brain mets. I think this shift happened around T-DM1 and Perjeta getting approved. There had been such a long lapse in HER2-targeted drug approvals between Herceptin (in 1998!) and T-DM1 in early 2013, and suddenly there were these new drugs offering significant real-world survival benefit and a patient population that wouldn’t trash industry’s costly study programs.
An FDA speaker summarized their new guidelines for safely including brain mets patients in trials, emphasizing the frequency of brain mets in cancer patients (70k new diagnoses per year) and the importance of conducting a trial that accurately represents the population that will ultimately be using the drug. The guidelines specify that patients with treated/stable brain mets should be eligible for enrollment in trials unless there is a “strong rationale” for exclusion. The morning session also included a recap of the tucatinib HER2CLIMB data; there wasn’t much we hadn’t seen before, but it was a reminder of what can be (brain mets included in the label!) when a sponsor dares to run a forward-thinking trial. Looking ahead, rose-colored glasses in place, that could be the norm.
I’ve said it a thousand times: I love the design of HER2CLIMB. One of the really interesting exploratory endpoints is time of first CNS progression to second progression or death. Treating beyond progression is one of those things that makes people a bit squeamish, especially since it’s become so controversial in the use of checkpoint inhibitors (re: the pseudoprogression debate), but in HER2+ breast, we already have a version of this: it’s called Herceptin. You never stop. There’s something really appealing about identifying a CNS-targeted foundation drug on which other HER2+ combos are built. I’m not saying tucatinib’s the one, but the idea is worth exploring.
Back to the data. Here are the results of the treatment beyond PD exploratory analysis:
Check out the blue PD column – an eight-month duration of response from first CNS PD to second PD/death. Eight months is a reasonable DOR in a heavily-pretreated population in general, nevermind when we’re looking at a brain mets cohort. I only lasted about eight months on Herceptin, Perjeta and Abraxane, and back then I was barely asking it to do anything.
HER2CLIMB wasn’t even the best part of the day. The really exciting stuff was about the genomic discordance between primary tumors and brain mets. Are they genetically concordant, the way, say, a primary tumor shares itself with a liver met? No!
Here’s a HER2+ example:
This chart shows the genetic variability:
But what of the intracranial lesions? Is there diversity between them? How many brain biopsies am I going to have to do?
Just one. Whew.
The speaker on this section, Dr. Brastianos of MGH, also highlighted the high frequency of CDK pathway dysfunction in brain lesions. According to a Guardant test from earlier this year, I’d picked up one of those somewhere. Abemaciclib is creeping up to the top of my wish list. (I’m hormone-negative, but I like a challenge.) CDK 4/6 mutations seem to be one of the mutations that occur commonly in brain, but could be missed if we were using a visceral lesion for a tissue biopsy. This may help justify the use of liquid biopsy, if it can capture ctDNA that’s coming loose from the brain.
The MGH work can be a segue into a paper that describes the benefits of understanding this discordance and investigating it – and using it to treat. Just a day before the SNO event, the NEJM published a paper describing gains in mortality rates in lung cancer, where the reductions in NSCLC mortality have outpaced growth in incidence. Men who were diagnosed in 2001 had a 26% survival rate; for those diagnosed in 2014, this jumped to 35%. (SCLC mortality was also down, but as a result of declining incidence.)
The improvement in NSCLC survival was attributed to advances in treatment, particularly targeted therapies and immunotherapy. It should be noted that in NSCLC, compliance with NCCN-recommended biomarker testing (EGFR, ALK, ROS1, PD-1 status, etc.) may be as high as 87% for EGFR “in some markets” but more variable (i.e., lower) for other markets. We know these drugs work, and they’re approved in lung, and patients still aren’t getting tested.
My experience is that breast cancer patients are tested for hormone and HER2 status at first diagnosis by IHC, then crickets. Repeat biopsies are unusual, especially if a patient relapses soon after adjuvant treatment. Some trials require a fresh biopsy at study entry, but that’s usually to confirm things like HER2 status. If you’re at a center equipped to perform its own sequencing, which is increasingly common, you’ll get their special proprietary comprehensive genomic report. (There’s no barrier to this; you just buy a sequencer from Illumina and plug it in.) I was told I got one of these tests at The Institute, but I never saw the report and know nothing about it, including which or how many markers it queried. I’m sure I was billed for it. I fought for every other sequencing test I’ve had, despite evidence both hard and anecdotal that identifying actionable targets and treating them improves survival. With brain mets patients at greater risk of mortality, should we not be looking for these opportunities more aggressively? Does SeaGen have to do everything?