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The Latest in Ocular Melanoma with Dr. Inderjit Mehmi | The Eye Believe Podcast · The Eye Believe Podcast

• 0:03
  hey everyone welcome back to the Eye Believe Podcast
• 0:06
  I'm Megan and I have the wonderful Doctor
• 0:08
  Mehmi here with me today welcome to the podcast
• 0:11
  good morning thank you for having me
• 0:13
  I'm very excited you're here
• 0:15
  so we're gonna talk about some updates and some history
• 0:19
  some things coming from ASCO
• 0:20
  so let's kind of give them
• 0:22
  a brief overview of what we're gonna touch on today
• 0:25
  right so Megan
• 0:26
  as you know that you know
• 0:27
  ocular melanoma is an important disease
• 0:29
  even though it's rare um
• 0:31
  but there's been a lot going on over the last say
• 0:35
  five to seven years right
• 0:36
  because you know prior to that
• 0:38
  we didn't really have any adequate therapies
• 0:40
  for this disease we were using
• 0:42
  you know
• 0:42
  whatever was available for other types of melanoma
• 0:45
  or other cancers and try to see if we could improve
• 0:49
  some of the outcomes
• 0:50
  but I'm happy to say that you know
• 0:52
  the first ever drug was approved for uveal melanoma
• 0:56
  for stage 4 or unrescectable disease um
• 0:59
  and that was Kimmtrak and since then
• 1:02
  there's been a tide that's been shifting
• 1:04
  and more and more research is getting done um
• 1:07
  to get this disease controlled
• 1:10
  even before it becomes metastatic
• 1:11
  so we'll take the time today
• 1:13
  to look at some of the background of the disease
• 1:15
  what are some of the numbers
• 1:17
  what's the prognosis of different subtypes
• 1:20
  um how do we classify these disease
• 1:23
  this disease and then also we'll look at um
• 1:26
  liver directed therapy
• 1:27
  once the ocular melanoma occurs in the liver
• 1:30
  and then we'll look at systemic therapy
• 1:33
  when it's beyond the liver
• 1:34
  or even within the liver and then
• 1:36
  I also wanted to focus on
• 1:39
  some of the combination approaches for stage 4
• 1:41
  um uveal melanoma
• 1:43
  and also what are
• 1:44
  some of the studies that were presented at ASCO 2025
• 1:47
  and some of them are pretty exciting um
• 1:50
  because those are the patients
• 1:51
  who have been previously treated with
• 1:53
  number of therapies and
• 1:55
  you know some of them don't respond as we want them to
• 1:57
  and as we would like them to
• 1:59
  so these therapeutic options
• 2:01
  hopefully
• 2:02
  will get those individuals in control as well
• 2:05
  that sounds fantastic that's a hefty lineup
• 2:07
  so you guys stay tuned because we got a lot to go over
• 2:11
  so we could start off with sort of
• 2:13
  where does uveal melanoma develop
• 2:16
  I mean there are
• 2:16
  you know three different compartments or 3
• 2:18
  4 different compartments
• 2:19
  where uveal melanoma can develop
• 2:21
  it could be Iris the ciliary body or the choroid itself
• 2:25
  um and typical symptoms can be
• 2:27
  you know
• 2:28
  sort of changes in vision or flashes of light
• 2:31
  sometimes eye pain things like that
• 2:33
  or sometimes on a routine exam at a
• 2:36
  at a in a retinal exam
• 2:37
  somebody will find something and
• 2:40
  and it starts to work up
• 2:42
  as far as the numbers are concerned
• 2:43
  it's not the most common melanoma right
• 2:46
  but it it is the most common type of tumor in adult
• 2:51
  as far as the eye tumors are concerned in
• 2:53
  in the kids it's retinoblastoma
• 2:55
  but in adult population
• 2:57
  uveal melanoma is the most common ocular uh
• 3:01
  malignancy and it represents about
• 3:03
  only about 5% of all melanomas
• 3:06
  and there were about 2,000 cases um annually
• 3:10
  you know and 8,000 cases globally um
• 3:13
  and there are some risk factors
• 3:15
  but the typical Assumption
• 3:17
  that it's related to sunlight
• 3:18
  and all that we don't really know about that um
• 3:22
  you know but some of the
• 3:24
  you know having a freckle in that area um
• 3:27
  or having some BAP one
• 3:29
  and if one germline mutation
• 3:32
  syndrome called dysplastic nevus syndrome
• 3:35
  you know
• 3:35
  these are some of the associations with uveal melanoma
• 3:39
  and unfortunately once you treat the primary disease
• 3:42
  within the eye itself
• 3:43
  about 50% will go on to develop metastatic disease
• 3:47
  with 90+ percent having liver predominant metastases
• 3:51
  in combination with lungs and other spaces
• 3:54
  you know in the past we didn't have a great of
• 3:56
  of greatest of survival for this disease
• 3:59
  you know only about you know
• 4:03
  one year survival was about 13 to 25% um
• 4:07
  and you know the the outcomes were very dismal
• 4:10
