Dr. Janjigian:
Welcome to From Diagnosis to Durability: Elevating Outcomes in Gastroesophageal Adenocarcinoma, our ASCO Post Roundtable. I'm Dr. Yelena Janjigian, Memorial Sloan Kettering medical oncologist in New York City. And I'm joined today by my colleagues, Dr. Maron and Dr. Molena, who will each discuss unique aspects of this case as a medical oncologist, but also a surgeon. Our final case will focus on patient with distal esophageal HER2-positive disease, my favorite topic.
All right, so this is a 55-year-old woman who is a singer and has a history of hiatal hernia and type two diabetes, chronic bile reflux. And she's really keen on seeing a team that is outside the box thinkers. She's really interested in avoiding surgery, scared of surgery. And so she's there, presents with progressive dysphasia, 40-pound weight loss, a bit of a distrust to the system and was avoiding her doctors. In an endoscopy, there's a distant esophageal mass, moderately differentiated, and endoscopic ultrasound showed a T3N0 tumor. Her concern is really voice preservation and being able to continue to use her body to and work.
So on endoscopy, clearly this is the adenocarcinoma and on biopsy, HER2-positive IHC3+, microsatellite stable, PD-L1 positive CPS 5, claudin positive as well, with 90% expression. So really the dilemma, she was offered a combination of durvalumab with flood and surgery by her other team elsewhere. And she presents seeing the medical oncology team, but also the surgery team at our institution to discuss what else is out there, "Can I really avoid recurrent laryngeal nerve paralysis? I want to try to not have surgery, and what are my nonoperative pathway options?"
So really the importance, of course, of this case is that she does have multiple targetable biomarkers, including tumor targets and also immune checkpoint blockade targets. So Daniela, I'm sure you see these cases because our patients are increasingly younger and younger. And how do you counsel these patients?
Dr. Molena:
Well, I'm always very happy when there are either targets or good PD-L1 expression or options for patients. Honestly, I'm a surgeon. I love to operate people, but I love to see them cured. And if we can cure them without an operation, I'm happy about that. And so when I see patient like that, we're lucky enough that at our center, we have a trial that is specific for this disease.
But before the trial, it was there. Yelena and I sometime make reasons why patients should go on a treatment like this because we've seen it. We've seen great response. I feel comfortable and confident that if surgery is needed in the future, we'll be able to do it safely. But if there is an option and a possibility to avoid that and still have cure, then I am definitely all in it.
And so I talk with that very honestly with the patient. I tell them it's not standard of care. I tell them that probably this kind of approach is only available in center like ours where we have trials, where we think a little bit out of the box, but maybe in the future I'll be available for other patients as well. And then I tell them that the most important thing is very close surveillance after and during treatment, because surgery is always an option, and we can always do it if needed down the road.
So, the only fear that as a surgeon sometime I have is saying, all right, are we missing the boat? Is it something going to come up in the future that can make surgery not possible? But in my honest view is when you have a really good team and a strong collaboration, you look at these patients very, very carefully and very closely, I think that happens very rarely. So, that's my experience.
Dr. Janjigian:
Thank you. And Steve, so tell us a little bit about the approach with durvalumab and FLOT and what else are we doing that we could do building on that for HER2-positive disease?
Dr. Maron:
So, durvalumab and FLOT has really been a game changer for us, in that now we do have access for nearly all of our patients for receiving neoadjuvant PD-L1 blockade, whereas we had a big gap in our care, and this is in conjunction with aggressive chemotherapy. But the problem we see is that many patients have considerable toxicity from their chemotherapy. Our older patients can really struggle with this, and especially for patients where it's really important that they have good function of their hands, of their feet, if you have durable neuropathy, this could really be a life-changing toxicity that you get.
And so when I see something like this HER2 positivity, it makes me think, can I lean in on the immunotherapy? Can I lean in on the HER2 blockade and deescalate the chemotherapy, yet still get really high objective response, deep pathologic complete response, and increased cure? And so when I see a case like this, it makes me think, can I treat with the KEYNOTE-811 type paradigm or even actually escalate that to FLOT to get these deeper responses?
And when we then get these deeper responses, as we've seen with more recent data, can we go one step further and even avoid the surgery? I know Dr. Molena is an incredible surgeon, but I don't think she'd be upset if I put her out of business.
Dr. Molena:
I'm not sure you'll ever put me out of business.
Dr. Maron:
I can try.
Dr. Molena:
I'm sure there's more complicated patients coming my way.
Dr. Janjigian:
That's right. Well, we could just cure more people with metastatic disease, right?
Dr. Molena:
Exactly.
Dr. Janjigian:
But that's a great point, Steve. So of course we know all HER2 patients can be quite... HER2 disease can be quite different in responses. So, just to make your life easier, I'll make it... I mean, the case was a great case because very high level of HER2 overexpression by IHC, uniform staining. And on next generation sequencing, we see high level of amplification, and this looks like there is a RTK wild type, no EGFR amplification, no MEK amplification, and it's a very sort of mild, favorable P53 mutation variant. So, do you find that reassuring?
Dr. Maron:
Very much so. And the data we've published together, we've found that the patients with the highest degree of amplification, with the most homogeneous amplification of HER2 do the best, especially in the absence of known resistance mechanisms such as KRAS alterations.
Dr. Janjigian:
Great. And so what would you offer this patient? Well, I could tell you the patient went on a study. She did receive FLOT plus pembrolizumab and trastuzumab and was very excited to see that in our informed consent together, again, approved by all of our very skilled and thoughtful thoracic surgeons, there is a nonoperative management option with a DMT review, disease management team review, and support. These patients are being followed very carefully.
And what we do also in this trial is that we give the six cycles of perioperative therapy. So, you give longer perioperative therapy practically because we know that patients tolerate treatment better before surgery rather than after, but also to allow for maximum response. And these patients are able to, of course, get dose reductions if needed. I think anything beyond six cycles of FLOT can be quite tough, and we also don't want to lose the opportunity to cure someone with surgery.
And so this patient had a great response, clinical complete response resolution of all FDG avidity in the primary tumor and on serial biopsies. They get very close, 10 biopsies of this area were negative. And of course, she's being monitored closely for recurrence, and we're also monitoring them with circulating tumor DNA.
So, the key takeaway for this case is that we know now emerging data from studies like SANO teach us that patients can undergo nonoperative management with closed surveillance, but that most patients with adenocarcinoma do need surgeries. In fact, there's still very high probability that they will need surgery further down the line if the tumor has local recurrence. But we are so far in this study have not had any cases like that.
For well-selected patient populations such as this patient, particularly with both tumor targeting and immune checkpoint blockade option, we are able to intensify therapy and may be able to do this broadly, adopting it to nonoperative paradigm, as of course, was already studied in certain subsets of MSI tumors. And then we are always really hoping for further improvement in treatment options and surveillance to be able to predict who will be the patients with complete response and how we can make sure that those responses are durable to really optimize this approach.
And this brings us to the end of case 3. Please see the other segments for further discussion about the latest research in gastroesophageal cancer, and of course, visit us at ascopost.com. Thank you very much.
