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.

®, 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.

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

: 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.

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.

Articles

Sandip P. Patel, MD, discusses the exploration of sacituzumab govitecan in the EVOKE-01 and EVOKE-02 trials in NSCLC and expands on future treatment directions with the agent in this patient population.

Sacituzumab Govitecan Plus Pembrolizumab Elicits Antitumor Activity in NSCLC  

The Exploration of Sacituzumab Govitecan in NSCLC

Dr Patel on the Exploration of Sacituzumab Govitecan in NSCLC

Sandip P. Patel, MD, medical oncologist, professor, medicine, Precision Immunotherapy Clinic, University of California, San Diego (UCSD), Moores Cancer Center, UCSD Health, discusses the utilization of sacituzumab govitecan-hziy (Trodelvy) in non–small cell lung cancer (NSCLC), highlighting trials in which the TROP2-directed antibody-drug conjugate (ADC) is being evaluated in this patient population.

Sacituzumab govitecan is a TROP2-directed ADC currently utilized in breast and bladder cancers, Patel begins, adding that TROP2 is also found on NSCLC epithelial cells, making it a promising target. ADCs, characterized by monoclonal antibodies combined with potent payloads, aim to maximize their anticancer effects and simultaneously minimize the systemic toxicity associated with the chemotherapeutic agents they contain, Patel explains. The phase 2 EVOKE-02 study (NCT05186974) is evaluating the efficacy of the combination of sacituzumab govitecan and pembrolizumab (Keytruda), a PD-1–directed immunotherapy, in patients with advanced or metastatic NSCLC, particularly in cases where immunotherapy alone may be insufficient, he explains.

The proposed mechanism of this combination involves the ADC inducing inflammation in the tumor microenvironment and facilitating the infiltration of antigen-specific T cells that synergize with the PD-1 inhibitor. This treatment approach is now also being explored in the ongoing EVOKE-03 study (NCT05609968), Patel says.

In patients with frontline NSCLC without driver mutations who have a PD-L1 score above 50%, sacituzumab govitecan plus pembrolizumab has demonstrated efficacy, Patel explains. However, this combination is also effective in patients with PD-L1 scores below 50%, a group that has historically been less responsive to PD-1–directed monotherapy, Patel emphasizes. Ongoing research, particularly in the EVOKE-03 study, is investigating sacituzumab govitecan plus pembrolizumab in the population of patients with PD-L1 scores greater than 50%. This combination is an area for future clinical investigation in patients with PD-L1 scores below 50% who lack a frontline actionable driver mutation, he states.

In clinical trials, in addition to assessing efficacy, attention to toxicity is crucial, especially when investigating combined treatments, he states. The EVOKE-02 study demonstrated manageable additive toxicities with the addition of sacituzumab govitecan to pembrolizumab, which were primarily cytopenias and gastrointestinal adverse effects. Larger studies, including the EVOKE-03 study, will further explore the potential for pulmonary toxicities, such as pneumonitis, with this combination, with consideration for the toxicity contribution of both the immunotherapy and ADC components, Patel explains.

Overall, the EVOKE-02 study shows promising activity with sacituzumab govitecan plus pembrolizumab in NSCLC, catering to patients with different PD-L1 scores. Caution should be exercised when investigating this combination in patients with PD-L1 scores less than 50%, he explains. Several other TROP2-directed ADCs are in clinical development in NSCL, he concludes.

Videos

Sandip P. Patel, MD, discusses the utilization of sacituzumab govitecan in non–small cell lung cancer, highlighting trials in which the TROP2-directed antibody-drug conjugate is being evaluated in this patient population.


The focus on novel antibody-drug conjugate (ADC) development in non–small cell lung cancer (NSCLC) signifies a fundamental shift in the treatment paradigm, with several anticipated approvals on the horizon, according to Benjamin Philip Levy, MD, who said that continued research is necessary to improve understanding of the clinical activity, safety, and optimal sequencing of these agents.

Fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is currently the only ADC to be FDA approved

for the treatment of adult patients with unresectable or metastatic NSCLC harboring activating 

 mutations who have previously received systemic therapy.

 However, several other ADCs are showing promise in advanced stage disease, including the TROP-2 directed ADCs sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan (Dato-DXd; DS-1062a). These agents have both demonstrated efficacy in the second line, and smaller datasets signal their potential clinical activity in the first-line setting.

