ADCs in Non-Small Cell Lung Cancer

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Edward S. Kim, MD, MBA: I’m going to turn it over to Dr Spira now and he’s going to walk you through some of the actual targets of interest.

Alexander Spira, MD, PhD, FACP: Thanks, Ed. It does amaze me; you pointed out [that] there’s a lot that’s already approved. I think what’s lost in this is that the technology to combine an antibody—the linker protein that hooks it all together, and then the warhead of the drug conjugate—seems so simple. And it is right now. You can almost put an infinite number of targets and warheads on, which makes this area ever growing. But here are the main areas of interest as we talk about non-small cell lung cancer in particular. HER2, we know about the story in breast cancer and heard a lot of it at ASCO [American Society of Clinical Oncology’s Annual Meeting] a couple of weeks ago. We know that they’re activating mutations, which is different from what we think about HER2. When you think about HER2 breast cancer, you’re really thinking about IHC [immunohistochemistry]. But here, you’re talking about HER2-activating mutations, which are present in about 2% to 3% of lung cancers. HER3, slightly different¼I actually did another talk on this just a few days ago. It’s an antibody-drug conjugate [ADC] against HER3. These are targets for a couple of reasons. One, it’s overexpressed, but they’re actually looking at ADCs in these “naked antibodies,” as we like to say, for things such as NRG1 fusions also. One of the hottest topics [is] there are now approved drugs for certain malignancies, not in lung cancer yet, but TROP2. TROP2 is an embryonal transmembrane protein that sits on the chromosome. It’s expressed mainly in cancer cells, and very overly expressed in multiple human epithelial cancers, and we’ll talk a lot about that today. CEACAM5, so it’s related to carcinoembryonic antigen, the CEA [carcinoembryonic antigen] test that we do. There’s an antibody-drug conjugate against that. And then finally c-MET. There are some being developed in c-MET, which is very common in lung cancer. Again, slightly different, but also works in the exon-14 skipping mutations that we already have approved drugs for. But here we’re talking more about overexpression as well. So there are a lot of targets right now, and I’m sure there’ll be many more coming. Here are some in particular that are being looked at in small cell lung cancer: We have trastuzumab deruxtecan and ado-trastuzumab emtansine. The DESTINY-Lung01 studies (NCT03505710, NCT02289833). T-DXd, I think that’s how a lot of us refer to trastuzumab deruxtican. There has been a lot of data on that recently at ASCO and the breast world. But there’s clear evidence in the non-small cell lung cancer world [also]. And I believe it’s already on guidelines for these HER2 insertion mutations. TROP2, we’ll spend a little time talking about these today. Datopotamab is an antibody against TROP2 with the warhead deruxtican. Sacituzumab govitecan is actually already for triple-negative breast cancer [TNBC] and bladder cancer as well. None of these have approvals yet in the lung cancer world, but they’re obviously being studied and part of what we’re talking about today. You can see the TROPION-PanTumor01 (NCT03401385) and TROPION-LUNG01 (NCT04656652) studies as well as the EVOKE (NCT05089734) studies. Patritumab deruxtecan is obviously similar to datopotamab, with a similar warhead but a different antibody. As we talked about before, you can mix and match these. This is the HERTHENA-Lung01 study (NCT04619004), and this is actually being studied in the EGFR world. So a slightly different concept that we’re thinking about because EGFR is not HER3, but there’s an interaction there, and either HER3 overexpression or by working alongside as another element of the pathway. There’s some clear activity there. CEACAM5, I mentioned that before, tusamitamab ravtansine, CARMEN-LC05 (NCT04524689) study. And finally, the c-MET drug that we talked about before, ABBV-399, teliso-V [telisotuzumab vedotin]. The LUMINOSITY (NCT03539536) study is ongoing for patients with c-MET overexpression, being studied both in EGFR as well as in patients with c-MET overexpression. Now I’ll talk briefly about the DESTINY-Lung01 study. This is a multicenter, international randomized study looking at 2 cohorts. Basically, you had to have metastatic lung cancer refractory to standard treatments. The typical things; measurable disease, asymptomatic METs [metastasis] in the CNS [central nervous system] at baseline, and then HER2 status. And HER2 is looked at in 2 ways. Cohort 1 was overexpression. So this is the traditional way we think about HER2, as in breast cancer HER2 overexpression. Either IHC 3-positive or 1-positive. Forty-nine patients at 6.4 mg/kg and 5.4 mg/kg had 41 patients. The second cohort, cohort 2, was HER2 