FDA Approval of Zolbetuximab SPOTLIGHT / GLOW study - Upper GI Cancer with Claudin 18.2 Mutation

Introduction Hello and welcome back to another episode of the Oncology Brothers Podcast. I am Rahul Ghosain here with my brother and Co host Rohit Ghosain. Today, we're focusing on recent advancements in the treatment of G junction and gastric cancer, specifically the recent approval of zolbatuximab based on findings of the Glow and Spotlight studies. To breakdown these studies, their key findings and discuss side effect management, we're joined by the lead author of the Spotlight study, Doctor Kohei Shatara, Director of GI Oncology at the National Cancer Center Hospital in Japan. Go ahead. Thank you so much for joining us. Speaker 2 Thank you for having me. Speaker 3 Go ahead. Welcome. Prior to zolbetuximab approval, standard of care for metastatic gastric GEJ ednocarcinoma for her two negative and MSS disease has been chemotherapy. But things changed post approval of zolbetoximab. Can you start us off by touching on zolbetoximab, particularly mechanism of action and how prevalent quadrin 18.2 positive status is in GEJ or gastric cancer? Mechanism of action of zolbetuximab Yeah. So cloudy is a warms or high junction plotting which has a fence function and regulates probabilities. Cloudy 18.2 is mainly expressing normal gas mucosa cells especially site of Thai junction. But during minor transformation to gas cancer, it is exposed on tumor cell surface and become accessible and invisible target for cancer treatment and job attacks. MOB is a fasting cross IGU monoclonal antibody against clothing 18.2, which induce ADCC and CDC activity. So activities many dependent immunological reaction by NKS macrophage as well as a complementary dependent activities. And interestingly, in vitro there is no activity of job attack. SO it suggested this is not driver persuade or signal persuade. So more activity is based on immunological reaction. Important record 18.2 expression currently defined as moderate to strong expression in 75% or more tumor cells could be identified in around 30 to 40% of GASSIC acid. So this is relatively higher compared with other biomedical like all right. Speaker 1 Now that we have that foundation, go ahead. Can you touch on the studies that led to disapproval, glow and spotlight in first line metastatic G junction and gastric cancer? Study Design and Outcomes Let's start off with the study design and then we'll take a dive into the results of PFS and overall survival. Speaker 2 First trial is a spotlight study. This is a global phase three and a civil control trial to compare Zorbutax MAP +4 folks as a fast line compared with four folks plus placebo as a control arm and the key eligibility criteria include patient with clothing positive defined as moderate to strong expression is 75% or more. This is a based on central assessment and the key primary endpoint of this study was progression free survival. Oval survival as a key secondary endpoint was also statistically tested if PFS was significantly improved. This is a spotlight study and there's another similar phase three, the named growth study. The only difference is backbone chemotherapy growth study applied Capox capsidamine based resume as a control arm and there's some difference of country distribution. GROW is a more China driven trial, nearly half of patients from China, but both are global study and lead to regulatory approval. Speaker 3 Thanks for going over that, Cohey. With regards to the study design, we give full forks in general in our clinic every two weeks while K boxes every three weeks. In particular to the study designs, Orbitoximab was administered every three weeks. If we have a Fourfox patient, what is the dose of zolbetoximab? And importantly, are you giving zolbetoximab in that case every two weeks? Speaker 2 Oh, this is a very important question for clinical practice. Actually during this two phase three trial in both studies zolbetoximab was given every three weeks 800 milligram per squameria as loading dose 4 by 600 milligram at subsequent cycle. So there is a difference of treatment schedule between for Fox and the diesel document, but there's a nice simulation to show the very comparable or similar PK profile between every two weeks administration observe document starting with 800 milligram followed by 400 milligrams rather than 600 every two weeks. And based on this is simulation, current FDA label or other regulatory approval allow both every three weeks and every two weeks schedule. So after approval observe tax map. In Japan, we commonly use four forks as every two weeks in combination reserve tax map every two weeks. Speaker 1 Absolutely. OK. Now that we have to study design, can we take next few minutes to talk about the findings that led to the approval PFS And as you brought up, we also have overall survival here. Findings that led to the approval Yes, actually both global study met both PFS and OS endpoint. This slide shows a combined population. So combined patient population in both 2 studies including more than 1000 patient and actually PFS was improved from 8.2 to 9.2 in medium. So there is only one month difference in medium. But as you can see here a couple of mere cab shows a nice separation especially after medium and the hazard ratio was a .71 and looking at the two year or three-year PFS rates, it showed the more than 10%, around 10% difference between two. I'm suggesting a very good doable response in service tax, memory, treated population and looking at the over survival medium was improved from 13, 2.7 months in contrast to 16.4 months with the production of combinations. So difference in medium was 2.7 months and hazard ratio was .77 very similar to that of PFS. This OS capital MEC have also showed very nice separation at the tail of curb with more than 10% or close to 10% difference in two year or three-year survival rate. Considering this kind of survival benefit since we only have a her targeted strap you like a trusted mob and a checkpoint inhibitor like an involvement and pamphleys or arteries survival benefit was similar or not. The failure of this. So clearly this is a clinical meaningful in gastric cancer patient