  but like I said in the last few years
• 4:12
  there is a tremendous amount of progress
• 4:14
  that's been made with first approval of Kimmtrak
• 4:17
  that will go over um
• 4:19
  that's improved the overall survival
• 4:21
  and then now
• 4:22
  we're developing some targeted therapy options
• 4:25
  where we're looking at some key
• 4:26
  mistakes in the uveal melanoma
• 4:28
  you know how it survives
• 4:30
  um and then
• 4:30
  trying to interrupt those signaling pathways
• 4:33
  to see if we can um
• 4:35
  control the disease
• 4:36
  we don't typically use the
• 4:38
  you know
• 4:39
  staging system for this I mean
• 4:41
  most of the time it's based on the
• 4:45
  the base diameter
• 4:46
  and the height of the tumor within the eye um
• 4:49
  so that'll give us some staging
• 4:51
  but more often we rely on the classes
• 4:54
  and that's the genetic sort of characteristics of this
• 4:59
  um um
• 4:59
  cancer based on that
• 5:01
  it's divided into class 1
• 5:02
  and then class one's divided into a and B and class 2
• 5:06
  and then other characteristic genetics
• 5:08
  like prame positivity and chromosomal abnormalities
• 5:11
  will give us a good idea what the
• 5:13
  risk of recurrence is
• 5:15
  for this uveal melanoma is down the road
• 5:17
  with that information we can taylor make a follow up
• 5:23
  right if somebody is at low risk of recurrences
• 5:26
  they may not need the scans as soon
• 5:29
  you know as often
• 5:30
  versus somebody who's at high risk of recurrences
• 5:33
  so not only it gives us idea of
• 5:35
  you know who's gonna recur for the most part allows us
• 5:38
  you know how to follow these patients and 3
• 5:41
  develop clinical trials to intervene early on
• 5:46
  before the uh
• 5:47
  advanced disease develops
• 5:49
  to see if we can reduce the risk of recurrences
• 5:51
  and I will go over some of those actually two
• 5:56
  um adjunctive clinical trials that
• 5:59
  that are trying to achieve that goal
• 6:02
  so once the you know
• 6:05
  the ocular melanoma
• 6:07
  within the eye has been treated with either radiation
• 6:10
  plaque therapy or proton beam therapy and
• 6:12
  and rarely uh enucleation
• 6:15
  we subdivide divide
• 6:16
  these patient populations into low risk of recurrences
• 6:19
  intermediate risk of recurrences
• 6:21
  high risk of recurrences
• 6:22
  based on the classification that I talked about
• 6:24
  and the test that we use is called
• 6:27
  by a company called Castle Bioscience and Decision
• 6:31
  Dx-UM is the test that we use
• 6:34
  and the high risk patients that have
• 6:38
  you know within the next three to five years
• 6:39
  after their initial disease is treated
• 6:41
  they have a risk of recurrence
• 6:42
  is much higher for those individuals
• 6:45
  in the past
• 6:46
  we've had a number of different clinical trials with
• 6:49
  using medications
• 6:50
  that were already available for other diseases
• 6:52
  and see if we can reduce the risk of recurrences
• 6:54
  but the outcomes weren't you know
• 6:59
  at what we wanted the
• 7:00
  the reduction in recurrences was
• 7:03
  wasn't worth the toxicity that it brings
• 7:06
  and the treatment tended to be for a year or more
• 7:10
  so because of that you know
• 7:11
  it's not very popular to use those treatments
• 7:14
  for these patients rarely
• 7:16
  we see a handful of patients
• 7:19
  who've been exposed to drugs
• 7:21
  like Sunitinib and
• 7:21
  and things like that
• 7:23
  to reduce their risk of recurrences
• 7:26
  but now we're looking at actually two different trials
• 7:30
  um one of them is
• 7:32
  with
• 7:32
  the drug that's already approved for stage 4 disease
• 7:35
  that is Tebentafusp or Kimmtrak
• 7:38
  unfortunately
• 7:39
  that drug is reserved for a certain group of patients
• 7:43
  who have an HLA subtype A0201
• 7:49
  if you have that subtype
• 7:50
  and you're high risk for recurrences soon um
• 7:53
  multiple cancer centers will have the clinical trial
• 7:57
  called Atom
• 7:58
  A. T. O. M.
• 8:00
  and essentially
• 8:01
  it'll look at patients with high risk of recurrences
• 8:04
  and then randomize them to either observation with
• 8:09
  you know imaging
• 8:10
  scanning for any recurrences
• 8:11
  versus giving them Kimmtrak for one year
• 8:15
  and then we'll follow the patients
• 8:17
  and see if we can reduce the risk of recurrences
• 8:20
  and get the drug
• 8:22
  made you know
• 8:22
  have it be available early on
• 8:25
  if it's successful in reducing risk of recurrences
• 8:29
  um like I said that
• 8:30
  that trial should be available um
• 8:33
  within the next two to three months
• 8:36
  um so I urge patients 1
• 8:39
  you know it when
• 8:40
  when they do get diagnosed with a uveal melanoma
• 8:44
  have the Castle Bioscience test done