mutated. So this is not what you typically think about. And I think it’s important to remember this as we look at the data, that there are differences here when these are HER2-mutated patients. Treated initially the first 42 patients and then expanded for a total of an additional 49 patients. Here are some of the responses in this patient population. This is the 91 patients in cohort 2. In this, the overall response rate was 55%, 1% complete, 54% partial, and 37% stable. Remember, we’re thinking a lot more about stable disease, especially if patients have been through a couple of lines of therapy. Now looking at the disease control rate, which is responses plus stable disease, is 92%, which is actually pretty good. In other words, very few people progressed at that first scan and did not have any benefit. The median time of response is literally the first scan. If you’re going to respond, it’s going to happen early. And the duration is a little more than 9 months. Again, nothing’s perfect in life, but a 9-month duration of response in this patient population. Now we’ll look at datopotamab. This actually started as a phase 1 study looking at patients with refractory relapsed advanced non-small cell lung cancer. Measurable disease, ECOG [Eastern Cooperative Oncology Group performance status scale]1, stable treated METs in the CNS were allowed. Patients were asked for a biopsy—it’s an antibody-drug conjugate against TROP2, what’s the TROP2 expression? It would be great to develop a biomarker. Phase 1 escalation study with an expansion starting at 0.27, got to 10 mg/kg with the MTD [maximum tolerated dose] established as 8 mg/kg once every 3 weeks. You can see the 3 expansion cohorts: 180 patients divided up between 4, 6, and 8 mgs per kg.¼The overall response rate was 24%, 26%, and 24%, so not a lot of difference between the dose levels. The confirmed response rates are for patients that had several scans that showed a response. So a response and then a confirmatory scan, which is usually at least 4 to 8 weeks after. About the same numbers. A couple of people dropped off in that first cohort, and in the second cohort there, a couple also, and the rest are unconfirmed. Disease control rate: 70% to 80% across all arms. Only between 9% and 20% of patients actually did not have a benefit. Duration of response not evaluable/not reached in the 4 mg. In the 6 mg and 8 mg to 9 mg cohorts, the median duration response is between 9 and 10.5 months, so pretty good. If you responded, you went for three-quarters of a year. The median progression-free survival, as you can see, varied between the cohorts as well, between 4 and 6.9 months. Based upon some of that data, the phase 3 randomized study in second-line lung cancer was done, and has completed enrollment. To get into this study, you had to have stage 4 lung cancer without an actual gene mutation. It was actually a separate protocol looking at patients with actual gene mutations. Phase 3 to 4, treated with platinum therapy as well as PDL immunotherapy. They needed to have a screening biopsy looking for biomarkers. And obviously, in the second-line setting, the randomization is versus the standard of care with a drug we never like to give. We tend to give it in clinical trial more than we would probably like to, but it’s a randomization of Dato-DXd [datopotamab deruxtecan], 6 mg/kg was the go-forward dose vs docetaxel. [In] the EVOKE study, as I mentioned before, sacituzumab is approved for second-line triple-negative breast as well as in the bladder world. It’s also an antibody-drug conjugate against TROP2 with a slightly different antibody, a different linker, and a different payload, but the same concept, as we talked about. Stage 4 disease, they need to have progressed past the standard therapies as well. Measurable disease, reasonable ECOG status. Five hundred twenty patients tried to be enrolled in this study, [which is] just getting started. And it’s the randomization of the standard sacituzumab doses. It’s given 10 mg/kg on day 1 and day 8 on a 21-day cycle versus, again, the standard of care in second-line docetaxel. The study is ongoing; I think it just got underway. Now we’re going to talk about the EGFR-mutated world. The ongoing study is called HERTHENA. I know Dr Kim probably came up with all these great names, but the HERTHENA-Lung01 study; he’s shaking his head, patritumab study.