Janssen's Wildgust Breaks Down Bispecific Antibodies in Development for Non-Small Cell Lung Cancer and Multiple Myeloma

July 22, 2020

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab, a bispecific antibody being developed to treat non–small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.

Bispecific antibodies received plenty of attention at last year’s meeting of the American Society of Hematology, and the momentum continued in late May during the virtual annual meeting of the American Society Society of Clinical Oncology (ASCO). As the name suggests, these therapies are manufactured proteins that can bind to 2 separate antigens at the same time, bringing extra power to the fight against cancer.

During ASCO, Janssen presented results from the CHRYSALIS study on amivantimab,1 a bispecific antibody being developed to treat non—small cell lung cancer (NSCLC). The pharma giant, along with its parent company, Johnson & Johnson (J&J), had previously received a breakthrough therapy designation in December for teclistamab, another bispecific antibody indicated for potential treatment of multiple myeloma.2

Mark Wildgust, PhD, vice president of Global Medical Affairs/Oncology at Janssen, who leads a team of scientists and physicians developing new, targeted therapies for oncologic and hematologic conditions, expounded on the similarities and differences of these 2 novel dual-targeted therapies with Evidence-Based Oncology™ (EBO).

Wildgust explained that intervening earlier in the premalignant setting is a primary goal. To that end, Janssen has 6 bispecific antibodies in development—all first-in-class therapies. He also touched upon medication aff ordability, noting that availability and regulatory approval are moot points if a drug is not accessible, because although it is proven safe and eff ective, patients can’t benefi t from a treatment if they can’t get it.

This interview has been edited slightly for clarity.

EBO: Two bispecific antibodies in development, amivantamab for NSCLC and teclistamab for multiple myeloma, have some similarities, but one is being developed for a solid tumor and the other for hematologic cancer. Can you discuss the similarities and differences?

WILDGUST: Both are built on the same duobody platform, which is what we call it. Bispecifics are essentially monoclonal antibodies that bind to 2 different targets—that’s why we call them bispecific. The method by which we make them is the same, but they are actually quite distinctly different.

Let’s take teclistamab. We actually create 2 individual antibodies: 1 targets CD3 and 1 targets BCMA. We then break those apart and glue them back together so that they can basically target CD3 and BCMA. So, that’s teclistamab.

Now, the same process is used for making amivantamab as well: 1 [antibody] targets EGFR and 1 targets c-MET. We break these 2 antibodies apart and glue them back together and create that single bispecific. So, the similarities kind of end there. Then we get into the diff erences. Teclistamab binds to BCMA. BCMA is essentially an antigen target that’s almost ubiquitously expressed on myeloma cells. Then you have CD3. Why CD3? CD3 is essentially picking up T cells, which express CD3. The BCMA-CD3 teclistamab is really what we would call a T-cell redirector. It essentially picks up the T cell on the monoclonal antibody and then it binds to the BCMA antigen that’s expressed on the myeloma cells. And so, you’re essentially bringing the T cell to the cancer cell to kill it. So, that’s how teclistamab works. Amivantamab, though, targets EGFR and c-Met, so it’s not redirecting T cells. With amivantamab you’re targeting 2 distinct antigen targets. And then there’s a variety of immune-type mechanisms by which binding of EGFR or binding of c-Met separately kills the cancer cell. Why should you target EGFR and why should you target c-Met?

When you think about NSCLC, there are those cases that are driven by driver mutations and those that are not. Those that are driven by driver mutations are things like EGFR, ALK, ROS, RON—and EGFR is quite distinct as a driver mutation. Lots of different compounds are out there for EGFR-expressing NSCLC, like gefitinib and erlotinib [Tarceva] and osimertinib. But we’ve learned over the last 10-plus years that in many EGFR lung cancers, one primary mechanism of resistance is through c-Met.

So, the idea of targeting EGFR and c-Met is that potentially, you can target both the driver of the cancer and the resistance mutation, too.