• 8:46
  so we know if they're high risk or not
• 8:48
  and if they are high risk
• 8:50
  I urge them to you know
• 8:52
  find a center nearby and participate
• 8:54
  and we'll be one of the centers in Southern California
• 8:57
  so and happy to help any of
• 8:59
  any of the individuals that they're looking
• 9:02
  and the second trial is
• 9:05
  um from uh
• 9:07
  Doctor Jose Lutzky over at the university of Miami
• 9:10
  Silvester Cancer Center and Dr. Lutzky and um
• 9:17
  the ocular oncology team at Dallas Southwestern
• 9:20
  um they looked at a molecule called HDAC4 inhibitor um
• 9:25
  and the HDAC4 or or some of that mechanism
• 9:32
  if it's uninterrupted it allows these genes to be
• 9:39
  made into proteins that allow
• 9:42
  uveal melanoma cancers to spread or recur
• 9:46
  by giving that HDAC inhibitor
• 9:48
  we're suppressing those gene products
• 9:51
  and not allowing
• 9:53
  the cancer to sort of come back and spread
• 9:55
  so simply put
• 9:57
  and so that particular drug is looking at about
• 10:01
  I think 60 patients um
• 10:03
  and here it's not a randomized trial
• 10:06
  it it'll have a synthetic control
• 10:09
  meaning some of the historical data that we have
• 10:11
  for that kind of matched group of patients
• 10:15
  see if we can reduce the risk of recurrences
• 10:18
  and the drugs I believe
• 10:19
  is given about either twice or three times a week
• 10:22
  I'll have to check the details on that
• 10:25
  and the the really good thing about this trial is that
• 10:30
  you can have you could have had your eye tumor
• 10:34
  uveal melanoma treated about six months prior
• 10:37
  so usually these trials look at
• 10:40
  you know look to
• 10:41
  start treatment within about three months of
• 10:44
  initial treatment
• 10:45
  but here we have a longer time to act
• 10:48
  again we'll be looking at high risk patients
• 10:50
  with the Castle Bioscience testing
• 10:54
  and uh so that's another but
• 10:56
  and also this trial isn't restricting patients uh
• 11:01
  with only HLA-A0201
• 11:03
  like the Kimmtrak trial is okay
• 11:07
  and then so that's the second and the third trial
• 11:10
  we have some initial data um
• 11:13
  by Doctor Suthee Rapisuwon from um
• 11:15
  at DC Area he had presented at ASCO last year
• 11:20
  um
• 11:21
  individuals treated with Opdivo and Yervoy or ipilimumab (Ipi) and nivolumab (Nivo)
• 11:25
  and showed decreased risk of recurrences
• 11:28
  with a significant margin
• 11:30
  and that trial was in a smaller number of patients
• 11:33
  but it's gonna get expanded and into a phase 3 study
• 11:37
  um I think that's another trial that won't
• 11:42
  restrict patients to their HLA subtype
• 11:45
  so that trial
• 11:47
  probably is a little bit further down the pike uh
• 11:49
  but it should be coming up soon
• 11:51
  so in in a disease where we didn't even have
• 11:55
  you know metastatic treatment approved by the FDA
• 12:00
  now we're talking about you know
• 12:02
  stepping early on
• 12:04
  trying to reduce the risk of recurrences
• 12:06
  of the initial disease diagnosis and treatment
• 12:09
  and so that just
• 12:10
  speaks to the progress
• 12:11
  that we're trying to make in this disease space
• 12:14
  so absolutely that's a big deal right
• 12:17
  that is a huge deal right
• 12:19
  um and then
• 12:22
  since these trials are still
• 12:24
  attempting to achieve those goals
• 12:26
  that means you know
• 12:28
  some of those high risk patients
• 12:29
  that don't have access to these trials
• 12:31
  or we don't know if these trials are gonna be able to
• 12:34
  you know accomplish their preset goal
• 12:37
  that means that 50% of the patients
• 12:39
  will still have disease
• 12:40
  recurrences in the liver and other places
• 12:44
  so what are some of the treatment options
• 12:46
  that are already approved
• 12:48
  in this space
• 12:50
  those options are you know
• 12:52
  we look at where the disease is how big
• 12:55
  or how much disease burden there is
• 13:00
  you know what kind of makeup does the patient have
• 13:04
  you know are there a lot of medical problems that would
• 13:08
  you know kind of cause issues
• 13:10
  if we gave them one treatment versus another
• 13:12
  do they have autoimmune problems
• 13:14
  you know things like that
• 13:16
  so how much disease where the disease
• 13:19
  the makeup of the person that will help us decide
• 13:22
  how should we tackle their advanced disease
• 13:25
  once it's recurred if it's
• 13:27
  you know a few spots
• 13:28
  you know one or two spots in the liver
• 13:31
  um
• 13:32
  you can go after them with what's called liver directed
• 13:35
  therapy so why expose the patient to
• 13:38
  you know toxic treatments with long term side effects
• 13:42