¼These are different patient populations. These are patients with EGFR mutations. Remember, EGFR-mutated patients, either exon-19 or L858R, are the 2 most common EGFR mutations. They need to have gotten osimertinib as well as at least 1 platinum-based chemotherapy regimen. Progression of stable brain metastases was allowed, and tumor tissue is required. There were 2 parts to this early cohort: fixed dose HER3 DXd, so fixed dose patritumab/deruxtecan is given at 5.6 mg/kg, or the other set of patients started at 3.2 and then up-titration to either 4.8 or 6.4 mg/kg. This is a randomized phase 2 study, randomized in different doses, trying to optimize the doses, but everybody gets drug on the study. We’ll now talk about a different antibody-drug conjugate, the tusamitamab ravtansine or the antibody against CEACAM5. CEACAM5 is expressed in lung cancer cells. This is a little bit more complicated study to do because to get on the study, the Sanofi folks have developed what looks like a biomarker. You have to have a high CEACAM5expression. Obviously, that’s a little bit of a challenge because you need to have CEACAM5 expression before you enroll in the study, and this is not something currently being tested on next-generation sequencing. I know they’re trying to work on blood-based assays to come up with a good marker, but this has to be done by central testing as of right now. No EGFR, BRAF, ALK, ROS aberrations, and no treatment for metastatic disease. P exclusion criteria; unresolved corneal disorders. That’s something we see a lot of in the antibody-drug conjugate world. A lot of the warheads get secreted in the eye so you can get some eye irritation and corneal irritation in particular; a lot of them have eye exams, and that’s because of the payload, the maytansinoids are notorious for that. Cannot have gotten any therapy before. It’s a 3-part randomization to pembro [pembrolizumab] plus tusa [tusamitamab], platinum-based therapy plus pembro plus tusa. And then in moderate expression, tusa plus pembro plus platinum plus pemetrexed. So there are a few different arms of the study. It actually gets to be fairly complicated. The primary objective here is to really get the tolerability and then look at the recommended doses as it moves forward. But great study. I think one of the challenges with the study is trying to get these results back. Central testing with limited tissue is always a challenge. But it’s a great concept, and they had really good single-agent activity beforehand. Here is some of that data right now. So, here’s some of the safety, tusamitamab, in long-term treated patients with non-squamous, non-small cell lung cancer expressing CEACAM5. Among 11 patients treated greater or equal to 12 months, 7 had a PR [partial response] and 4 patients had stable disease as the best overall response. That’s 11 out of 12 had disease control, which is pretty remarkable. The median duration of response here, for those 7 patients with response, was almost 2 years. In the lung cancer population, we don’t typically talk [about] almost 2 years. That’s almost unheard of. And one of the things that are being looked at is the CEACAM5 expression level. And in this patient population, the confirmed PR occurred in patients with both moderate and high CEACAM5 expression levels. So, again, one of the things being looked at on this clinical study is, what’s the CEACAM5 expression you need for efficacy because it does look like we have a biomarker. Finally, we’ll talk about the LUMINOSITY study. This is telisotuzumab or teliso-V, the second or third line in c-MET positive non-small cell lung cancer. Two patient populations here, either non-squamous withEGFR wild type or non-squamous with EGFR mutated. And the patients had to have c-MET expression as well, by IHC by central confirmation. You could not have gotten more than two lines of prior therapy. The reason we look at two populations here is that c-MET is actually one of the major resistance pathways for patients who receive EGFR inhibitors. So it’s not uncommon that they develop c-MET overexpression as a mechanism of resistance; this is trying to overcome that. As part of the central assay here, looking at c-MET expression across the 2 different cohorts, several different levels here, breaking it down. And then go/no-go decision depending on the initial response rate and then expanding thereafter. There’s a separate population for squamous cell population as well, who are also overexpressing the c-MET. The dosing here of the drug teliso-V is given 1.9 mg/kg every 2 weeks. Here are some of the results in the first 23 patients, the median progression-free survival was 2.4, months and the median overall survival was 5.6 months, again very preliminary data. Polling question: Which target do you think holds the most promise for non-small cell lung cancer? I’ll open it up to the audience. Looks like we have about 70 people on. We’ve got 5 different answers here, so HER2 looks like number 1, I think that’s a very good option there, but the other ones obviously have some positives as well. So it looks like most people voted for HER2, and I think that’s probably true, at least in my humble opinion, just based on some of the data we see. As I mentioned before, TDxD [trastuzumab deruxtican] is actually on NCCN [National Comprehensive Cancer Network] guidelines right now.

Transcript edited for clarity.