Now, there’s another element about EGFR/c-Met that’s unique as well. The different kinase inhibitors I just mentioned—like osimertinib and gefi tinib and Tarceva—target EGFR from an intracellular perspective, and amivantamab targets it in an extracellular manner.

So why does that matter?

When you think about lung cancer and exon 20 insertion, why don’t the classical EGFR inhibitors work in that space? They don’t work because they don’t have the ability to bind within the conformational pocket. By targeting the receptor from an extracellular perspective, you don’t have that issue. We know that about 10% of EGFR lung cancers are of the exon 20 insertion type. They currently have no standard of care. By targeting EGFR extracellularly, we can target that and potentially address something where current EGFR inhibitors don’t work.

So, similarities, but quite a few more differences.

EBO: Are these therapies meant to be curative?

WILDGUST: That’s a good question. Let’s take multiple myeloma for a second, a highly complex, heterogeneous disease. Once patients become refractory, we know that their overall survival is quite poor. I think in the refractory setting it’s very unlikely that we will give patients cure, but what we’re really trying to do is achieve really deep, durable responses, for as many patients as possible, with the idea that if we can get deep, durable responses, we can give them a meaningful amount of time.

In the relapse setting, I think that it’s about harnessing the immune system, harnessing those T cells to be able to try to target those cancer cells. As we learn more about teclistamab, I think the question will be, how can we use it to build curative-type regimens? One of our focuses at J&J and Janssen is to develop individual molecules or compounds, but at the same time, we’re very much interested in building curative regimens. So, I think for teclistamab in its current setting, unfortunately, I don’t think there is the potential for cure, mostly because of the disease complexity and heterogeneous nature. I think that teclistamab has the potential to be part of a regimen for cure in the earliest setting, and that’s certainly something that we will explore.

Now, in terms of amivantamab, there are a couple of places to think about it. The first is where we just got the breakthrough designation, for patients with the exon 20 insertion. A patient with lung cancer who has an EGFR exon 20 insertion unfortunately has a survival of probably about a year and a half. Their outcomes are very poor.

I don’t think it’s really about cure, but more about trying to build regimens right now that can give patients more time. For patients with exon 20 insertion, for patients who have progressed after initial therapy—that’s where the breakthrough designation is for amivantamab. Once a patient has had initial therapy and progresses with exon 20, their median life expectancy is probably less than a year. What we’re trying to do now is give them more time. That’s the goal.

Ultimately, we would love to get to cure, and that’s part of our overall initiative. We actually have an ongoing lung cancer initiative across J&J; we brought the 3 different parts of the company together to look at how we can intervene earlier in the premalignant setting and premalignant stage. That’s the place

where we can think, potentially, about cure for some of these patients, and that’s part of our overall approach in terms of disease intervention.

EBO: Especially for lung cancer, because it’s so often diagnosed in such a late stage that by the time it’s caught, it has metastasized.

WILDGUST: Unfortunately, most patients are caught at stage IV because it’s relatively asymptomatic. Most patients might have a cough. It may seem like they have something that seems quite benign, so unfortunately, most patients get caught late. More than 1.8 million patients die a year from lung cancer worldwide,3 and the median life expectancy for a patient with newly diagnosed stage IV lung cancer is less than 2 years.

You saw some of the quite exciting data that came out at ASCO on one of the other compounds, looking at a checkpoint inhibitor in chemotherapy, and we’re heralding the outcomes of that. But we’re talking about moving survival by a couple of months. Median survival is still less than 2˜years, right? For EGFR-driven disease, the outcomes are a little bit better, but still, the outcomes are very poor. We’ve got a long way to go to help patients with lung cancer....

You asked me about cure. We’re trying to give patients more time by advancing new, innovative therapies. You talked about teclistamab and amivantamab; we have 6 different bispecifics in the clinic. All of them are brand-new, first-in-class therapies, and we’re hopeful that these can help advance care for patients.