  potentially when you can just target the liver itself
• 13:46
  you know those spots
• 13:48
  and then there's
• 13:48
  there's a group of patients that will have long term
• 13:51
  control with that
• 13:54
  but most of the time these liver directed therapies
• 13:57
  for example chemo embolization
• 13:59
  immuno embolization RFA
• 14:01
  you know all these treatments
• 14:03
  um they'll have disease control
• 14:05
  but eventually new disease pops up
• 14:08
  so for those patients you know
• 14:11
  one of the other liver directed therapy option is um
• 14:15
  the hepatic perfusion with melphalan
• 14:18
  and that's approved as Hepzato
• 14:20
  based on the phase 3 trial focus and showed
• 14:24
  you know really good disease control
• 14:28
  um
• 14:28
  overall response rate in these patients were about 32%
• 14:32
  um median progression-free survival (PFS) of nine months
• 14:35
  um and that data has been updated and that's
• 14:38
  you know kind of holding steady
• 14:40
  and now there is sort of another approach with Hepzato
• 14:46
  or hepatic perfusion with melphalan
• 14:48
  in combination with Opdivo and Yervoy
• 14:51
  *CHOPIN*
• 15:02
  no problem
• 15:03
  and this particular trials coming out of Europe
• 15:06
  and they treated only about less than 10 patients
• 15:09
  but showed remarkable responses
• 15:13
  almost
• 15:13
  like five out of seven patients had disease control
• 15:18
  and it seems like
• 15:19
  when we treat the liver with metastases
• 15:24
  there is sort of a negative impact on the immune system
• 15:29
  by having metastatic disease in the liver
• 15:32
  and once you treat the liver
• 15:34
  that negative impact of the liver
• 15:36
  on immune system is taken away
• 15:38
  so Opdivo and Yervoy
• 15:39
  perhaps works better to control the disease
• 15:43
  so that trial is actually getting expanded
• 15:46
  um so we'll
• 15:47
  we'll look to see its results in the next few months
• 15:50
  I think it's gonna get reported at ESMO
• 15:52
  or perhaps ASCO or one of these major conferences soon
• 15:56
  so we're looking forward to that
• 15:57
  so that's the combination study
• 15:58
  where we're looking at liver directed therapy
• 16:00
  in addition to rest of the body treatment as well
• 16:03
  to improve survivals reduce risk of
• 16:07
  you know um progression um
• 16:10
  and and improving these survival advantages
• 16:14
  and then obviously
• 16:16
  we can't go any further without talking about Kimmtrak
• 16:19
  you know it's
• 16:19
  it's the sort of the first drug that was ever approved
• 16:24
  for metastatic uveal melanoma for patients who are HLA
• 16:28
  A0201
• 16:28
  positive and it showed that when you give patients
• 16:33
  Kimmtrak versus physician's choice treatment
• 16:38
  that you improved overall survival
• 16:40
  and that benefits been you know
• 16:44
  first it was reported in New England Journal
• 16:46
  Medicine as one year overall survival advantage
• 16:49
  and now it's been updated to three years
• 16:51
  and subsequently um
• 16:53
  and the the
• 16:54
  one of the
• 16:55
  really good thing about Kimmtrak
• 16:57
  is that we can predict is toxicity and
• 17:01
  and then make sure that the patient uh
• 17:05
  tolerate these drugs most of the toxicity happens
• 17:09
  within the first three treatments
• 17:12
  and after that the risk of toxicity is really low
• 17:14
  most of the time it's limited to rash
• 17:17
  uh occasional fever
• 17:19
  uh but any of the low blood pressures
• 17:21
  fever uh chills
• 17:24
  any of those
• 17:24
  they tend to be limited through the first uh
• 17:28
  three treatments and they're really
• 17:30
  you know we have enough experience to
• 17:34
  sort of you know
• 17:36
  reliably control those issues
• 17:38
  and keep the patients on the drug
• 17:40
  and then they're ongoing studies of Kimmtrak
• 17:43
  with other things you know
• 17:45
  uh to see if we can improve the responses with Kimmtrak
• 17:48
  so we talked about Hepzato
• 17:50
  we talked about Kimmtrak
• 17:52
  there are two trials that looked at Optivo and Yervoy or Ipi Nivo
• 17:56
  one was Doctor Patel's trial from MD Anderson
• 17:59
  now at Colorado University
• 18:01
  and the another one was from Spain
• 18:03
  and both of them
• 18:05
  pretty much identical response rates by 18
• 18:07
  to 20% toxicity that we know of
• 18:11
  Ipi Nivo from other disease spaces
• 18:13
  um
• 18:15
  so that's an option for some of those patients who have
• 18:18
  you know
• 18:21
  that they're they don't have autoimmune problems
• 18:24
  or they have significant amount of disease in another
• 18:27
  so it's it's something we can try
• 18:29
  but it's not sort of the first thing we reach for
• 18:31
  because we know that Opdivo Yervoy
• 18:33