operation. Speaker 3 Certainly given the the PFS and now combined OS benefit, this has changed our standard of care treatment option. Cohey, with regards to testing for Claudin 18.2, this is based off of IHC testing which is usually available in house. Claudin182 testing However, if one is practicing in rural settings and don't have in house IHC testing, can this rather be covered part of NGS panel at all? Speaker 2 Yeah, this is another important question because nowadays the NGS is also commonly performed in gastric cancer or other sorry tumors. Unfortunately NGS especially exon test is not useful for clothing because this is not usually based on amplification. Right there her tube, her tube expression especially IC3 plus is a very well correlated visa hurt amplification. But same is not true for clothing because this is a just a tight tight junction protein and expression. So we need IG testing in near future if we have a more access to RNA based technology and there's some correlation between RNA expression and protein expression. So some central vendor like carries provide a such data of RNA and we have a some in house data to show nice relationship between IC and RNA. But this seem to be not available widely. So I see should be used at this stage to select patient to be treated by cell protection. Speaker 1 What I anticipate in clinical practice with NGS, you'll be requesting this and as you brought up, even other vendors are now starting to include these tests because this is indeed the standard of care. Speaker 2 Yeah, yeah. Speaker 1 Good to hear. OK, So we keep saying that this is standard of care, but before this drug was approved, a good portion of my patients even today are just on chemotherapy of that progressive disease. Combining zolpidem with irinotecan-based chemotherapy They were not exposed to zolpetuximab upfront. Is this safe to combine at the time of progressive disease with irinotecan based chemotherapy? Should we continue with FOLFOX and then add zolbutuximab? Would single agent be an option? Should we drop Oxali and irinotecan and just continue with five FU? Any thoughts here? COVID. Speaker 2 This is a still research topics. We don't have enough data or almost nothing to combine chemotherapy like Tikka or Apache Doxo in combination with the abduction of the abduction of itself is a very safe. We need to manage geotoxicity at the first infusion. But otherwise this is a very safe drug. So I assume it could be safely combined with other agent like Apache Doxil or Iron Tikka. But to be honest there's no data to support its use in quicker practice. I would just suggest using 5A3 and oxide progen combination. But that if patient already exposed to 5A3 and oxide progen and experienced this operation, I would not suggest using combination reserve tax because 5A3 and oxide progen already shows a resistance for such corporation. So to change other available agent like a pocket acid and I'm sure now should be more preferable for such patient. If there's no other treatment option, patient already received Packard XL in the TTM, then maybe we can combine with the fraternity introduction as a last option if a drug approval status or indication allow or reimbursement allow it. But at this stage we don't have enough data to support such treatment. Speaker 3 We'll see how the future study plays out with different combination, but certainly at this point in time, standard of care still remains full. Fox only being combined with zolbetoximab. If one has MSI high disease, we're going to use immunotherapy even when Clotton 18.2 is present. Chemotherapy with checkpoint inhibitors But what about that population where you have high PDL 1 score combined with positive Clotton 18.2? Speaker 2 This is Worms are most frequently asked the question after we presented this kind of data. Actually there's no direct comparison around my study to show the difference between chemo and it's a tax model and chemo plus checkpoint inhibitor. So I believe either option should be fine because of the lack of a random study. Maybe everyone now listen to FDA or that discussion to decide the optimal threshold of checkpoint inhibitor CPS or PDL 1 to use checkpoint inhibitor in front line and a final conclusion or agreement seem to exclude the patient with CPS less than one from the indication of checkpoint refutor. Looking at the subgroup analysis of combined random study, CPS 1 to 9 show the relatively limited benefit like a hazard ratio .9 very close to CPS less than one. So if patient had a clothing positive and CPS less than 10, such in direct comparison between these two phase three study and combined analysis of checkpoint and filter may support use of reserve tax map rather than checkpoint and filter. And patient with CPS 10 or higher usually drive benefit in this random study of checkpoint and filter with a hazard ratio rest on point 9.70. So maybe checkpoint inhibitor is more preferred option. But eventually a combination may overcome such, you know, debate. And it should be a most effective treatment because combined effective both treatments should be very reasonable approach and already failed to try and support such combination. So this could be future option. Speaker 1 Absolutely. Till we wait for the combination trials, we're stuck with the cross trial comparison and this is what we have where zolbatuximab might be a potential option for low CPS, whereas for high CPS checkpoint inhibitors. Coming back to side effects, Cohen, you briefly alluded to the GI toxicities that come along because of the on target effect, nausea, vomiting, diarrhea and then some peripheral neuropathy, something that we have to also worry about with oxaliplatin. GI toxicities I'm very curious to hear your thoughts on how to manage these side effects. Speaker 2 Yeah, as you mentioned, that could bind normal stomach tissue because of high affinity. Despite the tight junction function, it actually induced nausea and bonding, especially during a faster administration and inpatient with their intact stomach efficient underwent gastrectomy, especially total gastrectomy. There is no such toxicity. So clearly this is on target toxicity and the most importantly several premedication