Initial results from the ongoing phase 2 EVOKE-2 trial (NCT05186974) demonstrated that the addition of sacituzumab govitecan to pembrolizumab (Keytruda) produced high response rates in the frontline setting for patients with advanced NSCLC. Across all patients, the overall response rate (ORR) with the combination regimen was 56%, with a disease control rate of 82%. Patients in cohort A, who had a tumor proportion score (TPS) of at least 50% achieved an ORR of 69%, and patients in cohort B with a TPS score below 50% achieved an ORR of 44%. Preliminary data suggest that responses are durable, and the median duration of response was not reached at the time of data cut-off.

“ADCs are coming [down the pike in NSCLC]. We have T-DXd for patients who harbor 

exon 20 mutations, but we're going to have to learn very quickly how to adapt and leverage these other ADCs that may be approved,” said Levy, an associate professor of oncology at Johns Hopkins University School of Medicine and the clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center, part of Sibley Memorial Hospital in Baltimore, Maryland.

, Levy discussed the current landscape of emerging ADCs and their early activity in advanced lung cancer, the potential utility of oncogene-directed ADCs for patients with driver mutations, and the importance of ongoing investigations of sacituzumab govitecan and datopotamab deruxtecan in the first and second lines.

: Please discuss the key highlights from your presentation on oncogene-directed ADCs in lung cancer from the 

 As these [novel] ADCs roll out, we may start categorizing them as onco[gene]-directed, meaning that some of these ADCs may be efficacious [for patients expressing] driver alterations. My presentation is [focused on] those [agents] that have activity in both 

-mutant disease as well as patients with 

 overexpression. We will be reviewing the data for 

 exon 20 mutations with T-DXd and the efficacy we've seen in an updated analysis that was presented at the International Associated for the Study of Lung Cancer [IASLC] World Lung Cancer Conference. We'll be reviewing the patritumab deruxtecan (HER3-DXd) data that were also presented at the IASLC World Lung Cancer Conference, and its activity in 

mutant lung cancer. [Lastly], MET-directed ADCs like telisotuzumab vedotin (ABBV-399; Teliso-V) are being looked at for patients with 

 overexpression happens in patients without 

 mutations, but we also know it happens in the resistant setting for patients who have had received a prior TKI [and who] are 

 positive. Hopefully [our review of these data will] lay the foundation for where we're heading moving forward.

Please provide an overview of the 2 TROP-2 directed ADCs currently in development for patients with NSCLC.

There are 2 TROP-2 directed ADCs currently in development. One is sacituzumab govitecan. This agent was [investigated for use] in lung cancer back in 2017 and efforts [to utilize it] in the second line and in the first line [are being reignited]. Dato-DXd also has been looked at as a single agent in a highly pretreated group of patients with NSCLC. We now have phase 3 data looking at Dato-DXd versus docetaxel in the second line [from the TROPION-LUNG01 study (NCT04656652)]. These data were presented at the 2023 ESMO Congress and showed a PFS advantage in patients with nonsquamous histology. Both TROP-2 directed ADCs have activity in the second line. Both have [also] been looked at in the first line in small datasets and showed meaningful activity. The question is: could these ADCs replace platinum chemotherapy? I'm not sure that's going to happen, but I'm excited to see the data that roll out in the next 6 to 12 months with these drugs.

How do these 2 agents differ from each other in terms of clinical activity or safety?

If we look at the activity of these 2 drugs, it's too early to tell whether they're the same or not. The settings [in which they have been evaluated] have been a bit different. I think we'll find [that] out from the phase 3 EVOKE-01 trial [NCT05089734] of sacituzumab govitecan vs docetaxel, which will hopefully be presented in the next 6 to 12 months. We will then be able to compare those data with the TROPION-Lung01 data [NCT04656652] of Dato-DXd versus docetaxel. These are 2 similar studies. We already know the data for TROPION-Lung01, but we need to find out the data for EVOKE-01 to see how [the agents perform] with a similar comparator arm of docetaxel. If you look at these agents in the front line, specifically in combination with immunotherapy, they look about the same in terms of their activity.

Toxicities do differ here. We know that there may be more cytopenias with sacituzumab govitecan, and we know that there may be more stomatitis with Dato-DXd. We have to be proactive in managing that. Although these 2 drugs are both TROP-2 directed ADCs, they may have different activity and they do have different toxicities. We'll have to see how they're leveraged in our clinic and how they might get approved.

What is your main message for colleagues based on your presentation?

In my opinion, Dato-DXd will be approved in the next 6 to 12 months. It will be important to look at the data and understand toxicities, how to manage them, and potentially how to sequence these therapies.

