THERANOSTICS- TRANSLATING IMAGING TO THERAPY IN CANCER

Transcript

• 00:01Alright. So our next speaker
• 00:03on the,
• 00:05imaging translation is doctor Pam
• 00:06Koons, who did her undergrad
• 00:09and her medical,
• 00:10studies at Dartmouth.
• 00:12Then she completed medical residency
• 00:13and chief residency oncology fellowship
• 00:15at Stanford. She joined Yale
• 00:17in twenty twenty. She's the
• 00:18division chief of, GI medical
• 00:20oncology there here, and the
• 00:22director of the center for
• 00:23GI cancers at Yale Center,
• 00:24in the Smilow Cancer Hospital.
• 00:26She has focused her career
• 00:27on patient care and clinical
• 00:29research in the field of
• 00:29neuroendocrine tumors, and she is
• 00:32one of the two gurus
• 00:33of the NETHER three trial,
• 00:34which I'm sure we'll hear
• 00:35about.
• 00:40Great. Thank you so much.
• 00:41It's a pleasure to be
• 00:43here.
• 00:44So I will be talking
• 00:45about theranostics. So I'm going
• 00:47to first start with some
• 00:48definitions and then give three
• 00:50examples.
• 00:51So theranostics is an approach
• 00:54using a combination of molecularly
• 00:56targeted therapy and diagnostic imaging
• 00:58using the same target.
• 01:00So imagine you have a
• 01:01population of patients for whom
• 01:02you would like to select
• 01:03a target.
• 01:05You have an imaging tool
• 01:06that can identify that target,
• 01:08and then you have a
• 01:09therapy that can go to
• 01:10that exact same target.
• 01:13I like to use the
• 01:14lock and key principle as
• 01:15we think about describing theranostics.
• 01:18So the lock is the
• 01:19target in the case of
• 01:20neuroendocrine tumors. That's the somatostatin
• 01:23receptor or prostate cancer. That's
• 01:25prostate specific membrane antigen.
• 01:27There's then a,
• 01:29compound of a ligand, linker,
• 01:31and radionuclide.
• 01:32The chelate chelator grabs on
• 01:34to the radionuclide, and that
• 01:35can either be an imaging
• 01:37radionuclide
• 01:38or in the case of
• 01:39therapy,
• 01:40a therapy
• 01:41radionuclide such as lutetium one
• 01:43seventy seven, which emits beta
• 01:45particles,
• 01:46or actinium two twenty five
• 01:47and lead two twelve, which
• 01:48emit alpha particles.
• 01:51So in nineteen forty one,
• 01:53Saul Hertz was the first
• 01:54to use I one thirty
• 01:56one therapeutically
• 01:57for treatment of hyperthyroidism
• 01:59and later thyroid cancer. And
• 02:01I third one thirty one
• 02:03in nineteen fifty one became
• 02:04the first radiopharmaceutical
• 02:06that was FDA approved for
• 02:08thyroid disease.
• 02:10So theranostics is really a
• 02:12package deal. We think of
• 02:13them as theranostic
• 02:15pairs.
• 02:16So there's a diagnostic imaging
• 02:18component and a therapy component.
• 02:20So in the field of
• 02:21neuroendocrine tumors, we have two
• 02:23options for imaging,
• 02:25gallium sixty eight or copper
• 02:26sixty four DOTATATE PET, and
• 02:28the therapy pair is lutetium
• 02:30one seventy seven DOTATATE.
• 02:32And in prostate cancer, that
• 02:34pairing is an imaging tool
• 02:36of gallium sixty eight PSMA
• 02:37eleven PET, and the therapy
• 02:39is Lutetian PSMA six seventeen.
• 02:43So I think theranostics is
• 02:45more hope than hype, although
• 02:46it's been a lot it's
• 02:47been hard to convince the
• 02:48oncology community.
• 02:50It's here to stay and,
• 02:51in my opinion, is one
• 02:52of the most exciting new
• 02:53cancer therapies.
• 02:54We've really seen an explosion
• 02:56of both clinical trials and
• 02:58publications as you can see
• 02:59really just in the last
• 03:00decade.
• 03:02So the three examples I'd
• 03:03like to give are in
• 03:04neuroendocrine tumors, prostate cancer,
• 03:07and meningioma,
• 03:08and this includes
• 03:09key clinical trials with Yale
• 03:11investigators in all three of
• 03:12these areas.
• 03:15My own area of clinical
• 03:16research and patient care is
• 03:18in the field of neuroendocrine
• 03:19tumors, and I'd like to
• 03:20use this as a model
• 03:21to help us think about
• 03:22theranostics.
