Tevimbra (tislelizumab-jsgr) for esophageal cancer and gastric cancer

Transcript

My name is Kirollos Hanna. I'm the director of pharmacy with Minnesota Oncology, a US oncology practice. I'm also an assistant professor at the Mayo Clinic College of Medicine. I'm really excited to talk to you all today about a new immunotherapy option titled tislelizumab-jsgr. Within the United States, this drug is branded under the brand name Tevimbra. It is important to note that in Asia this immune checkpoint inhibitor has been in the market for quite some time. Now when we look at tislelizumab, it is not the first-in-class medication. It is a PD-1 inhibitor, and I'm sure as many of you are familiar, our PD-1 PD-L1 inhibitors work to really prevent the immune system from being evaded by the tumor. So when we look at PD-1 or PD-L1 inhibitors, they're able to bind to PD-1 or PD-L1, which is the ligand to ultimately allow the immune system to rev up and to attack specific cancer cells.

As it relates to tislelizumab, within the United States, it does have an FDA approval for esophageal cancers as well as gastric cancers based on the Rationale 302 study as well as the Rationale 305 study, which we'll discuss during this quick overview. Now in terms of administration, it is important to highlight that tislelizumab is administered as a 200 mg intravenous infusion. It is given every 3 weeks. And for the most part, the recommendations on label are to administer the first dose of the medication over 1 hour or 60 minutes. And if patients tolerate therapy, you'll find that most patients do tolerate therapy well and the rates of infusion reactions or unlikely these patients can then move on to a 30-minute infusion after tolerating at least one dose at that 60-minute mark.

Now it is really exciting to highlight some of the clinical efficacy as it relates to tislelizumab. Both the gastric cancer space as well as the esophageal cancer space have had immunotherapies within this particular space. And it is also important to call out that within both the gastric and the esophageal cancer space, you'll sometimes find that there are nuances that are going to be important to pay attention to. With some therapies, it will matter if a patient is PD-L1 positive or PD-L1 negative. So you'll start to look at the degree of PD-L1 expression, and sometimes that is called out. In the case of tislelizumab in the gastric cancer space, there is a small degree of expression that is required, which I'll delve more into. In other cases as well, you might find the guidelines and some of the recommendations revolve around things like DNA mismatch repair or microsatellite unstable tumors or that microsatellite instability high tumor type because we certainly know that the immune system plays a critical role in that particular population as well.

Now, it's not fully understood why both in the esophageal and gastric cancer space, that we sometimes do also tend to see certain subsets of patients have resistance to immunotherapy. This is an ongoing area where we are continuing research to delve more in depth as to what biomarkers or characteristics of the disease are prevalent as it relates to some mechanisms of resistance. Now, to highlight quickly before we delve into the clinical trials, what the indications are both in esophageal and gastric cancers, it is important to highlight that tislelizumab is approved as monotherapy or as single agent in adult patients with unresectable or metastatic esophageal squamous cell carcinoma. You'll find it abbreviated throughout as ESCC, and these are patients who have progressed after prior systemic chemotherapy, oftentimes that's cytotoxic in nature and that these patients were not previously exposed to a PD-L1 inhibitor. In the gastric cancer space, it is approved as frontline treatment in the unresectable or metastatic space.

However, this is in combination with platinum and 5-FU based chemotherapy. These are adult patients and these patients have to be HER2 negative as it relates to the gastric cancer or gastroesophageal junction adenocarcinomas. And these patients do have to have some degree of PD-L1 expression. So when you look at the on-label approved indication, it does require PD-L1 expression of at least 1%. So that's going to be something that is going to be important to keep in mind.

Now, I want to delve right in and highlight the clinical trial that led to the approval both in that esophageal population as well as the gastric cancer population. We'll first focus on the esophageal population. As I mentioned, this is a previously treated unresectable or metastatic esophageal cancer patient. When you look at the guidelines and the recommendation for frontline management, you'll find a lot of CAPOX-based regimens, 5-FU plus oxali-based regimens. You might see some immunotherapy as well in some of those combinations in the frontline population, but again, pay attention to some of the caveats I called out like PD-L1 expression or mismatch repair or DNA mismatch repair. So these are going to be important things that we have to keep in mind in terms of what they were previously exposed to.