This is a whole new class of drugs that [we have] never really had to wrestle with. We've always been in the lane of either targeted therapy, chemotherapy, or immunotherapy. Along comes this new class, and we're going to have to learn about them quickly as they gain approval. We're going to have to try to understand who these drugs work for. Most importantly, [we will have to learn] how to mitigate toxicities for these drugs so that that journey is clean for patients and that we can be proactive in the management of these adverse effects.

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 11, 2022. Accessed November 16, 2023. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung

Gilead’s phase 2 EVOKE-02 study of Trodelvy (sacituzumab govitecan-hziy) in combination with Keytruda (pembrolizumab) demonstrates promising clinical activity in first-line metastatic non-small cell lung cancer. News release. Gilead. September 10, 2023. Accessed November 16, 2023. 

https://www.gilead.com/news-and-press/press-room/press-releases/2023/9/gileads-phase-2-evoke02-study-of-trodelvy-sacituzumab-govitecanhziy-in-combination-with-keytruda-pembrolizumab-demonstrates-promising-clinical-activity

Benjamin Philip Levy, MD, discusses the current landscape of emerging antibody-drug conjugates (ADCs) and their early activity in advanced lung cancer, the potential utility of oncogene-directed ADCs for patients with driver mutations, and more.

Emerging TROP-2 Directed ADCs Show Promise in Advanced NSCLC

Dr Sabari on the EVOKE-02 Trial With Sacituzumab Govitecan in NSCLC

Joshua K. Sabari, MD, assistant professor, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Health’s Perlmutter Cancer Center, discusses the ongoing phase 2 EVOKE-2 trial (NCT05186974) investigating sacituzumab govitecan-hziy (Trodelvy) in non– small cell lung cancer (NSCLC); emerging data on antibody-drug conjugates (ADCs) in the second– or first-line treatment setting; and the planned phase 3 EVOKE-03 trial (NCT05609968) of sacituzumab govitecan plus pembrolizumab (Keytruda) as a frontline treatment.

The EVOKE-02 study is a global, open-label, multi-center, phase 2 trial designed to assess the combination of sacituzumab govitecan and pembrolizumab, with or without chemotherapy, irrespective of PD-L1 expression, Sabari begins. The study included patients with advanced or metastatic NSCLC who lack actionable genomic alterations. Patients were assigned to 1 of 4 cohorts based on disease status and PD-L1 expression, Sabari details. Cohort A included patients with squamous/non-squamous NSCLC and a tumor proportion score (TPS) greater than or equal to 50%, while Cohort B included those with a TPS less than 50%. Patients in Cohorts A and B received the combination regimen.

After enrollment in a safety run-in cohort, patients will be assigned to Cohorts C or D based on disease status for carboplatin combinations. Cohort C will enroll patients with non-squamous NSCLC with any PD-L1 expression level, and Cohort D will enroll patients with squamous NSCLC with any PD-L1 expression level. Patients in Cohorts C or D received sacituzumab govitecan, pembrolizumab, and chemotherapy. The trial's primary end point was objective response rate.

Preliminary results from cohorts A and B of this trial were presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer,

 Sabari states. Results demonstrated that 56% of patients across both cohorts achieved an overall response rate (ORR) of 56% with sacituzumab govitecan and pembrolizumab, with a disease control rate of 82%, he reports. Notably, the ORR was 69% in the PD-L1 high cohort, and this cohort was limited to 30 patients, Sabari adds. Although complete PFS data are pending, the preliminary swimmer's plot suggests that these responses are also durable, he notes.

Limited ADC data in the frontline setting necessitates further exploration of these agents in NSCLC, Sabari continues. There is also a need for second-line studies like the phase 3 EVOKE-01 trial (NCT05089734), which compares sacituzumab govitecan vs docetaxel, he says. Concerns about ADC-associated toxicities impacting frontline use of the combination were somewhat alleviated in EVOKE-02, as the combination of sacituzumab govitecan and pembrolizumab did not significantly increase toxicities, Sabari explains. Expected adverse effects such as diarrhea or interstitial lung disease did not increase in frequency, demonstrating the safety of sacituzumab govitecan in combination with a PD-1 inhibitor, Sabari says.

Additionally, investigators anticipate data from the ongoing, open label, global, randomized, phase 3 EVOKE 03 trial (NCT05609968), Sabari states. This trial is currently evaluating sacituzumab govitecan and pembrolizumab vs pembrolizumab monotherapy as a first-line treatment for patients with metastatic NSCLC with PD-L1 TPS of at least 50%. Ongoing research in ADC combinations for frontline use in the PD-L1 high population will provide valuable insights into the evolving landscape of NSCLC treatment, Sabari concludes.