could be helpful to decrease the instance of these geotoxicity. And these pre medication include Colico steroid and K1 inhibitor 5 HD three inhibitors and olanzapine is not so effective in pregnant study. But nowadays Olansby is the ones of standard of care for patients treated by a plot number based therapy to prevent nausea or anorexia. So I tend to use olanzapine also. And another important aspect is your adjustment of infusion rate. So throwing infusion at the 1st 30 to one hour, 30 minute to one hour followed by first infusion after patient patient safety confirmation. This kind of step up those infusion is helpful. This kind of toxicity is usually manageable. As you can see in this table, actual instance of noise and bonding were higher in sub of the placebo, around 20 to 30% increase of all grade nausea and bonding and around 10% instance of nausea and bonding grade 3 or higher. But that's mentioned before that applied all kind of antimonics and a step up to the infusion. I believe this kind of instance is clearly decreased. Maybe we could interrupt the dose and give additional antimonics rescue medication after 30 minutes or around nearly 40 minutes break, usually patient could be treated by the infusion. So this is another interesting aspect because this is a different from typical infusion related reaction because we could restart their infusion. So in my clinic, based on this clinical trial experience as well as a clinical practice, I never have a patient who discontinues or protection of because of I believe you could manage it. Speaker 1 Can I come back to it's an on target effect when we're using every two weeks, it's a lesser dose. Have you seen less nausea in that every two week regimen versus every three regimen when we're giving 600 milligrams? Speaker 3 And is it only the issue for first two cycles or three cycles and it rather improves after? Speaker 2 Well, both are very important aspect. First, such an infusion related to nouns and vomit usually occur the fast administration and incidence and the severity is clearly decreased at sub second cycles. So I don't want to say only limiting fast or second cycle. But some patient experience mild symptoms at the SAD infusion. But usually this is a relatively rare even because usually happened at first cycle and the decreased at subsequent cycles. So regarding their every two weeks versus every three weeks, we don't have enough data. But interestingly fast administration and it's dose is similar. We got regardless of every two weeks and three weeks administration 800 milligram Earth grammar. Tricky aspect is this highest dose of initial infusion induce more highest highest incidence of a nose and bounding. So what we are country doing in our Japanese research group is to test fix the dose of without roading 400 milligram every two weeks from the beginning in combination with Firefox to compare current standard the dosage observe talking of 800, we can afford by 600 or 400. This is a randomized study to see whether removing loading that may decrease instance of nose and vomiting. I hope we could report such a result in the near futures. Speaker 1 Go ahead before we wrap up, given that Cloud in 18.2 Space is now starting to get crowded, be it for Zolba, Tux Map or any other agents. Any final thoughts for our listeners? Speaker 2 This is a very important aspect because many agent have been tested in this space including enhanced antibody, bispecific agent, Cartesian therapy or ADC agent. ADC agent have been tested in large random studies. ADC is almost like a cytoxic agent to 0 toxins. It should be managed. I believe this is one of the most promising agent. CAR T is a relatively new technology and not widely used in GA cancer. But a Chinese study of chronic 18 targeted CAR T shot a very promising result with a 40 to 50% response rate in data line setting. And recent press release from company indicate improvement of TFs with CAR T compared to with sad Ryan later and Kim's right, I believe we could see the detail. So this forms are very attractive field and target population. The outcome should be improved in these new Asian. Speaker 3 Well, exciting times indeed. Congratulations on this approval. I'm glad to have more treatment options available for our patients today. Thank you so much, Doctor Shatara for taking the time to go over glow and spotlight studies that have in fact led to the approval of zolvitoxifab for metastatic GE junction and gastric cancer. For our listeners, let us go over a quick Rahul. Neither of us were involved in the clinical trials for zolpituximab, but this has now been approved for almost about 3 months. It was nice to learn the insurance and outs of the trial from leading author himself, Doctor Kohei Shatara from Japan, whose efforts have resulted in the approval of Zolpituximab. Rahul, have you had a chance to use this in your practice yet? And what are your key takeaways for this conversation today? Speaker 1 Yeah. Key Takeaways First thing here is the importance of testing for Klotin 18.2 and of course MSI high status, PDL one status and her two expression For us, we've been lucky that we have in house IT testing for Klotin 18.2. You brought up if I've used this yet in my practice for first few months, I have these patients that have Klotin 18.2 mutation, but I've been on first line treatment which is chemotherapy and the dilemma has been they've not been exposed to zolbutuximab. What next? We know that single agent response is very low. In my practice in a slow progression, I am considering this with five FU as a combination or moving right along with what's available and then maybe trying to circle back with zolpituximab, a patient that's being diagnosed with gastric junction. Now this is standard of care. And of course, we have to keep nausea, vomiting and decreased appetite as common side effects in mind. Rohit, your thoughts here? Speaker 3 Rahul, I couldn't agree more with how you're managing. Managing side effects with any new treatment is always the key. Based on the data we have overall survival with all the toximab plus chemo, this is indeed the new standard of care. Thanks for joining us. 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