Leveraging ADCs in Lung Cancer: Snapshot of Existing Challenges and Opportunities

Although efforts to effectively utilize antibody-drug conjugates (ADCs) with targets beyond HER2 in lung cancer have yielded lackluster efficacy results, these agents may still play a role in the treatment of select patient subgroups and/or when combined with chemotherapy or immunotherapies, according to Kashul Parikh, MBBS.

“There may be [a] role [for ADCs] in combination, but it remains to be seen that these will be synergistic and whether they would also bring in more toxicity,” said Parikh, who is a thoracic oncologist and assistant professor of oncology at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, in an interview with OncLive^®, regarding a recent State of the Science Summit™ on lung cancer.

In the interview, Parikh expanded on efforts made to elucidate the role of ADCs with varying targets in lung cancer, including data showcasing the limited benefit achieved with HER3- and TROP2-targeted agents, and spotlighted ongoing research dedicated to evaluating ADCs in combination regimens.

Parikh also discussed the need for improved identification of patients who may benefit from adjuvant immunotherapy in early-stage non–small cell lung cancer (NSCLC) and the use of PD-L1 expression to guide treatment decision-making in the absence of other targetable mutations.

OncLive: What challenges have been experienced when attempting to translate the success of ADCs into the solid tumor space?

Parikh: ADCs have been around for a while, and our colleagues in the hematology space have utilized these agents for several years. Unfortunately, we have been a little slower to replicate those successes in the solid tumor setting. Granted, lung cancer is generally a much more complex tumor, and therefore, targeted therapies tend to be more challenging to develop.

When we look at the currently available ADCs for lung cancer, the first one that should come to mind is fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. That [agent] is approved for HER2-mutant lung cancers as well all HER2-expressing cancers now. We’ve had the most successful experience with this one. Other ADCs in development include those targeting TROP2, [such as] sacituzumab govitecan-hziy [Trodelvy] and datopotamab deruxtecan [dato-DXd], and the HER3-directed ADC patritumab deruxtecan [HER3-DXd]. We’ve also had a few failures, one of which was the CEACAM5[-targeted] ADC, tusamitamab ravtansine [SAR408701]. Moreover, the development of rovalpituzumab tesirine, a DLL3-targeted ADC, has been discontinued. In mesothelioma, we had anetumab ravtansine, which [targets mesothelin,] and again [it was deemed] too toxic and [its development] has been discontinued. Telisotuzumab vedotin [ABBV-399] is a c-Met ADC and is currently [being evaluated] in phase 3 trials. That is another hopeful option for the future.

What does current evidence suggest about the efficacy of HER3- and TROP2-targeted ADCs in NSCLC?

Amongst the [agents] that are under investigation, sacituzumab govitecan and dato-DXd, are probably the most ahead [in terms of development], aside from T-DXd. We recently [saw data from] TROPION-Lung01 [NCT04656652] and EVOKE-01 [NCT05089734], which were phase 3 studies looking at these ADCs compared with docetaxel. Unfortunately, the benefit [with these ADCs] has not been that impressive. We would have anticipated them to be significantly better than docetaxel. The median progression-free survival was better with dato-DXd vs docetaxel by about half a month, but clinically, this was probably not relevant. There was no difference in overall survival [OS] between dato-DXd and docetaxel. The EVOKE-01 study looked at sacituzumab govitecan compared with docetaxel. Unfortunately, this study also did not meet its primary end point. This has been a letdown in the lung cancer space. These drugs will probably still have an indication in lung cancer, but I don’t think it’s going to be as general as we hoped.

Bearing in mind these challenges, do you feel there is a role for ADCs in combination regimens in NSCLC? What considerations are there regarding toxicity and efficacy?

We anticipate that these drugs will be more effective in combination with chemotherapy or immunotherapy. For example, the [phase 1b] TROPION-Lung02 trial [NCT04526691], which evaluated dato-DXd with pembrolizumab [Keytruda] with or without platinum-doublet chemotherapy, has shown objective response rates of 40% to 50% based on whether we’re using a doublet or triplet regimen in the first line as well as subsequent lines of treatment. [Some of] these ADCs have been shown to have significanttoxicity. There’s an overlap between immunotherapies and pneumonitis; that is one thing that I would watch out for.

The phase 3 studies looking at combinations with dato-DXd are [the phase 3] TROPION-Lung07 [NCT05555732], TROPION-Lung 08 [NCT05215340], and AVANZAR [NCT05687266] trials. We also have the [phase 3] EVOKE-03 trial [NCT05609968] evaluating sacituzumab plus pembrolizumab [vs pembrolizumab alone]. Right now, I don’t see any immediate indication. The only interesting data from EVOKE-01 [showed] a signal for improved OS with sacituzumab govitecan in a small subgroup of patients who had no responses or no benefit with immunotherapy. For patients who are refractory to immunotherapy or whose best response to immunotherapy has been progressive disease, I might try to procure sacituzumab govitecan off label.

What are some key lung cancer trials being conducted at Mayo Clinic that you are excited about?

At Mayo Clinic, we pride ourselves in offering patients a variety of clinical trials, both from early- to late-phase studies. We have a dedicated phase 1 clinical trials unit for all our early-phase studies, and then we have our individual disease sites offering clinical trials for those malignancies. In the thoracic oncology group, some of the studies that we are extremely excited for are our phase 3, first-line studies. We have the AVANZAR trial, and we have the Pragmatica-Lung study [NCT05633602]. This is something that we want to put patients on because these National Cancer Institute studies answer very important questions. The subsequent-line studies are where we have some of our most exciting agents. We’ve got cellular therapy studies with CAR T-cell therapy directed against ROR1, and trials of bispecific antibodies, such an EGFR inhibitor targeting TriNKET. We’ve also got studies with PRMT5 inhibitors for patients with MTAP deletions. These molecules are extremely promising.

[We also have] some studies of ADCs that we are excited about. A specific one that comes to mind is a [phase 1 trial (NCT05103683) evaluating the] claudin 6­–targeted ADC [TORL-1-23], which is open for patients with NSCLC, [ovarian cancer, and other advanced solid tumors]. We do have a couple of [investigator-initiated trials;] one [that is of] great interest to us is a second-line small cell lung cancer trial. [As we know,] these patients often don’t have good treatments after their first-line chemoimmunotherapy.