Supplements and Featured Publications
Judy Wang, MD, discusses how ADCs are transforming NSCLC treatment with improved responses, biomarker-driven care, and CNS activity.
Antibody-drug conjugates (ADCs) are rapidly redefining the treatment landscape for patients with advanced non–small cell lung cancer (NSCLC) whose disease progresses after frontline therapy by improving response rates and extending durability of benefit, with the potential to move beyond the metastatic setting into earlier lines of care, according to Judy Wang, MD.
“Having a therapy that covers a patient head to toe is really powerful, and if that comes from ADCs that would be a huge plus because of its targeted ability, and [they have] a relatively better toxicity profile compared with some of the conventional therapies that we’re used to using in the advanced setting,” Wang said in an interview with OncLive®.
In the interview, which proceed a State of the Science Summit™ in Lung Cancer cochaired by Ben Creelan, MD, and Eduardo Sotomayor, MD, Wang, a medical oncologist and associate director of Drug Development at Florida Cancer Specialists & Research Institute in Sarasota, discussed the growing importance of comprehensive genomic profiling, the promise of central nervous system (CNS) activity, and the practical considerations to navigate as these therapies become more widely integrated into routine practice.
Wang: These ADCs have been approved in advanced NSCLC, either in EGFR-positive disease or in patients with c-MET–high expressing disease, which is great, as these patients often get a positive response to platinum-based chemoimmunotherapy. Invariably though these patients will [develop progressive disease]. What we are using in the second-line setting, outside of a trial or these other approved targeted agents, are drugs like docetaxel. With single-agent chemotherapy in the second line for NSCLC we’re really looking at an objective response rate of 20%, which is underwhelming.
Now we have these opportunities to offer these targeted therapies in which we’re seeing better response rates, longer durations of response, and ultimately, better tolerance, with a safety profile that is better than some of these conventional chemotherapy [drugs]. In the advanced setting, we’re seeing positive results, and with drugs that do well in the advanced setting, we’re always asking ourselves, ‘Can we push them into earlier lines? Can we offer patients earlier opportunities [to receive] these drugs which may promote even better response rates and durations of response?’
So far, these ADCs in the advanced setting are specific to actionable genomic alterations or signature driver mutations, so either EGFR-positive disease with conventional deletion 19 or L858R mutations, or c-MET overexpressing [disease] in the case of Teliso-V. It’s important for us to understand the genomics of these cancers before we start making important decisions in terms of treatment strategies. When I counsel my patients for the first time, I tell them that often it’s not enough to know that you have lung cancer. We need to understand the genomics of your disease, because it has both predictive and prognostic implications. We have really traversed far past [needing to know only] traditional [markers such as] EGFR, ALK, and ROS. We are now looking at multiple alterations, including BRAF, HER2/neu, as well as EGFR, ALK, and ROS, and all these other alterations like KRAS and RET. Being able to remember all that can be challenging, and a great way to [ensure all those markers are captured is by ordering] comprehensive genomic profiling with next-generation sequencing. This really helps us get an understanding of the disease and helps us make decisions in terms of treatment opportunities and how to sequence [these agents].
It’s become more important to look at genomic profiling in the earlier-line settings and the potentially curative settings for potential opportunities to offer targeted therapies in the neoadjuvant and adjuvant settings. When we talk about curative settings, that brings into mind the importance of having a good multidisciplinary approach. [You should be] working together with your surgeons and pulmonologists, so that you can understand the patient’s disease, [determine] the times to collect the tissue, and [perform] the testing, [in order to] implement the right therapies at the right times based upon the sequencing in their profiling. What we really need to do is continue to advocate for and encourage early genomic profiling with comprehensive profiling.
