Alex Shoushtari, MD Profile picture
Jun 29, 2020 26 tweets 15 min read Read on X
Hi #medtwitter + new onc fellows! I treat patients with advanced #melanoma, especially rare ones like #uvealmelanoma (UM). This #tweetorial will discuss:

1) Why UM is unique
2) When does(n’t) immunotherapy work for UM
3) Why we prefer clinical trials for advanced UM

1/x
UM affects about 5/million, and about 3-5% of advanced melanomas in the US arise from the uveal tract (iris, ciliary body, choroid). Of these, iris is rarest + least aggressive, so we often call it “choroidal” melanoma.

Get your dilated eye exams, folks!

2/x Image
Choroid and cilio-choroid melanomas can be aggressive. ~50% of the largest tumors metastasize; about 20% of medium ones do.

Look at that lack of plateau! Plenty of mets happen late, >5 years out. It's sad but fascinating when immune system controls disease for years, then (🤬) Image
When UM spreads, it most often goes to the liver for reasons we still don’t well understand. Most who die of disease will die of liver failure. For this reason, treatments can be PO/IV or just liver-directed. UM AJCC staging reflects size, not site of met (unlike skin mel).

4/x Image
Primary UM biology is fascinating. Labs like Bastian and @JWHarbourMD have molecularly defined primary UM since mid-2000s. The highest risk primary tumors can be molecularly defined: BAP1 > SF3B1 >> EIF1AX, 3p loss, RNA profiling. No BRAF V600 mutants.

5/x ImageImage
Genomic risk stratification changed surveillance patterns starting in late 2000s. Most pts were getting no surveillance; now, CT/MRIs of liver are common, esp if known high risk. This has important implications for interpreting survival data later.

bjo.bmj.com/content/97/2/1…

6/x
So if they metastasize, what then? If you read no further, remember: send them to me or another referral center. I won’t discuss the revolution in cutaneous melanoma driven by #Immunotherapy or BRAF V600-targeted therapy; I assume you’ve seen @NobelPrize announcements. 7/x
This revolution has largely left behind our patients with #uvealmelanoma. Why? Early data with CTLA-4 inhibitor ipilimumab looked to help ~5% shrink tumors…similar to skin melanomas. So many of us felt rapid improvements were just around the corner. 8/x

acsjournals.onlinelibrary.wiley.com/doi/full/10.10…
But PD-1 blockade, a blockbuster in skin melanomas and many other tumors, was a decided dud. Only 4% response in (mainly) 2nd/3rd line retrospective study! Median OS from 2nd/3rd line was dismal, 8mo. 9/x

acsjournals.onlinelibrary.wiley.com/doi/full/10.10… Image
PD-1 blockade occasionally had durable responses, but molecular analysis recently showed genomic outliers in 2 cases with hypermutation and novel germline mutation in MBD4. Cool biology, seen in other neoplasms too, but not useful for most patients.

nature.com/articles/s4146…

10/x ImageImage
I picked most recent whole genome study from our Aussie friends that confirms many prior studies: primary UMs have a low, low, low tumor mutation burden (TMB). Outliers were only in iris (sun-exposed) or rare MBD4 germline carriers.

11/x

nature.com/articles/s4146… Image
OK so the "high TMB/T cell inflamed=PD-1 mono-tx" paradigm won't work. But what about combined PD-1 + CTLA-4 blockade with nivolumab + ipilimumab (nivo+ipi)? It has a track record of response in a subset of tumors where PD-1 doesn’t work alone. (fCOI: I consult for BMS)

12/x
There are now 2 retrospective reports of nivo+ipi in UM; one US-based (@YanaNajjarMD @FunchainMD, others) and one Europe-based . ORR in both is low, 12-16% (vs skin ORR 55-60%). Toxicity looked just as high, unfortunately.