So particularly now in the squamous cell carcinoma population, the Rationale 302 study was multi-center randomized. It was a one-to-one randomization open-label trial that looked just above 500 adult patients with unresectable advanced or metastatic ESCC who have progressed on at least one prior systemic therapy. Now, when we looked at the study schema, particularly within this trial, these patients were randomized in a one-to-one fashion to receive tislelizumab at the 200 mg every 3 week dosing or investigator's choice of chemotherapy. So when you look at that investigator's choice of chemotherapy, that could have been a taxane, it could have been irinotecan, really whatever the standard of care is based on the geographical region that these patients were treated and treatment was continued until progressive disease or unacceptable toxicity in this population.

Now, it is important to highlight that this study, the major efficacy outcome, was looking at overall survival in the entire population, so the ITT, but we also looked at things like progression-free survival response rates as well as the duration of response. When we broke it out then and then looked at the actual efficacy outcome, the hazard ratio as it stemmed from the primary endpoint of overall survival was 0.7, meaning that there was a 30% relative risk reduction of having an overall survival event, so ultimately succumbing to the disease. The median overall survival benefit that was observed with tislelizumab in about 250 patients was 8.6 months versus the investigator's choice of chemotherapy was about 6.3 months.

Now, when we looked at the progression-free survival as well, the hazard ratio there was 0.83. And when we looked at the degrees of responses, so the overall or objective response rates were about 15% in the patients who received tislelizumab and only 6.5% or 6.6% in terms of the investigator's choice of chemotherapy. I'm going to wait before I delve into some of the safety information that we saw from Rationale 302 until I cover the efficacy outcomes from 305, which was in the gastric population because the safety profile is something that many of us are very accustomed to as it relates to immunotherapy. Now I do want to mention within the esophageal population, so again from the Rationale 302 study, in the NCCN guidelines, tislelizumab does have a category 1 recommendation as well. Now this is obviously dependent on prior therapy exposure. If you've progressed on prior know immunotherapy, it may not be the most appropriate option, but it's right there in line as we've seen other immunotherapy as well in that squamous cell carcinoma histology population in the esophageal group of patients.

So to pivot and then talk about gastric cancers, it's important for us to highlight here the Rationale 305 study. Now, the 305 study looked at a previously untreated unresectable metastatic patient had gastric or gastroesophageal junction tumors adenocarcinomas that expressed some degree of PD-L1 expression. The cutoff here was at least 1%. So you don't really have to have a high degree of expression, but the important thing to call out is that these patients were HER2 negative because we know the HER2 space is also a targetable mutation in this population as well. So the Rationale 305, this was randomized multi-center placebo controlled study. It was a double-blind trial in this population. So when we look at the study schema, it is important to highlight that these patients receive either tislelizumab or placebo in combination with CAPOX or cisplatin 5-FU combinations. So that is the standard of care in terms of a chemotherapy backbone, but then you either combine it in the study with immunotherapy or placebo to see the benefit observed.

Now here they looked at various tools that can assess for PD-L1 expression. They looked at combined positive scores. This is something that many of us are already familiar with, but you might also see if you look or delve into the data, something abbreviated as TAP, which is tumor associated immune cells and looking at the degree between the tumor and the tumor associated immune cells and the degree of PD-L1 staining in that tissue as well. So this is the tumor microenvironment versus the combined positive score, which looks at your tumor micro environment as well as looking at your immune cells as well. So these are going to be important things to highlight. And again, CAPOX or cisplatin 5-FU were the backbone of this. Now, when we looked at the with tislelizumab, with chemotherapy versus placebo with chemotherapy, there were about 400 plus patients in each of those arms.