Joshua K. Sabari, MD, discusses the ongoing phase 2 EVOKE-2 trial  investigating sacituzumab govitecan-hziy in non– small cell lung cancer; emerging data on antibody-drug conjugates in the second– or first-line treatment setting; and the planned phase 3 EVOKE-03 trial of sacituzumab govitecan plus pembrolizumab as a frontline treatment.

Dr. Sabari on the EVOKE-02 Trial With Sacituzumab Govitecan in NSCLC

Dr Levy on the Ongoing Development of TROP-2 ADCs in NSCLC

Benjamin Philip Levy, MD, associate professor, oncology, Johns Hopkins University School of Medicine; clinical director, Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center, Sibley Memorial Hospital, discusses the ongoing development of the TROP-2 directed antibody-drug conjugates (ADCs) sacituzumab govitecan-hziy (Trodelvy) and datopotamab deruxtecan (Dato-DXd; DS-1062a) in non–small cell lung cancer (NSCLC), their different toxicity profiles, as well as the potential categorization of emerging ADCs as onco-directed therapies in this patient population.

Both sacituzumab govitecan and Dato-DXd show potential in non-small cell lung cancer (NSCLC), Levy begins. Sacituzumab govitecan, which was originally evaluated in 2017 for NSCLC, is being reexamined in both the second– and first-line settings, Levy states. Additionally, datopotamab deruxtecan was initially explored as a monotherapy for heavily pretreated patients with NSCLC. However, it is now being compared with docetaxel in the second-line setting of a phase 3 trial, with recent data indicating that the agent confers a progression-free survival advantage in patients with non-squamous histologies, he explains.

These TROP-2 directed ADCs have both shown efficacy in the second-line, and efforts to utilize these agents in earlier lines have shown initial activity in smaller datasets, Levy continues. The continued investigation of these agents raises the question of whether these agents may replace platinum chemotherapy, he says. Although this outcome is currently unlikely, forthcoming data may further elucidate their potential impact on the treatment paradigm.

Although cross-trial comparisons require caution, these ADCs appear to demonstrate similar activity when combined with immunotherapy in the frontline, Levy expands. The phase 3 EVOKE-01 trial (NCT05089734) of sacituzumab govitecan vs docetaxel may confirm their similarity, as these data could be more easily compared with that of the phase 3 TROPION-Lung01 trial (NCT04656652), Levy emphasizes. However, they display more distinct toxicity profiles, with sacituzumab govitecan being associated with a higher frequency of cytopenias, and Dato-DXd being associated with increased stomatitis. Vigilant management strategies are essential for optimizing patient outcomes, he states.

As ADCs like sacituzumab govitecan and Dato-DXd continue to emerge, they may be categorized as onco-directed therapies. This indicates that a given agent may provide particular benefit for patients expressing specific driver alterations, Levy continues. Notably, ADCs with activity against both 

-overexpressing NSCLC, have demonstrated encouraging results. Trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has demonstrated efficacy in patients with exon 20 mutations, while patritumab deruxtecan (HER3-DXd) and telisotuzumab vedotin (ABBV-399; Teliso-V) both have breakthrough designation in NSCLC, he elucidates.

The advent of ADCs in NSCLC represents a paradigm shift in the approach to treating patients with NSCLC, with potential approvals for T-DXd and Dato-DXd on the horizon, Levy addes. Improved understanding of their clinical profiles, toxicities, and sequencing will be pivotal to ensuring effective patient care and informed decision-making, he concludes.

Benjamin Philip Levy, MD, discusses the ongoing development of the TROP-2 directed antibody-drug conjugates sacituzumab govitecan-hziy and  datopotamab deruxtecan in non–small cell lung cancer, their different toxicity profiles, as well as the potential categorization of emerging ADCs as onco-directed therapies in this patient population.

Recent Updates on TROP2-Directed Antibody-Drug Conjugates in NSCLC | Supplements and Featured Publications

Sacituzumab Govitecan Plus Pembrolizumab Elicits Antitumor Activity in NSCLC

Dr Patel on the Exploration of Sacituzumab Govitecan in NSCLC

Emerging TROP-2 Directed ADCs Show Promise in Advanced NSCLC

Dr. Sabari on the EVOKE-02 Trial With Sacituzumab Govitecan in NSCLC

Dr Levy on the Ongoing Development of TROP-2 ADCs in NSCLC