  has significant risk of toxicity with colitis
• 18:36
  in about 30 to 40% of the patients
• 18:38
  a lot of patients tend to have rash
• 18:40
  uh hypothyroidism that's immune mediated
• 18:43
  and then risk of liver lung
• 18:45
  kidney injuries you know in
• 18:46
  in measurable numbers
• 18:47
  so something that's available but you know we
• 18:52
  we consider the patient makeup seriously before we uh
• 18:56
  consider those treatments
• 18:58
  and then
• 18:59
  so those are what's available in our toolkit now right
• 19:04
  what's coming down the pike is something exciting
• 19:09
  um my senior partner
• 19:11
  Doctor Hamid presented some of the data for a second
• 19:15
  sort of similar drug to Kimmtrak
• 19:17
  that targets a different marker called Prame
• 19:19
  on uveal melanoma cells
• 19:22
  and that was presented a few years ago
• 19:24
  um at ESMO
• 19:25
  and we had probably here at our site
• 19:29
  the most number of patients within
• 19:31
  for that uveal melanoma and they had durable control
• 19:34
  and that this this is not any confidential data
• 19:37
  this is data that's already presented
• 19:39
  so I'm hoping at some point Immunocore will consider
• 19:43
  you know
• 19:44
  bringing back their Prame targeting bispecific
• 19:47
  into the uveal melanoma space
• 19:49
  right now they're trying to develop it
• 19:51
  more into the cutaneous melanoma
• 19:53
  but I'm sure they have considerations
• 19:55
  of bringing it back at some point
• 19:57
  at least we'll continue to champion that
• 20:00
  can you explain Prame
• 20:01
  for anybody that doesn't know what that is
• 20:04
  yeah so Prame is a sort of a
• 20:07
  you can think of it as a
• 20:09
  protein that's present in developing cells
• 20:11
  when we are becoming who we are in
• 20:14
  in utero and and
• 20:16
  and then at some point that Prameantigen disappears
• 20:21
  but in melanoma
• 20:23
  it comes back and it's expressed all over again
• 20:27
  um
• 20:28
  and it's a poor prognosis marker in cutaneous melanoma
• 20:31
  and uveal melanoma
• 20:34
  but it's targetable as well
• 20:36
  so Prame antigen
• 20:39
  the drug from Immunocore called brenetafusp
• 20:42
  on one end it has the t cell activating moiety
• 20:45
  the CD3 binding and the other end is prime
• 20:48
  so not only it activates the t cells
• 20:51
  it also brings the active t cells
• 20:53
  in proximity of the uveal melanoma cell
• 20:56
  because it has that Prame target
• 20:59
  so it's it's a matchmaker in a sense
• 21:01
  but also kills the cell
• 21:03
  the melanoma cells from that activity
• 21:05
  so that that's Prame
• 21:07
  and Prame's not just present in a melanoma
• 21:10
  there's ovarian cancer that present uh
• 21:12
  that have prime on it uh
• 21:14
  non small cell lung cancer and endometrial cancer
• 21:17
  so some of the other cancers also express Prame
• 21:20
  so the Immunocore drug
• 21:22
  brenetafusp has a long reach from that
• 21:24
  at least hypothetically speaking
• 21:26
  so this data
• 21:27
  set was presented by Doctor Hamid at ESMO in 2022
• 21:31
  I believe
• 21:32
  and it had about five patients with uveal melanoma
• 21:38
  and three of those five had durable responses
• 21:41
  um so that's something
• 21:43
  you know we are always advocating for these therapies
• 21:45
  and I've talked to Immunocore multiple times to sort of
• 21:48
  you know re-look at
• 21:51
  you know this
• 21:52
  this particular molecule in uveal melanoma space
• 21:54
  and I'm hoping you know
• 21:56
  down the road they'll consider that
• 21:59
  the biggest news since um
• 22:02
  immune therapy and melanoma in general is
• 22:05
  you know tumor infiltrating lymphocytes
• 22:08
  where we're able to take one of the tumor
• 22:11
  representing tumor in the body
• 22:13
  surgically remove it
• 22:14
  and then isolate the lymphocyte from these tumors
• 22:18
  and expand them and reinfuse them into the
• 22:21
  into patients where we got those cells from
• 22:24
  and that's shown
• 22:27
  I'd say amazing benefit uh
• 22:29
  in cutaneous melanoma and a drug named AMTAGVI
• 22:34
  or lifileucel from Iovance
• 22:35
  is already approved for refractory melanoma
• 22:38
  and uh
• 22:40
  and you know
• 22:41
  that story is also developing in uveal melanoma
• 22:45
  the data is very limited
• 22:46
  it's not reliable at the moment
• 22:48
  but university of Pittsburgh
• 22:50
  Medical Center in Pittsburgh
• 22:53
  does have a trial for TIL therapy in uveal melanoma
• 22:57
  so you know
• 22:58
  that's something to to consider for some
• 23:00
  some of the selected patients
• 23:02
  the challenge with um
• 23:07
  TIL therapy is you know
• 23:08
  there are components to TIL therapy
• 23:10
  that are fairly difficult to tolerate
• 23:12