• 03:23So NETs are epithelial neoplasms
• 03:26derived from Nurnichen cells throughout
• 03:27the body most commonly found
• 03:29in the GI tract.
• 03:31NET incidence and prevalence are
• 03:32on the rise, making this
• 03:33a more important public health
• 03:35problem.
• 03:36Chromosome alterations are common, yet
• 03:38somatic mutations are rarely actionable.
• 03:40Therefore, we've not been able
• 03:41to take advantage of some
• 03:42of the standard other targeted
• 03:43therapies in the field.
• 03:45The World Health Organization classification
• 03:47system has really evolved over
• 03:49the last thirty years and
• 03:50now includes
• 03:52degree of differentiation
• 03:54and grade that includes k
• 03:55I sixty seven. And lastly,
• 03:57pathognomonic
• 03:58for NETs is somatostatin
• 04:00receptor
• 04:01expression, which occurs in over
• 04:03eighty to ninety percent of
• 04:04patients.
• 04:05There are several therapeutic
• 04:07categories, including SSAs,
• 04:09targeted therapies, cytotoxic
• 04:11chemo, immunotherapy,
• 04:13and lastly, the newest component
• 04:15is radioligand therapy.
• 04:18The two clinical trials that
• 04:19put radioligand therapy on the
• 04:21map for NETs are NETTER
• 04:22one, which looked at lutetium
• 04:24dotatate versus octreotide
• 04:26in progressive
• 04:27midgut NETs with a low
• 04:29k I sixty seven.
• 04:31This trial met its primary
• 04:32endpoint of progression free survival
• 04:34and ultimately led to the
• 04:36first FDA approval of lutetium
• 04:38dotatate and GAP NETs.
• 04:40NETTER two was a follow-up
• 04:42study, looked at lutetium dotatate
• 04:44versus octreotide in the first
• 04:46line setting in slightly higher
• 04:48Ki sixty seven, also met
• 04:50its primary endpoint of progression
• 04:52free survival, and actually represents
• 04:55the first randomized trial to
• 04:57look at first line therapy
• 04:58in any solid tumor and
• 05:00is included in the NCCM
• 05:01guidelines.
• 05:03NEDR three is a trial
• 05:04that just launched about a
• 05:06week ago.
• 05:07We are a lead site,
• 05:09and I'm serving as international
• 05:11cochair for this study. So
• 05:12this is a randomized study
• 05:14of lutetium dotatate
• 05:15versus octreotide,
• 05:17also in the first line
• 05:18setting for lower k I
• 05:19sixty seven, but high tumor
• 05:21burden patients,
• 05:22those who have larger tumors
• 05:24or symptoms from tumor bulk
• 05:25or hormones.
• 05:26In red, you can see
• 05:28that Yale will be serving
• 05:29as a key site for
• 05:30pharmacokinetic
• 05:31and dosimetry
• 05:32sub studies.
• 05:34We are one of two
• 05:34sites in the US doing
• 05:35this, and this is in
• 05:36partnership with the Pet Center.
• 05:39So many of the challenges
• 05:41and opportunities
• 05:42stem from the patients that
• 05:43we see in clinic.
• 05:45Number of patients have kidney
• 05:46disease and are not currently
• 05:48eligible for giving radioligand therapy,
• 05:51and I think this is
• 05:51an opportunity for us to
• 05:52think about.
• 05:54Extensive bone metastases have a
• 05:56theoretical risk of increased myelosuppression,
• 05:58and this is poorly studied.
• 06:00The new WHO cry or
• 06:02classification of well differentiated grade
• 06:04three tumors were historically
• 06:06excluded from trials,
• 06:08but now in two recent
• 06:09studies have just been included.
• 06:11The area of retreatment is
• 06:13an active area of research
• 06:14included in three ongoing trials.
• 06:17And then development of MDS
• 06:18and AML, which occurs in
• 06:19about two to three percent
• 06:21of patients receiving radioligand therapy,
• 06:24I think is something that
• 06:24we need to examine further
• 06:26and identify which of these
• 06:27patients are at risk.
• 06:30Just as an example, there
• 06:32are also a number of
• 06:33early phase trials looking at
• 06:34combination therapies with radioligand therapy,
• 06:37including cytotoxic
• 06:39chemotherapy,
• 06:40immunotherapy,
• 06:41DNA damage response inhibitors, which
• 06:43I think is a fantastic
• 06:45opportunity for Yale to lean
• 06:46into given our deep expertise
• 06:48in that area and other
• 06:50agents such as tyrosine kinase
• 06:51inhibitors.
• 06:54Moving on to prostate cancer.