jitc.biomedcentral.com/articles/10.11…
jitc.bmj.com/content/8/1/e0…

13/x ImageImage
When patient tumors shrink, they can stay shrunk for a while: median duration was 25 months in European cohort. In our cohort, it was only 6 months (but small numbers, short f/u). So nivo+ipi can be a good option for a small subset of pts. We just don't know which ones. 14/x
So, with this median OS climbing from historical 6-12 mo to now 15 mo, have we shifted the standard of care? Is nivo + ipi the best option for patient with new UM? The answer is, unequivocally, NO. Clinical trials remain the standard. @NCCN guidelines agree:

15/x Image
If we are improving OS w/ nivo+ipi, we need to understand historical comparisons. Best data come from meta-analysis of 912 pts known by us cool kids as PUMMA.

Size of metastases (>3cm vs <3cm), blood values (LDH, alk phos), ECOG PS are prognostic.

16/x
sciencedirect.com/science/articl…
Overall OS ~10.2 months. Systemic tx, 9-11 months. Liver-directed therapy -> better OS, but population is also much less sick than those in systemic tx. So can’t say one is better…but we can power current prospective single-arm trials against this benchmark. 17/x Image
BUT, onc fellows, friends: pitfalls abound. Lots of missing data = ?confounders. Also, trials span from 2003 – 2018.

I suspect that we are catching tumors a lot earlier in 2020 than we were in 2003. Molecular risk stratification, MRIs/CTs improved.

Lead time bias? 18/x
If nivo+ipi were improving OS despite lead-time bias, I would need to see a durable tail, like the one we see in Checkmate-067. Do we see one in advanced UM? The answer, unfortunately, is no.

So we must keep searching for novel options. 19/x Image
We improve care by finding signals in Phase 1 trials. Tebentafusp is a nice example (fCOI: personal fees from @Immunocore). UM responded in Ph1 ➡️ Ph1 expansion ➡️ registrational *randomized* Ph2 against MD choice of pembro/ipi/chemo.

OS primary endpt. Progress!

20/x
The #uvealmelanoma community is REALLY good at filling large randomized trials internationally w/ @MRFCureOM, the International Rare Cancer Initiative, @MelanomaReAlli . The last large trial (negative... 😭), chemo + MEK vs chemo, accrued in ten months!!! We can do it! 21/x Image
But many companies have decided that UM is not worth investigating, even in a Phase 1 “safety” study. Today I counted 68 current Ph1 melanoma studies on clinicaltrials.gov (excluding BRAF V600). 26 (38%) explicitly excluded uveal.

22/x
To all my pharma friends: this is a BIG mistake. No big differences in safety risks for UM vs skin melanoma, so Phase 1 studies should enroll these pts. Who knows, you might get lucky and find a signal for a true orphan indication! Win-win!

23/x
Dear immunotherapy Ph1 designers, the field has debunked the notion that UM is an immunologic “desert.” Beautiful recent work by both @JNilsson_lab and @JWHarbourMD has shown plenty of infiltrates in UM mets. Let us in!

nature.com/articles/s4146…
nature.com/articles/s4146…

24/x ImageImage
We know that adoptive TIL at @theNCI (now at @UPMC) has had preliminary success as well: thelancet.com/journals/lanon…

25/x
For now, we celebrate the modest successes with nivo+ipi, or liver directed therapy, etc…but we must continue to ask patients with #ocular #uveal #melanoma to trust us and enroll in a clinical trial for this rare disease.

We will find major advances soon.