And when we looked at the degree of PD-L1 expression based on that TAP, the tumor associated micro environment, we saw an overall survival benefit. The primary endpoint, the median overall survival was 15 months versus 12.8 months with a hazard ratio of 0.78. But even when we looked at it a little bit further and looked at the combined positive score of 1% or greater, it was right in line with what we saw using other tests to look for PD-L1 expression. So the median overall survival was 15.1 months when we looked at the CPS of at least 1% and 12.9 months as it relates to placebo with chemotherapy. The hazard ratio was exactly the same at 0.78. Progression-free survival really in both arms that received tislelizumab with chemotherapy, it was 6.9 to seven months, and then the placebo plus chemotherapy in either arm, whether it was the PD-L1 expression using the TAP methodology or PD-L1 using the CPS methodology, it was 5.9 to 6.4 months.

We still saw a hazard ratio of about a 23%, 24% reduction in likelihood of an event associated with progression free survival. Response rates also across the board favored the combination of immunotherapy with chemo, with immunotherapy, with chemo being close to 50% and placebo with chemotherapy being around 40%. Now, it is important for us to highlight that we will certainly see some safety events from this particular product, but the good thing is I think many of us are very familiar with immune related adverse events associated with immunotherapy. PD-1, PD-L1 inhibitors, CTLA-4 inhibitors and such have been around for a long time. We've seen these stem in melanoma decades ago, and we've developed protocols and criteria and we see guidelines to help us navigate how we manage these patients.

A lot of your important adverse events to keep in mind that you may see in this population are going to be your liver toxicities. So always check for hepatitis, your ASTs and ALTs as regular laboratory monitoring parameters. You're going to see endocrinopathies, so don't just focus on hypothyroidism, but you could also see various other endocrinopathies like hypophysitis and various other things. You could see diabetes. Now the most common and why we monitor generally thyroid activity and thyroid function is because of the hypothyroidism that generally manifests. You may also see GI side effects, so some type of immune mediated diarrhea or colitis and managing that. And of course skin toxicities are going to be something that we see. So assessing the patients, looking at their extremities, looking at their chest, looking at their back are going to be also very important things that we assess for.

Now, based on where you're using this product, you could have it combined with something like CAPOX. So when we combine it with some of the other therapies, it is going to be important for us to keep in mind that you might have shared adverse events, and it's going to be important for us to really hone in on what is the causative agent. When you look at something like the CAPOX regimen, these patients are on capecitabine and can have skin toxicities, but that generally manifests in terms of something like a hand and foot syndrome versus an immune mediated rash.

So being able to differentiate and address one or the other is going to be very important. But you can also see shared toxicities like diarrhea. When you see that diarrhea, and if you tried anti-diarrheals for example, and they have it resolved, you might want to start to think that this may be immune-related and you might have to initiate a course of steroids in this patient population. Now, while we talked about some common immune-related adverse events with tislelizumab, immunotherapy really introduces anything that could stem from an inflammatory process. So just because you don't see a liver toxicity and endocrinopathy, a GI toxicity or a skin toxicity, it doesn't mean that your patient couldn't go on to develop myocarditis, myositis, uveitis.

There are extremely rare immune-mediated adverse events, and unfortunately despite the years that we have under our belt in terms of experience with immunotherapy, there's really no good predictive strategies of which patient is going to develop some type of immune-related adverse event, when they're going to develop that immune-mediated adverse event or how severe that immune-mediated adverse event is going to present. As for the most part, when we do see these, when you get into a grade two, grade three toxicity, we do start to consider holding and initiating some type of immunosuppression. Nine times out of 10, it'll start with steroids and be resolved with steroids. When you start to get into the grade fours, those generally to discontinuations. Not that you couldn't get a grade three that also leads to a discontinuation, but it is just important to highlight that for the most part, we do initiate steroids, whether it's topical for something like a rash or whether it's systemic for maybe something more severe, something refractory that's not responding to topical.

And in some cases, if it's severe enough, these patients may require hospitalizations utilizing things like TNF alpha inhibitors and much more aggressive immunosuppressants. I think overall within this gastric as well as this esophageal space, it's been a really exciting time for patients. Really excited to see this product come to market. And as I mentioned earlier in this conversation, we've known that this drug has been active and effective outside of the United States. There are multiple ongoing clinical trials within the US, and I anticipate that the future is likely going to be bright in terms of potential added indications.