• 06:56PSMA expression in prostate cancer
• 06:59occurs in about eighty to
• 07:00ninety percent of cases.
• 07:02The vision trial, which was
• 07:04a phase three trial in
• 07:05metastatic
• 07:06castrate resistant prostate cancer, looked
• 07:09at PSMA six seventeen lutetium
• 07:12PSMA six seventeen
• 07:13versus standard of care. It
• 07:15met both the, primary endpoints
• 07:17of progression free survival
• 07:19and overall survival and led
• 07:21to the FDA approval of
• 07:23this agent in just twenty
• 07:24twenty two for patients who
• 07:26progressed on both androgen receptor
• 07:28pathway inhibitors and taxane based
• 07:30chemotherapy.
• 07:32The follow-up study to this
• 07:33was the PSMA four phase
• 07:35three trial,
• 07:37which brought this a step
• 07:38earlier in the disease course,
• 07:40looked at lutetium PSMA six
• 07:42seventeen
• 07:43versus an ARPI
• 07:44change, so really eliminating taxanes,
• 07:48and and bringing the lutetium
• 07:50PSMA earlier. This also met
• 07:52its primer endpoint of PFS,
• 07:54and the FDA
• 07:56expanded its indication in twenty
• 07:58twenty five.
• 08:00What's exciting is that doctor
• 08:02Dan Petrillac is leading a
• 08:03new randomized phase two trial
• 08:06of luxigalutamide
• 08:08plus lutetium PSMA
• 08:09six seventeen
• 08:11in patients, with metastatic
• 08:13castrate resistant prostate cancer.
• 08:16Luxigalutamide
• 08:17is an oral PROTAC or
• 08:18proteolysis
• 08:19targeting chimera
• 08:21developed here in the lab
• 08:22of doctor Craig Cruz, who
• 08:24has appointments in the departments
• 08:25of chemistry and pharmacology.
• 08:28And then moving on to
• 08:30meningioma,
• 08:31over seventy to a hundred
• 08:32percent of meningiomas
• 08:34express somatostatin
• 08:36receptor type two, so that
• 08:37same receptor we talked about
• 08:38for NETs,
• 08:40and this is regardless of
• 08:41grade.
• 08:42Doctor Sylvia Kurz in neuro
• 08:44oncology is one of the
• 08:45study chairs for a new
• 08:47national clinical trial network trial
• 08:49through, RTOG.
• 08:51That's a phase two study
• 08:52of lutetium dootatate versus standard
• 08:54of care in progressive intracranial
• 08:56meningioma.
• 08:57This is also soon to
• 08:58open.
• 09:00Lastly, though this is not
• 09:01formally a radioligand therapy,
• 09:04biology guided radiotherapy
• 09:06is truly part of the
• 09:07theranostics family. So Syntyxt BGRT
• 09:11on this on a reflection
• 09:12x one unit
• 09:14tracks f eighteen FTG PET
• 09:15tracer emissions
• 09:17to really guide RT depending
• 09:19on how the tumors move.
• 09:22So
• 09:23biology guided radiotherapy is approved
• 09:25for both primary and metastatic
• 09:28lung and bone cancers.
• 09:30Yale was the first in
• 09:31the northeast to install a
• 09:32unit and the first to
• 09:34treat a patient with BGRT
• 09:35in a single plan.
• 09:38So I think picking on
• 09:39a theme that was mentioned
• 09:41earlier,
• 09:42theranostics
• 09:42in particular is multidisciplinary
• 09:45and interdisciplinary,
• 09:46and this partnership will really
• 09:48lead to excellence in both
• 09:49patient care and research innovation.
• 09:51This slide is not all
• 09:53inclusive, but really is an
• 09:54indication that this is cross
• 09:56departmental,
• 09:57cross centers, and cross groups.
• 09:59And I anticipate that this
• 10:01list will expand as we
• 10:02bring in more basic and
• 10:03translational science.
• 10:06So theranostics
• 10:07is really a game changer
• 10:08and has been for the
• 10:09field of neuroendocrine tumors so
• 10:11far. We hope to optimize
• 10:12its use through better patient
• 10:14selection,
• 10:15decreasing toxicities, and increasing efficacy.
• 10:18New trials have you seen
• 10:19as you've seen are examining
• 10:21novel ligands, radionuclides,
• 10:23and combinations,
• 10:24and starting to look at
• 10:26other new indications in solid
• 10:27tumors, such as colon, liver,
• 10:30pancreas, breast, and lung. And
• 10:32I think that Yale has
• 10:33an opportunity to be a
• 10:34leader in this space. So
• 10:35thank you.