Despite Diagnostic Challenges, ADCs Are Poised to Expand Treatment Options in Lung Cancer

Benjamin P. Levy, MD

As antibody-drug conjugates (ADCs) become an established part of the lung cancer treatment paradigm, the breadth of therapeutic targets are growing at a rapid pace. However, identifying which patients will benefit the most from treatment with these highly specific agents remains a challenge for clinicians.

“The whole idea is that this compound is supposed to bind on a target antigen on the cell surface of a tumor,” Benjamin P. Levy, MD, said in an interview with OncLive®. “It seems quite easy; a monoclonal antibody attaches to the cell surface antigen, it gets internalized, the warhead is released, and the cell goes through, apoptosis, and gets destroyed,” added Levy who is clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, and an associate professor of oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland.

ADCs are comprised of an antibody, a linker, and a payload. The antibody binds to the antigen target on the tumor cell; common ADC targets include HER2, TROP2, and HER3, with novel agents in development to target CEACAM5, MET, DLL2, and others. The linker connects the antibody with the payload and helps to maintain the stability of the agent and aids with the release of the payload into the tumor cell. Finally, the payload is a cytotoxic compound such as an antimicrotubule agent or a topoisomerase I inhibitor.¹

“What we’re learning, however, is the story is not that clear and there may be other mechanisms at play, [such as] the bystander effect,” Levy said. “Antigen expression on the tumor cell may not predict response of these drugs. So, these drugs may be able to be laced inside the cell and [once] internalized the warheads [are] released killing not only the actual cell that internalized it, but also killing bystander cells. Another mechanism of action is antibody dependent cellular cytotoxicity, which essentially means that these drugs not only bind to the tumor cell, but they’re able to engage immune cells and allow this compound to potentially function as a soft immunotherapeutic drug.”

Setting the Stage for ADCs

As ADCs are approved as single agents, opportunities to expand their utility have resulted in clinical trials evaluating these in combinations, in different sequences, and across tumor types.

In lung cancer, specifically, fam-trastuzumab deruxtecan-nxki (Enhertu) became the first ADC to receive approval for an indication from the FDA for the treatment of patients with non–small cell lung cancer (NSCLC). In August 2022, the agent was granted accelerated approval for the treatment of adult patients with unresectable or metastatic disease harboring HER2 mutations who were previously treated with systemic therapy. The decision also marked trastuzumab deruxtecan as the first agent approved for the treatment of HER2-mutant NSCLC.²

Subsequently, 2 ADCs have received breakthrough therapy designation from the FDA: patritumab deruxtecan and telisotuzumab vedotin. The designations were given in December 2021 and January 2022, respectively.^3,4 Levy said that by the end of 2023, another ADC approval is anticipated. “We’re going to have to learn how to use these drugs in our clinics in different patients, but also understand the toxicity of these drugs so that we can mitigate them in clinic,” he said on their practical application. “They’re coming, fast and furious. We’re going to have several ADCs that we’re going to be able to use in clinic every day in the next 3 to 5 years,” Levy added.

For ADCs to display the desired efficacy, selecting patients whose disease has the necessary features to maximize the benefit of these agents is critical. However, there are currently limited options available to aid clinicians in accurately identifying which patients will benefit from treatment with an ADC in a timely and repeatable manner.

“There’s immunohistochemistry, which looks at just expression on the surface [of cells],” Alexander I. Spira, MD, PhD, FACP, codirector of the Virginia Cancer Specialists Research Institute in Fairfax, Virginia, as well as the director of the Thoracic and Phase I Program and a clinical assistant professor at Johns Hopkins University School of Medicine in Baltimore, Maryland, said in an interview with OncLive. “There’s also FISH [fluorescence in situ hybridization], which looks more at the molecular [level], and there’s copy number expressions as well. It’s been tough. Companion diagnostics [for ADCs] are going to be worked on later down the road, as we figure out not only what’s the companion diagnostic, but how high [in terms of expression] do you have to be?”

Spira added that even though some patients may have very low expression of a given target antigen, this does not necessarily mean they will not derive benefit from an ADC, furthering complicating the process for clinicians. However, he noted that the development of a companion diagnostic for ADCs in lung cancer is still paramount because even if all patients can benefit from a treatment with an agent, it’s still very important to understand who is most likely to derive the greatest benefit.

For example, CEACAM5, expressed in approximately 25% of lung cancers, is another target of recent ADC development. The novel agent, tusamitamab ravtansine comprises a humanized monoclonal antibody that binds to CEACAM5 and a cytotoxic maytansinoid, DM4. Expression is evaluated using IHC expression, and those with higher expression (IHC 2+ defined as ≥ 50% of tumor cells) have demonstrated stronger response to treatment with the novel ADC. However, those with moderate expression had similar rates of stable disease and disease control.5

For instance, in a phase 1/2 trial (NCT02187848), among those with IHC 2+ (n = 64) the overall response rate was 20.3%, the stable disease (SD) rate was 43.1%, with a disease-control rate (DCR) of 64.1%. For those with moderate expression of 1%-50% (n = 28), the ORR was 7.1%, the SD rate was 53.6%, and the DCR was 60.7%.⁵

The agent is under investigation in the CARMEN-LC03 trial (NCT04154956) of patients with CEACAM5 IHC 2+.

Key Updates on ADCs

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, updated findings and new trial designs of several clinical trials evaluating ADCs in lung cancer were presented by investigators.

In the phase 1 TROPION-Lung02 trial (NCT04526691), the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd; formerly DS-1062) is being evaluated in combination with pembrolizumab (Keytruda) with or without platinum-based chemotherapy in patients with advanced NSCLC. Findings from the study showed that at the April 7, 2023, data cutoff patients who received datopotamab deruxtecan plus pembrolizumab (n = 61) experienced an overall response rate (ORR) of 38% (95% CI, 26%-51%) and had a disease control rate (DCR) of 84%.