EBO: For teclistamab, what biologic process underlies the effectiveness for patients with hematologic malignancies who have not responded to prior therapies or have relapsed disease?

WILDGUST: We know that the T cells in patients with multiple myeloma are still very active. So even in the patient who has been multiply treated or is refractory, we’re trying to harness the killing [power] of those T cells and redirect them to be able to kill the cancer cells. And because we know that BCMA is so widely expressed, we can target the antigen, that BCMA, and redirect the T cell there.

Then the question is going to be, are those responses durable? When you look at the teclistamab data, in particular—and we’re still in that dose-finding and dose-escalation phase with teclistamab, but also already at the 270 mcg/kg dose—we’re seeing two-thirds of patients responding. If we look broadly across the patients there, we’re seeing patients who are having not only responses, but durable responses. So, 16 of 21 patients in that trial—with time, we will report the data—still haven’t progressed.

When you talk about biological processes that underlie the effectiveness, I think the key question is, what causes resistance? Is it the T cell becoming exhausted? And if that’s the case, can we use checkpoint inhibitors to overcome that? Or is it the immunosuppressive eff ect of the bone marrow niche? Or is it loss of the receptor target? Did BCMA go away? Did the target go away?

We’re going to learn more about that in terms of patients who progress, and then from there, we can start to identify how we can better optimize care for these patients, using these T-cell—oriented or T-cell–redirecting types of compounds.

EBO: Is teclistamab being studied in patients who have relapsed on chimeric antigen receptor (CAR) T-cell therapy?

WILSGUST: Not yet, because we’re still in that dose-finding/dose-escalation phase, trying to understand what the right dose is. I think it is an outstanding clinical question. Could you target a patient who’s had a CAR T with a bispecific? I think there are 2 parts of that question.

The fi rst is, do they have the same antigen target? If you think about a BCMA CAR T and a BCMA bispecifi c, there’s a question of, is that the right thing to do? Because we don’t know why patients might have progressed on the BCMA-targeted therapy. Maybe it wasn’t the loss of that BCMA antigen, and if that’s the case, then targeting it with another BCMA targeting agent probably doesn’t make sense. But if it’s actually something diff erent, then there may still be potential to do that.

Now, if you have a CAR T and a bispecific that target diff erent antigens, I think that’s an entirely diff erent question, and I think the answer is, yes, you probably could use them one after another. That’s because you’re really then talking about a different target versus anything else.

EBO: Does amivantamab, which targets activating and resistant EGFR and MET mutations and amplifications in NSCLC, have potential in other solid tumor cancers?

WILDGUST: We know that EGFR is expressed in other cancers as well, and so is MET. And so, as part of our development plan, we will look at other cancers where EGFR and MET are potential drivers. I think the biggest unmet need is in NSCLC. As I mentioned earlier, patients with exon 20—expressing and EGFR-expressing lung cancer don’t respond to traditional EGFR-targeting agents. The outcomes for those patients are particularly poor. But dual targeting of EGFR and MET is particularly interesting because we know MET is a resistance pathway for EGFR. But discretely, there are other cancers that are MET driven, EGFR driven, and we will absolutely be thinking about exploring those other tumor types, looking at amivantamab.

EBO: In results for amivantamab presented at ASCO, the overall median progression-free survival (PFS) of 8.3 and 8.6 months, clinical benefi t rates of 67% and 72%, and their ranges, were comparable between all patients and those who received previous platinum-based chemotherapy, respectively. How much of a survival advantage is amivantamab really providing?

WILDGUST: CHRYSALIS is a single-arm exploratory cohort study. The idea was that we wanted to take the recommended phase 2 dose and then explore that in a cohort of patients who are exon 20. We’re not comparing it with something else, so I can’t tell you if it did improve survival. But the median survival is less than 12 months for a patient with exon 20 insertion who has progressed after prior therapy, so we know the outcomes for these patients are poor.