  there's a five days of chemotherapy associated with
• 23:15
  prior to TIL infusion
• 23:16
  the TIL infusion itself is I'd say relatively easy
• 23:20
  typically gets you know
• 23:21
  patients will have low grade fevers and chills
• 23:24
  just sort of t cell mediated reaction
• 23:28
  but after the cell infusion
• 23:30
  then we have to support these t cells with Interleukin-2 (IL-2)
• 23:33
  which can be potentially toxic in in short term
• 23:36
  and in the long run
• 23:38
  typically we give up to 6 doses of Interleukin-2 (IL-2)
• 23:42
  and that can cause low blood pressures
• 23:45
  heart rate issues um sometimes it can cause
• 23:49
  you know
• 23:50
  significant edema in the lungs and other places
• 23:52
  so the that
• 23:53
  that Interleukin-2 (IL-2) is given in an intensive care setting
• 23:57
  so that that's the challenge of TIL
• 24:00
  so that's why we have to select these patients
• 24:03
  really carefully what's coming down the pike
• 24:06
  uh so those are something that
• 24:08
  they're available within the clinical trial setting
• 24:09
  or as standard of care but
• 24:11
  the three trials that I thought were really important
• 24:16
  in uveal melanoma
• 24:18
  they were the one trial we highlighted with
• 24:21
  Ipi Nivo and Hepzato showing really good controls
• 24:27
  and then also
• 24:29
  the trial that I forgot to name was Chopin trial C H
• 24:32
  O P I N that's the Hepzato with Ipi Nivo
• 24:37
  that trial is gonna be reported sometime soon
• 24:41
  in the next couple of months
• 24:43
  not couple of months in a couple of meetings I'd
• 24:45
  I'd say and then uh
• 24:47
  in the future what should we looking at
• 24:49
  would be one study is called OCULE-01
• 24:52
  O C U
• 24:54
  L E dash zero one uh
• 24:57
  this trial in progress
• 24:59
  was presented as an abstract by Doctor
• 25:01
  Paul Nathan out of the UK
• 25:04
  and this particular trial is trying to look at
• 25:07
  how can we take away some of the brakes
• 25:10
  that are put on by the immune system onto itself
• 25:14
  uh and
• 25:15
  and that leads to less of a
• 25:17
  immune surveillance of the uveal melanoma tumors
• 25:21
  and to do this there's a drug that is developed
• 25:25
  that targets a particular enzyme called
• 25:28
  PI3 kinase C delta
• 25:31
  and by inhibiting by giving that drug
• 25:33
  it targets that particular enzymes in the t
• 25:36
  regulatory cells
• 25:38
  so that's the break on your immune system
• 25:41
  by giving that drug
• 25:42
  you're decreasing the t regulatory cell population
• 25:46
  which means there's a
• 25:47
  less of a brake onto the immune system
• 25:50
  and then the active component of uh
• 25:53
  the uh immune system called cytotoxic t cells
• 25:56
  they can act towards the UV
• 25:58
  melanoma much better than they did before
• 26:00
  so that's a trial that's coming it it's open
• 26:03
  it's accruing um
• 26:06
  I'm sure it'll it'll make its way into the US as well
• 26:09
  but right now it's in the UK
• 26:12
  and then
• 26:15
  obviously the clinical trial from Replimune with RP2
• 26:21
  uh is in another interesting study
• 26:23
  so RP two is sort of a vaccine that has um
• 26:28
  it's it's uh the
• 26:30
  the
• 26:31
  most of the component of the vaccine is an HSV1 virus
• 26:35
  but it's that the the part of the DNA that makes HSV
• 26:42
  infectious is taken out
• 26:45
  but then added parts to this are a molecule called
• 26:50
  or the the programming gene called PD1 and CTLA4
• 26:54
  so it's able to sort of wake up the immune system
• 26:59
  when we inject this particular vaccine
• 27:01
  or virus inoculated virus into the tumor itself
• 27:05
  and also give immunotherapy
• 27:07
  uh they presented their initial data on few patients uh
• 27:12
  couple of years back and showed good responses
• 27:14
  so now it's been expanded into a phase 3 study
• 27:18
  um that's ongoing and
• 27:20
  and that was a trial in progress at ASCO
• 27:24
  the other trial that looks very promising
• 27:27
  this is from ASCO 2025
• 27:29
  was first in human study of DYP 688
• 27:34
  now what the heck is that now we know that that
• 27:40
  uveal melanoma most of the uveal
• 27:43
  melanoma
• 27:43
  have this sort of genetic alteration in two proteins
• 27:48
  GNA 11 and GNA Q OK
• 27:50
  Almost 90+ percent of the patients will
• 27:53
  with uveal melanoma have that mutation
• 27:56
  so there are
• 27:58
  couple of different strategy to go after that
• 28:01
  because most of the melanoma will have that
• 28:03
  or uveal melanoma will have that alteration
• 28:07
  Ideaya Pharmaceutical is using Darovasertib
• 28:12
  with Crizotinib
• 28:14
  to disrupt this
• 28:18
  continuous information
• 28:19
  that flows through this mutation
• 28:21
  right so that phase 2 trials ongoing
