Breaking Boundaries: Advancements and Challenges in Treatment with ADCs in NSCLC

Joshua K. Sabari, MD

Joshua K. Sabari, MD, an assistant professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine and the director of High Reliability Organization Initiatives at Perlmutter Cancer Center, NYU Langone Health, discussed updates in the treatment of non–small cell lung cancer (NSCLC) with the use of antibody-drug conjugates (ADCs) in an interview with OncLive®. He provided updates from key trials within the space such as the phase 3 TROPION-Lung01 (NCT04656652) and AVANZAR (NCT05687266) trials, and also spotlighted the use of the ADC sacituzumab govitecan-hziy (Trodelvy) within the scope of NSCLC.

He also explained what safety concerns oncologists should be aware of when treating these patients with NSCLC. Additionally, Sabari provided further insights on the utility of ADCs and the current treatment landscape of NSCLC in another interview.

OncLive: How has sacituzumab govitecan impacted the treatment of patients with NSCLC?

Sabari: Data with sacituzumab govitecan early on in dose-escalation studies looked impressive. Phase 1 data showed a 15% to 20% response rate, and the agent was relatively well tolerated. This is a drug that’s FDA approved in breast cancer as well as in bladder cancer. Unfortunately, we just saw the results of the phase 3 EVOKE-01 study [NCT05089734] which evaluated sacituzumab govitecan vs docetaxel in those who received prior chemotherapy and immunotherapy treatment. The primary end point was OS and there was a benefit in OS numerically, but it was not statistically significant. [However], we look forward to seeing that full dataset.

What is interesting is that if you exclude the patients who had very robust responses to immunotherapy, it seems that those patients who don’t respond to immunotherapy in the frontline seem to derive more benefit from treatment with sacituzumab govitecan. This was not a pre-specified end point, but an interesting point to look at; I look forward to looking at the data moving forward.

What additional ADCs are being developed in this treatment space?

There’s a third ADC now being developed by Merck called MK-2870. We saw some data with [the agent] at the 2023 ASCO Annual Meeting with a 44% response rate in very small numbers of patients [n = 43] in the dose escalation [portion of a trial from China].

However, there is that same story that in the EGFR-mutant population [of patients with NSCLC with] response rates hover in that 60% range. We’ll need to see the further datasets for these Trop-2 ADCs. One thing that irks me is that we don’t have a biomarker to select patient response or to select durability of response for these agents. We are not measuring Trop-2 immunohistochemistry for expression, and there is no other biomarker outside of the actual genomic alterations at the moment.

What safety concerns should oncologists be aware of when treating eligible patients with NSCLC with ADCs?

It’s important to think about the toxicities of the ADCs. These are not targeted therapies, not immunotherapies, and are not chemotherapies. These are targeted chemotherapies with a unique toxicity profile and the toxicities may be related to the payload—there may be on-target toxicities and also off-tumor toxicities.

It’s important to think about this in your clinical practice. Some of the common payload toxicities that we see, such as cytopenias, are across the board for all of our ADCs. As oncologists, we’re very confident in treating leukopenia, neutropenia, and neutropenic fever. We do see those toxicities with these agents, but also thrombocytopenia and anemia should not be overlooked.

Nausea is a common toxicity as is alopecia due to the payload [of ADCs]. Some of the toxicities that are more unique to certain agents [include] for example with fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], interstitial lung disease [ILD]. With some of the other Trop-2 ADCs, particularly datopotamab deruxtecan, you see gastrointestinal toxicities—stomatitis and diarrhea.

Another [ADC] is tusamitamab ravtansine [SAR408701] which recently has been pulled and the program has been closed due to negative data per press release. Here, you do see some unique ocular toxicities such as keratitis and keratopathy that need to be managed appropriately in clinical practice.

In my own practice, particularly in lung cancer, I’m most concerned about ILD, worsening cough, shortness of breath, and any radiographic findings, even grade 1. I hold medicines and treat aggressively with steroids and then resume [ADC treatment] once those toxicities or once the grade improves for the ILD. You don’t want to get caught with raging ILD in a patient, particularly grade 2/3, as that becomes very difficult to manage in this patient population.

Are there any ongoing or planned studies of ADCs that are catching your attention?

There are many different combination strategies. When we develop therapies, they’re oftentimes developed in phase 1 and later-line settings but then quickly move into the frontline setting. In the Trop-2 space, there are multiple ongoing studies in frontline. This includes the phase 3 TROPION-Lung07 [NCT05555732] and TROPION-Lung08 [NCT05215340] studies, as well as the AVANZAR trial. Those are combinations with PD-L1 inhibitors and PD-1 inhibitors in the frontline setting plus the Trop-2 ADC.

We know that there’s an ongoing study– the phase 3 EVOKE-03 trial [NCT05609968]– which is simertinib govitecan in combination with pembrolizumab [Keytruda] in the frontline. We look forward to seeing those data emerge. There’s a potential opportunity for a lot of our ADCs targeting driver mutant populations. For example, regarding the population of patients with EGFR-mutant disease, and specifically looking at patritumab deruxtecan [HER3-DXd], there may be a potential opportunity for combination therapy with simertinib [Tagrisso], the third-generation EGFR TKI. There is a phase 1 study ongoing at the moment.

There are also next-generation ADCs that are exciting. There are dual payload ADCs, so imagine having 2 different chemotherapeutics. There’s also the use of conjugation to some immuno-stimulatory molecules which can be exciting. The bispecific T-cell engagers [(BiTEs) targeting] CD3 for example—we have BiTEs engaging CD3 and DLL3 as well as CD3 and EGFR—bring immune cells into proximity of tumor cells which is exciting moving forward.

Something that I think about a lot and may be changing practice soon is the conjugation of these ADCs or bispecifics to radionuclides—having some kind of theranostic approach, both therapeutic as well as diagnostic, if you have an imaging modality that can measure uptake and efficacy of these radionuclides.

What would you like your colleagues to take away from this research on ADCs?

The key takeaway for ADCs is to understand that these are not conventional cytotoxic chemotherapy [agents]. They’re not conventional chemotherapy and not immunotherapy. They bring all 3 of those together. The backbone consists of an antibody, a linker, and a cytotoxic payload, and we hope that it’s selective to tumor cells.

Unfortunately, a lot of our strategies have been biomarker agnostic. Due to that outside of T-DXd and patritumab deruxtecan, we haven’t seen significantly impressive data in the later-line setting in NSCLC. We’re trying to figure out the correct patient population for these particular studies. The only currently approved ADC in lung cancer is T-DXd in the second-line setting, but I am hopeful that the phase 3 study will be positive vs chemotherapy. There are many other exciting ADCs coming down the pike, so it’s still very early on.

I’m personally excited about the B7-H3 ADCs. There are also multiple MET ADCs in development, but it is important not to forget that there is unique toxicity to these agents. We talked a lot about the hematologic toxicities, but also unique toxicities for ADCs include ILD and ocular toxicities that should not be overlooked.