Edwin Lin, MD, PhD, resident physician, Mayo Clinic, discusses the utilization of antibody-drug conjugates (ADCs) and the importance of defining biomarker-based approaches for this treatment class in patients with non–small cell lung cancer (NSCLC).

The oncology field has experienced 2 significant paradigm shifts pertaining to ADCs. Lin says that the first paradigm shift to note is the increasing availability of ADCs across various malignancies. An ADC comprises an antibody connected to a chemical linker, which is then attached to a cytotoxic payload, according to Lin. This treatment approach has shown efficacy in patients with cancer, exemplified by the use of fam-trastuzumab deruxtecan-nxki (Enhertu) for those with pretreated, metastatic HER2-positive breast cancer, Lin explains. As time has progressed, a growing number of ADCs have emerged that are directed at targets in various cancer types, he notes.

The second evolution regarding ADCs is the efficacy of these agents, Lin expands, noting that over the past 20 years, the chemistry of ADCs has improved. Ongoing modification and experimentation with these agents have yielded better linkers and cytotoxic payloads, Lin explains. Although the antigen levels in the newer generation of ADCs are the same as those in earlier generations of these agents, the newer generation of these agents can induce more responses, he emphasizes. For example, the guidelines for determining HER2-negative disease have shifted with the advent of the phase 3 DESTINY-Breast04 trial (NCT03734029), in which trastuzumab deruxtecan generated superior efficacy over chemotherapy in patients with metastatic HER2-low breast cancer, he adds. Lin says that consequently, the HER2 treatment armamentarium is in a state of flux, and the guidelines need to be updated to keep up with the therapeutic innovations that have occurred with ADCs.

To summarize, an increasing number of effective ADCs are becoming available in NSCLC and other tumor types, he continues. Overall, better ADCs are on the horizon, underscoring the need for an assay that can profile multiple ADC targets, Lin concludes.

Videos

Edwin Lin, MD, PhD, discusses the utilization of antibody-drug conjugates and the importance of defining biomarker-based approaches for this treatment class in patients with non–small cell lung cancer.


Dr Lin on Defining Biomarker-Based Treatment Approaches in NSCLC

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 

®. “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.

“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.”

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 

 mutations who were previously treated with systemic therapy. The decision also marked trastuzumab deruxtecan as the first agent approved for the treatment of 

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.

 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 

. “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%.

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

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.

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.

“[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 

 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 

 amplification. The primary end point is ORR, and secondary end points consist of PFS, overall survival OS, and patient-reported outcomes.

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.

“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.”

Rosner S, Valdivia, Hoe HJ, et al. Antibody-drug conjugates for lung cancer: payloads and progress. 

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

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

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.htm

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). 

. 2020;38(suppl 15):9505. doi:10.1200/ JCO.2020.38.15_suppl.9505

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). 

. 2023;41(suppl 16):9004. doi:10.1200/JCO.2023.41.16_suppl.9004

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. 

. 2023;41(suppl 16):TPS9147. doi:10.1200/JCO.2023.41.16_suppl.TPS9147

Horinouchi H, Shibata Y Looman J, et al. Phase 2 study of telisotuzumab vedotin (Teliso-V) monotherapy in patients with previously untreated 

-amplified locally advanced/metastatic non-squamous non-small cell lung cancer (NSQ NSCLC). 

. 2023;41(suppl 16):TPS9149. doi:10.1200/JCO.2023.41.16_suppl.TPS9149

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). 

. 2023;41(suppl 16):TPS155. doi:10.1200/JCO.2023.41.16_suppl.TPS9155

Articles

As antibody-drug conjugates become an established part of the lung cancer treatment paradigm, identifying which patients will benefit the most from treatment with these highly specific agents remains a challenge for clinicians.

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

Luis Paz-Ares, MD, PhD, chairman, Medical Oncology Department, Hospital Doce de Octubre; head, Lung Cancer Unit, CNIO (National Oncology Research Center); associate professor, Universidad Complutense, discusses efficacy and safety findings from the phase 2 CARMEN-LC05 trial (NCT04524689) of tusamitamab ravtansine (SAR408701) in patients with nonsquamous non–small cell lung cancer (NSCLC) with CEACAM5 expression.

CARMEN-LC05 investigated the efficacy and safety of tusamitamab ravtansine in doublet, triplet, and quadruplet combinations with pembrolizumab (Keytruda) with or without platinum-based chemotherapy and pemetrexed (Alimta) in patients with nonsquamous NSCLC with moderate to high CEACAM5 expression and any level of PD-L1 expression. In all treatment arms, patients received tusamitamab ravtansine intravenously every 3 weeks at either 150 mg/m

Across all dose levels, the overall response rate (ORR) was 52% (95% CI, 31.3%-72.2%), and the median duration of treatment was 24.3 weeks. Additionally, 36% of patients achieved stable disease, 12% of patients had progressive disease, and the disease control rate was 88% (95% CI, 68.8%-97.5%).

The ORRs with the doublet, triplet, and quadruplet with tusamitamab ravtansine at 150 mg/m

 were 100%, 50%, and 50%, respectively. Responses were seen in patients regardless of PD-L1 or CEACAM5 expression, Paz-Ares says.