At least for right now, we’re looking at ADCs in the advanced setting, which can help us continue to prolong overall survival and quality of life [QOL] for patients in the metastatic setting after first-line platinum chemotherapy. But again, as we’re seeing these drugs do well in the second-line advanced setting, [we should ask whether we] can we move them into the first-line setting. Would that be [with] a combination approach with chemoimmunotherapy? Or could we even replace chemotherapy with these ADCs? These drugs, though they are targeted therapies, the means for which they cause damage to cancer cells is based on a payload that is still cytotoxic. What’s nice about that is we get to harness the power of ADCs with essentially a chemotherapeutic payload, but with the specificity to target something on the cancer. Therefore, are we able to then replace chemotherapy and get longer durations of response, maybe better QOL [with ADCs], because the toxicity profile could be improved compared with what we typically see with conventional chemotherapy? There’s certainly a drive for and an interest in moving ADCs into an earlier line of therapy and either looking at them in combination or even replacing chemotherapy with them in that first-line setting.
This is exciting, specifically for advanced lung cancer, but also for some of these driver-mutated lung cancers. Lung cancer typically can develop brain metastases––it’s very common compared with other cancer types. The longer patients have lung cancer, or if they’re diagnosed at more advanced settings, the higher the likelihood that they’ll develop brain metastases. Having brain metastases is an independent poor prognosticator. Our ability to detect and treat [brain metastases] early or even prevent the emergence of brain metastases is important for these patients, not only for their longevity, but also for their QOL. Being able to offer patients a therapy that systemically treats both their intracranial and their extracranial [and] visceral disease is really powerful, because we’re able to ensure, or at least hopefully confirm to ourselves, that we’re treating all aspects of disease. [On the other hand], with our other conventional therapies, we may feel like we’re having to manage two different things––the patient’s advanced lung cancer within their visceral organs, and then separately, their brain [because of the] potential development of brain metastases. That can be a challenge, especially if the metastases cause symptoms and delay a patient from getting therapy, because we can’t [address both things] at the same time.
The first [question] would be, ‘What’s the role of ADCs in the neoadjuvant [and] adjuvant settings? Do they replace chemotherapy? Do they replace certain therapies that we give, or do we look at them in combination?’ That needs to be teased out, and then, ‘How much of that therapy do we give?’ But more so, understanding that if we pursue combination approaches, ‘What could the adverse effects [AEs] be?’ Specifically, the toxicity profiles that we have to watch out for when we’re offering patients therapies in the neoadjuvant setting, especially if we want to be able to get them safely to surgery. The whole point of offering these therapies is to better their chance for a more full resection, a pathological response, ideally a pathological complete response. Being able to ensure that they can tolerate these therapies safely, get to surgery, and accommodate any potential toxicities that we may see in that setting, whether it’s in combination with other drugs or not, [is crucial].
Outside the academic center, it may be overwhelming to manage patients being treated on ADCs. I tell my patients, ‘Although I’m not treating you with conventional chemotherapy, because the payload is still based in something that’s cytotoxic, oftentimes, the AEs that you feel can still feel like [those associated with] chemotherapy. Patients still develop fatigue. Patients still develop cytopenia. Our oncologists outside the academic center still need to watch for blood count drops, white cell drops, platelets, things of that sort. [Patients can] still develop gastrointestinal AEs, including nausea and diarrhea. What’s interesting is, because these drugs have relatively long half-lives, the cadence of the development of these AEs may be different per patient. As opposed to when a patient gets their cytotoxic chemotherapy infusion, [where] they may feel poorly in the days right after their infusion, with an ADC they may not feel AEs until week two or even week three. That may catch a patient off guard [because] they weren’t expecting [the toxicities] to develop late. It really requires a high index of suspicion and counseling these patients ahead of time on what to expect for these AEs. Additionally, ADCs have unique AEs that are related to the type of payload and what the linker is that we may not necessarily see with conventional chemotherapy.