26/26
/fin

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More from @alexshoushtari

Mar 6, 2021
I am excited to share our manuscript "Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary #Melanomas" published at @CCR_AACR. I think it offers important clinical and translational insights into melanoma. 1/x

clincancerres.aacrjournals.org/content/early/…
All of the genomic and clinical data are available on @cbioportal at cbioportal.org/study/summary?… – thank you to @nikolausschultz Lab, esp @chatila_w + @fjsanchezrivera (bioinformatics/data viz), Arshi Arora (stats), and @sloan_kettering molecular path (all the sequencing) 2/x
This will be a loooong thread for my fellow #melanoma geeks! All other melanoma-curious oncologists and #medtwitter can skip towards the end where I try to highlight some themes for investigating other tumors. 3/x
Read 33 tweets
Aug 19, 2020
Hey everyone, the first-in-human clinical trial of tebentafusp, the HLA-specific fusion protein targeting gp100, is now online @CCR_AACR! Cool mechanistic proof of concept that you can get CD3+ cells into a poorly infiltrated tumor like #uveal #melanoma.

clincancerres.aacrjournals.org/cgi/content/ab…
A prelim efficacy signal for uveal melanoma in this trial with a dose (50mcg weekly) that is lower than the 68mcg weekly dose later expanded upon and presented at ASCO last year. Fingers crossed for our patients with this rare disease!

(note: I have fCOI with @Immunocore) Image
Cytokine Release Syndrome: uncommon but potentially serious side effect. Manageable with everyone's growing experience with adoptive T cell therapy. This trial predated the approval of tocilizumab for severe CRS. Hospitalization mandatory for first 3 doses on study. Image
Read 6 tweets
Jun 2, 2020
Throughout our medical training, many of us were taught it was "unprofessional" to voice our beliefs or broadcast political opinions. But we must acknowledge most of the (well-meaning) people counseling us to stay silent stood to gain by maintaining the status quo. #medtwitter
Those who maintain political activism harms the soul of medicine suggest it cripples the patient-doctor relationship. But I find this simplistic, even disingenuous. Surely most people can divorce political stance from compassionate care? Can't we trust them to make that decision?
When I am in a patient room, their well-being is paramount. When I leave that room, I need to apply that same level of dedication to bettering my community. We should be welcoming, not punishing, people who enter into political discourse.
Read 5 tweets
Mar 24, 2020
A few thoughts on outpatient oncology care here in #NYC.

10 days ago, we melanoma med onc @sloan_kettering agreed to cut back in person clinic from 1-2x / week to once / 1-2 weeks. My clinic frequency was quartered. I was excited to leave the apt (I'm allergic to combs). Image
My commute to work is entirely by foot, and I'm privileged to be able to do so. Ordinarily I walk by hundreds of people in 15 min.

Today, I counted about 30 people. We are successfully distancing! Yay!
The in person visits that remain are the most complicated ones, where infusion and scan review are done on same day. Our (very smart) new visitor policy doesn't allow family members to attend, with rare exceptions.

Skeletal, 50% staff on site in clinic.

So today was...eerie.
Read 9 tweets
Feb 13, 2020
Beautiful retrospective work suggesting the clone of melanoma that recurs after an initial complete response to checkpoint inhibitors is often different than the one that presented initially.
Our group has taken these data to heart. I've changed a few things about my approach in clinic as a result:

1) When patients ask if we can just retry the same medicine if the disease comes back, I try to take time to say "yes, but it may not work the same way as before."
2) This recurrence rate was a little higher than the clinical trial recurrence risks of 10-15%. While length of tx wasn't statistically associated with recurrence, I now am much more reticent to stop therapy if no toxicity and length of therapy is only 6 months.
Read 4 tweets
Nov 7, 2019
GITR + nivo efficacy ~ nivo efficacy.

Paper says, "...a clear signal has not emerged demonstrating that GITR agonism may be an effective therapeutic strategy in a broad patient population."

...yeah... OR maybe it doesn't add anything to PD-1.
jamanetwork.com/journals/jamao…
Some of my best friends work on GITR!!! But that kind of language should have been edited out as Pollyanna nonsense. Don't make me sic Vinay Prasad on all y'all...
To echo a couple of my colleagues, it's great that this very well run trial found a high profile venue to disseminate the important message. Kudos to them!
Read 4 tweets

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