Sacituzumab Govitecan Plus Pembrolizumab Elicits Antitumor Activity in NSCLC

Clinical evaluations with sacituzumab govitecan-hziy (Trodelvy) in patients with non–small cell lung cancer (NSCLC) point to efficacious outcomes in this population, and support further lung cancer research with this antibody-drug conjugate (ADC), which is approved for subsets of patients with breast and bladder cancer, according to Sandip P. Patel, MD.

The phase 2 EVOKE-02 trial (NCT05186974) evaluated the TROP2-directed ADC in combination with pembrolizumab (Keytruda) in patients with metastatic NSCLC, and data shared at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer showed early antitumor activity with the combination in this population. Notably, investigators have now launched the ongoing, open-label, global, randomized, phase 3 EVOKE 03 trial (NCT05609968), which is evaluating sacituzumab govitecan plus pembrolizumab vs pembrolizumab monotherapy as a first-line treatment for patients in this population.

“As a field, we are looking for well-tolerated combinations that improve [patients’] quality of life, as well as their quantity of life, based on the ability for patients to have supportive care as they [receive] treatment,” Patel explained.

In an interview with OncLive®, Patel discussed the exploration of sacituzumab govitecan in the EVOKE-01 and EVOKE-02 trials in NSCLC, highlighted the safety profile and potential toxicities of this treatment approach, and expanded on future treatment directions with sacituzumab govitecan in this patient population.

Patel is a medical oncologist and professor of medicine at the Precision Immunotherapy Clinic at the University of California, San Diego (UCSD) Moores Cancer Center, UCSD Health.

OncLive: Could you discuss how the mechanism of action of sacituzumab govitecan translates to its pan-tumor efficacy?

Patel: Sacituzumab govitecan is a TROP2-directed ADC currently utilized in breast cancer and bladder cancer. However, TROP2 is also expressed on NSCLC epithelial cells, so it represents an attractive target [in NSCLC].

ADCs [contain] monoclonal antibodies and are infused targeted therapies that are conjugated with a highly potent payload that’s delivered directly to the cancer cell. The goal [is to] maximize [the drug’s] effect against the cancer and minimize the toxicity of these potent chemotherapeutic payloads that otherwise could not be given systemically.

What was the rationale for combining this ADC with pembrolizumab in patients with metastatic NSCLC in the EVOKE-02 trial?

The EVOKE-02 study investigated sacituzumab govitecan in combination with pembrolizumab, a PD-1–directed immunotherapy, with the goal of [using] a combinatorial therapy [to improve] responses, particularly in patients in whom immunotherapy monotherapy may be insufficient.

The reported mechanism of action of the combinatorial effect relates to the ADC allowing for inflammation of the tumor microenvironment and infiltration of antigen-specific T cells, which would be unlocked with PD-1–directed therapy with pembrolizumab. This is some of the work that’s been done in the EVOKE-02 and EVOKE-03 studies to date.

How effective was the combination in this population?

In frontline, non–driver mutation NSCLC, the combination of sacituzumab govitecan plus pembrolizumab had a durable effect in patients with PD-L1 scores greater than 50% and an equally impressive effect in patients with PD-L1 scores less than 50%, [a cohort that has historically not] responded well to PD-1–directed monotherapy. [The cohort of patients with a PD-L1 score of at least 50% are included] in the EVOKE-03 study. However, for patients with PD-L1 scores less than 50% who don’t have a frontline actionable driver mutation, this is an area for future clinical research as well.

What was the safety profile of sacituzumab govitecan plus pembrolizumab, and did the combination show notable additive toxicity compared with the safety profiles of each agent alone?

One important [consideration] when conducting a clinical trial, in addition to the efficacy, is the toxicity, especially with a combinatorial regimen. In the EVOKE-02 study combining sacituzumab govitecan, a TROP2-targeting ADC, with pembrolizumab, a PD-L1–directed monotherapy, one area of interest was potential overlapping toxicities.

Broadly, the toxicity profile seemed to be additive related to the given agent, and [AEs were] mainly related to cytopenias and gastrointestinal effects. A couple areas of interest for larger studies, including the EVOKE-03 study, will include pulmonary toxicities, in particular, pneumonitis, which can have an immune component but can also be potentiated by the ADC portion of the regimen.

What are the clinical implications of the EVOKE-02 findings? How did this investigation lead to the launch of the EVOKE-03 trial?

Broadly, the EVOKE-02 study indicates activity with sacituzumab govitecan in NSCLC in combination with pembrolizumab, both in patients with PD-L1 scores greater than 50% and in patients with PD-L1 scores less than 50%. This [supports the] idea that we may be able to combine chemotherapy with a PD-1 inhibitor and sacituzumab govitecan, though we need to be cognizant of toxicities for [patients with] PD-L1 scores less than 50%. Investigating pembrolizumab plus sacituzumab govitecan as a combination for patients with PD-L1 scores [of at least] 50% is the basis of the EVOKE-03 study, which is ongoing.

What other TROP2-directed ADCs are in development? How do you see this class of agents affecting clinical practice in the future?

Several TROP2-directed ADCs are currently in clinical development. Sacituzumab govitecan is approved for use in refractory triple-negative breast cancer, as well as bladder cancer, and is being studied in NSCLC. Additionally, datopotamab deruxtecan [Dato-DXd; DS-1062a] is a TROP2-directed ADC being investigated in NSCLC and breast cancer. Many other TROP2-targeting ADCs are earlier in clinical development, including MRTX 1866 and HGS TROP2. [These agents have] subtle nuances regarding effector payload ratio and linker chemistry epitopes of TROP2 that are being bound.

Broadly, the class of ADCs has represented a tour de force in our ability to target unique proteins on the surface of cancer cells, maximizing the benefit for patients and trying to limit the toxicities. The clinical trials we have to date have shown that some of the toxicities are related to the payload, but are much less [severe] than what we would see if we gave [the payload] without the antibody.

Reference

Cho B, Dols MC, Cabanillas RR, et al. Sacituzumab govitecan + pembrolizumab in 1l metastatic non small cell lung cancer: preliminary results of the EVOKE 02 study. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA05.04.