• 28:23
  their phase 2 study looked
• 28:25
  you know single arm study
• 28:26
  had really good data benefiting these patients
• 28:29
  but the the treatment is somewhat toxic with diarrhea
• 28:33
  rash nausea
• 28:35
  vomiting
• 28:36
  and but there are ways to the protocol set up
• 28:38
  in play in place to control those side effects
• 28:42
  so one is using oral drugs to control that
• 28:47
  continuous information
• 28:48
  through that mutation of GNA 11 and GNA Q
• 28:51
  the other is you know can we use that
• 28:57
  mutated
• 28:58
  or altered protein that is made from GNA 11 and GNA Q
• 29:03
  mutated gene as an address to identify those cells
• 29:08
  and deliver a payload that can target those cells
• 29:14
  so that way you're avoiding any of the you know
• 29:18
  normal cells because they won't have that mutation
• 29:21
  right so the DYP 688 is a first in class uh
• 29:29
  double targeted targeted antibody and drug conjugate
• 29:33
  antibody drug conjugate in general
• 29:35
  is an antibody attached to a toxin
• 29:39
  so the antibody portion
• 29:40
  will recognize something in the cells
• 29:43
  on the surface of the cells and binds
• 29:45
  when that target is bound
• 29:48
  that antibody
• 29:48
  drug conjugate gets internalized into the cells
• 29:51
  and the toxin gets released and it kills the cells
• 29:54
  so that's the antibody drug conjugate
• 29:57
  sometimes they're an off target effect so here
• 30:02
  it's sort of a double target
• 30:04
  um
• 30:05
  there's a one target called PMEL17 or GP100
• 30:11
  and
• 30:12
  and the other target is that it delivers not a toxin
• 30:17
  but a potent inhibitor uh
• 30:20
  or disruptor
• 30:22
  of the information that flows through GNA 11 and GNA Q
• 30:26
  so not only it's only targeting uveal melanoma cells
• 30:31
  but it also delivers a potent drug that disrupts that
• 30:35
  GNA 11 GNA Q mutated um
• 30:39
  sort of signal that's always ongoing and letting the
• 30:42
  these cells grow metastasize
• 30:44
  so this trial is relatively new
• 30:50
  um and
• 30:52
  showed benefit in individuals who
• 30:55
  received prior therapies
• 30:57
  and they've tried about five different doses
• 31:01
  4 milligrams per kilogram
• 31:02
  8 milligrams per kilogram
• 31:04
  and so and so forth and the drugs given every two weeks
• 31:07
  and shown benefit that are
• 31:11
  you know relatively durable
• 31:14
  so this is something that we're really excited about um
• 31:18
  coming through into uveal melanoma space
• 31:20
  I know it's bit complex how the
• 31:23
  how these drugs work and in addition
• 31:27
  these brand new drugs sometimes
• 31:29
  it's difficult to sort of predict their toxicity
• 31:33
  but you know
• 31:35
  without clinical trial participation
• 31:37
  we won't know um
• 31:39
  we won't be able to predict their toxicity
• 31:41
  we won't be able to
• 31:42
  sort of have the benefit established and
• 31:44
  and take them further in the future
• 31:48
  as treatment options so these were the 3
• 31:50
  4 trials that I wanted to highlight
• 31:53
  that I think we need to access and accrue to um
• 31:58
  so we can expand our tools um
• 32:01
  to help our patients with uveal melanoma
• 32:05
  absolutely and I mean
• 32:07
  we've talked several times on this podcast
• 32:09
  about how important a clinical trial is
• 32:11
  for the whole community
• 32:13
  so I love that you're bringing this to us
• 32:15
  cause this is such great information
• 32:18
  right I mean
• 32:18
  I think if for the longest time
• 32:22
  this idea which is absolutely true
• 32:25
  that uveal melanoma is so rare that it's hard to do
• 32:28
  clinical trials you know it
• 32:30
  it's hard to do clinical trials
• 32:33
  it's hard to have a
• 32:36
  let it be pharmaceutical industry or what not
• 32:39
  you know have them buy in saying hey
• 32:41
  this is a space
• 32:42
  where you should consider clinical trials right
• 32:45
  um
• 32:47
  so it it was difficult before
• 32:49
  but now you know
• 32:50
  as medical oncologists you know
• 32:52
  we're kind of binding together
• 32:54
  you know my counterparts I
• 32:55
  I can count them on my both hands
• 32:57
  you know how many I work with
• 32:59
  cause there are so few of us
• 33:01
  and so if I don't have a trial
• 33:04
  I'll send them to
• 33:05
  Dr. Chmielowski in the neighborhood at UCLA and vice versa
• 33:10
  or I'll call up Stanford see if they have any trial
• 33:14
  Doctor Reddy Doctor Betof Warner
• 33:18
  you know see if they have a trial so we can collaborate
• 33:21
  UCSD same thing
• 33:23
  and then if nothing in this area
• 33:25
  OK let's see
• 33:26
  Colorado Doctor Sapna Patel is another
• 33:29
  amazing mind for uveal melanoma
• 33:31
  you know she can help us with the trial