The PFS data that we reported were about 8.5 months, but those data are still actually quite immature. There’s a lot of censoring there, because the follow-up is quite short. We still need to learn more about the PFS for those patients. But to see a PFS of between 8 and 9 months in this group of patients, when the median survival is 12 months, is very promising. It seems like [amivantamab] is providing real benefi t, because the median PFS for these patients would normally be a couple of months. The data look exciting and promising.

I think that’s why the FDA gave us a breakthrough designation for this therapy. One, because there are no currently approved therapies out there. And second, because there’s a high unmet medical need. Again, the data look very, very promising, and better than anything else out there at this point.

EBO: Do bispecific antibodies have other advantages?

WILDGUST: When we talked about amivantamab, we talked about targeting a receptor in a different way. That’s an advantage. But when you think about teclistamab, you have to think about it in terms of what other types of therapies are out there. You almost have to think about teclistamab as a bispecific and a CAR T.

And, fi rst of all, when we think about teclistamab and the CAR T, what are some of the differences?

First of all, we don’t see grade 3 or grade 4 cytokine release syndrome for teclistamab, and I think that’s particularly important. We see very low rates of neurotoxicity. But one of the things about CAR T cells is that you have to collect the patient’s T cells through apheresis, send them away, and have [the product] manufactured and come back. So, if a patient has a very aggressive myeloma, you can’t wait for the number of days it takes for that T cell to be sent off, to make a CAR T, and come back. Among of the benefi ts of the bispecific is that it’s on the shelf; it’s available straightaway for that patient who walks through the door.

It seems like teclistamab has a very good safety profile, which means it looks like a good option for patients in that regard. It doesn’t have the grade 3, grade 4, rates of neutropenia, anemia, and thrombocytopenia that you might see with CAR T therapy. I think there are advantages of them versus other similar targeting types of agents, like CAR Ts, which I think is good as well.

But the other advantage of a bispecific, particularly one like teclistamab, is that it’s taking those T cells that we know are active and redirecting them against the cancer. The advantage of something like amivantamab is that it’s dual-targeting. The potential to target both pathways is important, particularly as we know

that c-MET is a resistance escape pathway for EGFR. This is a good example of how you start to think about, how do I use my tools? How do I use the different types of tools to target the cancer and to try to provide meaningful responses and benefit for patients?

EBO: While these therapies are still very early in the study phase, are there general financial models that Janssen or J&J is discussing with payers to ensure that this treatment can reach patients?

WILDGUST: I think at the end of the day, not necessarily with these specifi cally, our overall goal is to make our medicines accessible and aff ordable for patients of our health care systems. That’s the key. While we strive to develop innovative therapies that are transformative, the only medicines that really deliver value are those that patients can access. We work really hard with different health care systems around the world, and different governments and different stakeholders, to try to make our medicines available through coverage, through reimbursement. And as part of our development process, we engage with diff erent payers to try to understand how we can bring these medicines to patients, looking at different ways in which we can negotiate price or different agreement methods so that we can provide access.

At the end of the day, if you have a drug that’s available, but not accessible, then the regulatory approval really doesn’t count for anything, whether it’s safe or effective, because unless that patient can get it, they can’t receive the benefi t. So we take that very seriously. And whenever we develop medicines, we’re not only thinking about regulatory approval, we’re also thinking about making sure that we can provide access. And that means access through payers as well.References

1. Study of JNJ-61186372, a human bispecific EGFR and cMet antibody, in participants with advanced non-small cell lung cancer (CHRYSALIS).

ClinicalTrials.gov. Updated June 2, 2020. Accessed June 8, 2020. https://clinicaltrials.gov/ct2/show/NCT02609776

2. Park K, John T, Kim S-W, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(15 suppl; abstr 9512). doi:10.1200/JCO.2020.38.15_suppl.9512

3. Lung cancer. The Cancer Atlas. canceratlas.cancer.org/the-burden/lung-cancer/. Accessed June 22, 2020.