The doublet, triplet, and quadruplet regimens were tolerable, Paz-Ares notes. One dose-limiting toxicity, increased aspartate aminotransferase, was seen in a patient who received tusamitamab ravtansine at 170 mg/m

 as part of the quadruplet regimen. Treatment-emergent adverse effects (TEAEs) of grade 3 or higher occurred in 68.0% of all patients, however, most were unrelated to the study regimens, Paz-Ares explains. In addition, 24.0% of all patients had corneal TEAEs, which were manageable with dose modification, Paz-Ares emphasizes. One patient in the doublet arm who received tusamitamab ravtansine at 170 mg/m

 experienced a grade 3 corneal TEAE. Furthermore, 16.0% and 28.0% of all patients had pneumonitis and peripheral neuropathy, respectively, and most events were grade 1/2, Paz-Ares concludes.

Editor's Note: This summary reflects the accurate value for the median duration of the study treatment, which was 24.3 weeks, rather than 24 months, as noted in the video at 0:28.

Paz-Ares L, Nagy T, Ravoire M, et al. Safety and efficacy of tusamitamab ravtansine in comination with pembrolizumab ± chemotherapy in patients with CEACAM5-positive nonsquamous NSCLC (CARMEN-LC05 phase 2 study). Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 13MO.

Luis Paz-Ares, MD, PhD, discusses efficacy and safety findings from the phase 2 CARMEN-LC05 trial of tusamitamab ravtansine in patients with nonsquamous non–small cell lung cancer with CEACAM5 expression.

Dr Paz-Ares on Tusamitamab Ravtansine in CEACAM5-Positive NSCLC

Yasushi Goto, MD, National Cancer Center Hospital, discusses primary efficacy findings from the phase 1 TROPION-Lung02 trial (NCT04526691) of datopotamab deruxtecan plus pembrolizumab (Keytruda) with or without platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC).

TROPION-Lung02 included 6 cohorts, where patients received datopotamab deruxtecan plus pembrolizumab with or without platinum chemotherapy intravenously every 3 weeks. In cohorts 1 and 2, datopotamab deruxtecan was given at 4-mg/kg and 6-mg/kg doses, respectively, with pembrolizumab given at 200 mg. In cohorts 3 and 4, datopotamab deruxtecan was given at dose levels of 4 mg/kg and 6 mg/kg, respectively, with pembrolizumab at 200 mg and carboplatin at an area under the curve of 5. Those in cohorts 5 and 6 received datopotamab deruxtecan at 4 mg/kg and 6 mg/kg, respectively, with pembrolizumab at 200 mg and cisplatin at 75 mg/m

In the entire patient population, the doublet elicited a confirmed and pending overall response rate (ORR) of 38%; with the triplet, this rate was 49%. Moreover, patients who received the doublet as first-line therapy had an ORR of 50%; those who received the triplet as first-line therapy had an ORR of 57%. The survival data, although immature, indicate efficacy with the doublet and triplet regimens, Goto says.

This multicohort phase 1 study includes a patient population with a variety of baseline characteristics, Goto notes. In total, 36%, 44%, and 20% of patients in the doublet cohort and 40%, 33%, and 25% of patients in the triplet cohort had a baseline PD-L1 expression of less than 1%, 1% to 49%, and at least 50%, respectively. Additionally, 17% and 19% of patients in the doublet and triplet cohorts, respectively had a history of brain metastases. Patients in both cohorts had a median of 0 prior lines of therapy (doublet, range, 0-4; triplet, range, 0-3).

Dr Goto reports honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb Japan, Chugai Pharma, Guardant Health AMEA, Kyowa Kirin International, Lilly Japan, Merck, MSD, Novartis, Ono Pharmaceutical, Pfizer, Shionogi, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, and TOWA; consulting or advisory roles with AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo/UCB Japan GlaxoSmithKline, Guardant Health, AMEA, Janssen, Kyorin, Lilly, Merck, Novartis, Ono Pharmaceutical, Pfizer, and Taiho Pharmaceutical; and research funding from A2 Healthcare (Inst), AbbVie (Inst), AstraZeneca (Inst), Bristol-Myers Squibb Japan (Inst), Chugai Pharma (Inst), CMIC (Inst), Daiichi Sankyo (Inst), Daiichi Sankyo/UCB Japan (Inst), EPS Holdings (Inst), Genomic Health (Inst), IQvia (Inst), Kyorin (Inst), Lilly Japan (Inst), Merck Serono (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), Taiho Pharmaceutical (Inst), and Takeda (Inst).

Yasushi Goto, MD, discusses primary efficacy findings from the phase 1 TROPION-Lung02 trial of datopotamab deruxtecan plus pembrolizumab with or without platinum-based chemotherapy in patients with advanced non–small cell lung cancer.

Mapping Advances Made With ADCs in Lung Cancer | Supplements and Featured Publications

Dr Lin on Defining Biomarker-Based Treatment Approaches in NSCLC

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

Dr Paz-Ares on Tusamitamab Ravtansine in CEACAM5-Positive NSCLC

Dr Goto on Datopotamab Deruxtecan Plus Pembrolizumab and Chemotherapy in Advanced NSCLC