• 33:33
  so the community is so medical oncology for uveal
• 33:36
  melanoma is so close knit that we tend to sort of
• 33:40
  you know lean on each other to help our patients
• 33:43
  and I think that's made the difference um
• 33:47
  for getting Kimmtrak approved
• 33:50
  hopefully that'll be the reason why Kimmtrak gets
• 33:53
  you know benefit
• 33:54
  shown benefit in adjuvant setting
• 33:57
  same thing with HDAC4 inhibitor
• 33:59
  same thing with Ipi Nivo in adjuvant setting
• 34:02
  so I I
• 34:03
  I think this this
• 34:04
  sort of a network that we have of medical
• 34:08
  oncologists
• 34:09
  that are truly championing these treatments for uveal
• 34:12
  melanoma patients it's absolutely making the difference
• 34:16
  I love that that's so great
• 34:18
  the fact that you guys are all coming together
• 34:21
  it's so huge for the community
• 34:22
  and we just appreciate everything you're doing
• 34:25
  yeah no
• 34:26
  I mean I think a huge
• 34:28
  sort of kudos goes out to A Cure In Sight
• 34:31
  and other non profit organizations that are actually
• 34:35
  you know making the difference too
• 34:38
  um because you guys are always on the horn about
• 34:40
  you know clinical trials about
• 34:43
  you know advocacy
• 34:44
  patient advocacy and and talking to pharma industry
• 34:47
  you know
• 34:48
  leveraging that relationship to get these trials going
• 34:52
  I I think a big kudos goes out to you guys as well
• 34:55
  um because without that
• 34:57
  we won't have the platform to reach out to the masses
• 35:02
  well thank you
• 35:03
  we appreciate that and yeah
• 35:05
  I mean we're all here doing our part
• 35:07
  just trying to move the needle and move the mountain
• 35:10
  and and do whatever we can do
• 35:12
  so you know
• 35:14
  thank you to everyone tuning in watching this also
• 35:16
  because you guys watching
• 35:17
  this is what is bringing all of the information to you
• 35:21
  we can't do it without the viewers
• 35:22
  so thank you to you and to our sponsors
• 35:24
  yeah no
• 35:25
  I exactly I
• 35:26
  I think it's it's a village that yes
• 35:29
  you know is responsible for all the progress right
• 35:32
  one person in the Silo cannot do that
• 35:34
  so I think it's all the parties involved
• 35:37
  all the stakeholders that have deep interest in
• 35:41
  in improving the outcomes in this disease
• 35:45
  they all deserve a pat on the back
• 35:48
  absolutely and like you said
• 35:49
  it takes a village we're all in this together and um
• 35:54
  it it's great to see everybody come together
• 35:56
  I think it's a really cool thing to see
• 35:58
  yeah um
• 35:59
  I mean I think
• 35:59
  one of my favorite
• 36:01
  things about going to these small conferences
• 36:03
  or big conferences is they can hold all these medical
• 36:06
  and colleagues that have interest in uveal melanoma
• 36:08
  just sit together and it's like
• 36:10
  you know what can we do next
• 36:11
  you know how can we collaborate
• 36:13
  um what can we bring forth uh
• 36:16
  either as you know
• 36:19
  academic institution research versus
• 36:21
  you know affiliation with the pharmaceutical industry
• 36:24
  how can we work together um
• 36:27
  and every single one of them have
• 36:29
  pretty much the same goal
• 36:30
  you know so
• 36:31
  and it's really encouraging to see that
• 36:34
  I agree yeah
• 36:36
  it's wonderful so Doctor Memi
• 36:37
  thank you so much for being here
• 36:39
  I have enjoyed this and I have learned so much
• 36:41
  and I know I speak for the whole audience
• 36:43
  that we just really appreciate your time
• 36:45
  and all of that wealth of information
• 36:47
  that you just brought us oh
• 36:49
  thank you
• 36:49
  thank you for giving me the platform to talk about it
• 36:52
  and you know
• 36:54
  I'm always optimistic
• 36:56
  that we're gonna
• 36:56
  move the needle in the right direction
• 36:57
  in the future
• 36:59
  absolutely
• 37:00
  and we look forward to having you back on in the future
• 37:02
  to talk about more updates that are coming
• 37:04
  so everyone subscribe
• 37:06
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• 37:08
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• 37:11
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• 37:13
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• 37:15
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• 37:16
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• 37:32
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• 37:35
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• 37:37
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• 37:38
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• 37:41
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