One big AE that we have to watch out for is interstitial lung disease [ILD]. We oftentimes see this toxicity, particularly with topoisomerase-1–based payload ADCs. With fam-trastuzumab deruxtecan-nxki [Enhertu] we may see rates between 15% and 20%, but the concern is, when this develops, it can result in very significant symptoms very quickly [that land patients] in the hospital [or worse]. Being aware of the potential AEs [associated with ADCs] and what to look for in terms of early signs [is key]. For ILD, [that might mean] a cough, a mild fever, not necessarily shortness of breath, but just a sense of [difficulty taking] a deep breath. I’m always listening for those subtle AEs, because those could be the start of ILD or pneumonitis, and early detection and intervention with holding therapy and steroids goes a long way. [Those sorts of interventions] can address and prevent the ILD from getting worse. We may be able to then rechallenge the patient with therapy, as opposed to those symptoms progressing [to a place that would prevent them from getting back on therapy].
Another [AE] I like to really focus on when I’m talking about ADCs, especially for dato-DXd is the commonality of mucositis. That’s important, partly because that really affects QOL. For patients, not being able to eat or drink and not being able to feel comfortable, [because of] tenderness or even just trouble with salivation, really affects QOL. We know that with dato-DXd, the likelihood of at least grade 1 to grade 2 mucositis is quite high, and there were cases of grade 3 [events in the pivotal trials] that prompted…treatment holds or treatment reductions. Implementing prophylactic therapies for mucositis, including potentially [administering] cryotherapy, [providing] ice chips during infusions, and prepping the mouth with a steroid-based solution [is important]. [Proper prophylaxis and follow-up] really demands that the oncologist is in tune with the potential AEs of ADCs but also [knows to] constantly question their patients about things that they may be experiencing so that they can intervene early and prevent these AEs from becoming more severe.
What stuck out to me was just the general excitement of the new therapies that are available now for [patients with] advanced small cell lung cancer [SCLC]. As opposed to NSCLC, SCLC is incredibly aggressive. These patients can have rapidly progressive disease, and unfortunately, patients can be quite symptomatic, whether it’s shortness of breath, SVC syndrome, and/or paraneoplastic syndrome. Now, seeing, at least in the past 2 years, the approvals of multiple drugs in both the limited-stage and the extensive-stage setting is exciting.
We heard from some of the other [faculty] about all these new strategies in SCLC and now that we have these drugs, how do we, just like we do in NSCLC, drive treatment selection through biomarkers? How do we know that this patient may do better or worse with various therapies, and whether there’s a role in looking at other targeted therapies in SCLC? That’s an exciting new area of investigation, and I’m curious to see what new drugs or what other clinical trial data are going to be coming out soon.
We’re really excited about new ADCs that we have in our clinic, and a lot of them are geared toward [patients with] advanced lung cancer. In my discussion, we talked about EGFR-directed ADCs like dato-DXd, sac-TMT, and Teliso-V. We have other studies in our portfolio that we’re looking at with bispecific ADCs. If we’re not targeting one marker, can we target two markers that we find to be overexpressed in some of these advanced cancers? That may help us better target the cancer cells by using a dual function bispecific antibody.
We have Avenzo Therapeutics’ bispecific EGFR-HER3-directed ADC, AVZO-1418. We’re [participating in] that study now, and we’re offering it to multiple patients, but our focus is in EGFR-mutant NSCLC. We also have Janssen’s EGFR-MET bispecific. What we often see is that in patients who have or are becoming resistant to EGFR-directed therapy, one means of resistance could be MET overexpression. Janssen has [invested in] a bispecific [ADC] that targets both EGFR and MET, and we’re enrolling patients with EGFR-mutated NSCLC to that [trial].
Outside of TROP2 and EGFR there are other markers that we’re looking at in the lung space. For example, HER3 is overexpressed in a lot of tumors, including NSCLC. We have DualityBio’s HER3-directed ADC. They’re looking at EGFR-mutant NSCLC. Additionally, BioNTech has a HER3-directed ADC that is being investigated in multiple tumor types as well. Additionally, we have a couple trials that are trying to target a marker called PTK7, which is overexpressed in a number of cancers, including advanced lung cancer. We have ADCs targeting that specific marker as well. There’s a lot going on in our clinic. We're seeing a lot of patients, and we’re trying out a lot of new ADCs. We’re excited to see where this landscape changes in the next couple years.