Additionally, patients who had platinum-based chemotherapy added to datopotamab deruxtecan and pembrolizumab (n = 71) achieved an ORR of 49% (95% CI, 37%-61%) and a DCR of 87%. The preliminary median progression-free survival (PFS) for all patients who received the doublet was 8.3 months (95% CI, 6.8-11.8) and 7.8 months (95% CI, 5.6-11.1) among those who also received chemotherapy.⁶

In terms of safety, most patients who received either the doublet or the combination and chemotherapy experienced a treatment-emergent adverse effect (TEAE), at 97% and 100%, respectively. Moreover, grade 3 or higher TEAEs were reported in 53% and 76% of patients, respectively. Patients in both arms experienced death (5% vs 7%), dose reduction of any agent (22% vs 19%), dose reduction of datopotamab deruxtecan (22% vs 15%), discontinuation of any drug (28% vs 38%), and discontinuation of datopotamab deruxtecan (23% vs 28%).

The novel ADC MYTX-011, which is a cMET-targeted ADC, is being evaluated in the phase 1 dose escalation and dose expansion MYTX-011-01 trial (NCT05652868). This first-in-human study of the agent will examine its safety and efficacy in patients with advanced NSCLC. The recommended phase 2 dose and preliminary antitumor activity will be determined. Enrollment for the trial is currently underway.⁷

“[MYTX-011] is essentially designed to target multiple tumor types,” Spira said. “We believe it’s a best-in-class [agent] with the hope is that it can bring a new mechanism of action towards targeting refractory cancers. The interesting thing about this is that it’s hopefully being able to work on tumors that are MET low, kind of building on the paradigm we’ve seen in HER2-positive tumors like [with] trastuzumab deruxtecan, where the drug can work in places that do not have very high levels of expression for the antigen but still bind and result in tumor cell death.”

Another cMET-targeted ADC, telisotuzumab vedotinis under investigation in a phase 2 study (NCT05513703). The first-in-class agent will be examined among adult patients with treatment-naïve advanced or metastatic nonsquamous NSCLC with MET amplification. The primary end point is ORR, and secondary end points consist of PFS, overall survival OS, and patient-reported outcomes.⁸

In another trial, the phase 2 VELOCITY-Lung study (NCT05186974), novel treatment combinations with ADC components are being evaluated in patients with treatment-naïve NSCLC. The open-label, multicenter trial will compare the safety and efficacy of the investigational monoclonal antibodies domvanalimab plus zimberelimab and sacituzumab govitecan vs etrumadenant plus domvanalimab and zimberelimab vs etrumadenant plus zimberelimab. The primary end point is ORR, secondary end points include PFS, duration of response, and OS.⁹

“The future of ADCs is bright,” Levy said. “We only have a nascent understanding of these drugs and how they can be put together, the synthetic biochemistry that goes into their production, and how they can be leveraged in our clinic. The next wave of ADCs is going to involve a few things. One, it’s going to involve more sophisticated monoclonal antibodies that can bind not only to 1 antigen on the tumor cell, but maybe 2. There are [also] barotropic ADCs, which can bind to different epitopes on the same antigen on the tumor cell. Then there are novel payloads; the payloads we have now are highly potent, but they are toxic. So, the movement is going to be in the generation of these monoclonal antibodies that are a little bit more sophisticated, as well as different warheads that may be more potent and more selective to tumor cells.”

References

1. Rosner S, Valdivia, Hoe HJ, et al. Antibody-drug conjugates for lung cancer: payloads and progress. Am Soc Clin Oncol Educ Book. 2023;43. doi:10.1200/EDBK_389968
2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 11, 2022. Accessed July 6, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung
3. Patritumab deruxtecan granted U.S. FDA breakthrough therapy designation in patients with metastatic EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo Company Ltd. December 23, 2021. Accessed July 6, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202112/20211223_E1.pdf
4. AbbVie announces US FDA granted breakthrough therapy designation (BTD) to telisotuzumab vedotin (teliso-V) for previously treated non-small cell lung cancer. News release. AbbVie. January 4, 2022. Accessed July 6, 2023. https://news.abbvie.com/news/press-releases/abbvie-announces-us-fda-granted-breakthrough-therapy-designation-btd-to-telisotuzumab-vedotin-teliso-v-for-previously-treated-non-small-cell-lung-cancer.html
5. Gazzah A, Ricordel C, Cousin S, et al. Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). J Clin Oncol. 2020;38(suppl 15):9505. doi:10.1200/ JCO.2020.38.15_suppl.9505
6. Goto Y, Su WC, Levy BP, et al. TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC). J Clin Oncol. 2023;41(suppl 16):9004. doi:10.1200/JCO.2023.41.16_suppl.9004
7. Spira AI, Johnson ML, Blumenschein GR, et al. Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer. J Clin Oncol. 2023;41(suppl 16):TPS9147. doi:10.1200/JCO.2023.41.16_suppl.TPS9147
8. Horinouchi H, Shibata Y Looman J, et al. Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated MET-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC). J Clin Oncol. 2023;41(suppl 16):TPS9149. doi:10.1200/JCO.2023.41.16_suppl.TPS9149
9. Spira AI, Chiu J, Wang CC, et al. VELOCITY-Lung: a phase (Ph) 2 study evaluating safety and efficacy of domvanalimab (dom) + zimberelimab (zim) + sacituzumab govitecan (SG), or etrumadenant (etruma) + dom + zim, or etruma + zim in patients (pts) with treatment-naïve metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol. 2023;41(suppl 16):TPS155. doi:10.1200/JCO.2023.41.16_suppl.TPS9155