Benjamin P. Levy, MD, is clinical director of Medical Oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital and associate professor of oncology at Johns Hopkins University School of Medicine.

Joshua K. Sabari, MD, is an associate professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine. He is also medical director, ofThoracic Medical Oncology at NYU Langone Health’s Perlmutter Cancer Center.

Edward B. Garon, MD, MS, reviews data from the EVOKE-02 study, and the panel offers their thoughts on antibody-drug conjugates for advanced NSCLC.

EVOKE-02: Sacituzumab Govitecan Plus Pembrolizumab in Advanced NSCLC

This is a synopsis of a Peer Exchange video series featuring Benjamin P. Levy, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Solange Peters, MD, PhD, of University Hospital of Lausanne; Joshua K. Sabari, MD, of NYU Langone’s Perlmutter Cancer Center; Edward B. Garon, MD, MS, of UCLA Jonsson Comprehensive Cancer Center; and Marina Chiara Garassino, MD, of University of Chicago Medicine Comprehensive Cancer Center.

Dr Levy notes ADCs [antibody-drug conjugates] are being studied in the first-line after showing promise in later lines of therapy. He asks Dr Garon to discuss data from the phase 2 EVOKE-02 study of sacituzumab govitecan combined with pembrolizumab as initial treatment for patients with metastatic NSCLC [non–small cell lung cancer]. Dr Garon explains the study showed the regimen appears safe, though combining novel agents can risk unforeseen toxicity. Efficacy must be proven superior to available options like chemoimmunotherapy. Dr Sabari agrees it is interesting but questions if it can replace standard pemetrexed-based regimens. Dr Peters is also hesitant to replace pemetrexed, given its proven benefits, but is open to sacituzumab govitecan potentially replacing taxanes like paclitaxel. She notes the EVOKE-01 second-line trial data will also help characterize the utility of this ADC.

In summary, the early stage EVOKE-02 data shows the feasibility of combining the ADC sacituzumab govitecan with pembrolizumab as first-line treatment for NSCLC, but whether efficacy will prove sufficient to change the standard chemotherapy-immunotherapy paradigm remains uncertain pending full results. The experts agreed ADCs are an interesting new approach but voiced some reluctance to omit proven chemotherapies like pemetrexed without compelling data.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.

Videos

Edward B. Garon, MD, MS, reviews data from the EVOKE-02 study, and the panel offers their thoughts on antibody-drug conjugates for the treatment of advanced NSCLC.

The expert panel reviews the results from the TROPION-Lung01 study.

Expert Perspectives on the Results of the TROPION-Lung01 Study in NSCLC

Dr Levy notes that while immunotherapy has improved first-line NSCLC [non–small cell lung cancer] outcomes, docetaxel with or without ramucirumab remains the only approved second-line regimen. He discusses promising data from the TROPION-Lung01 trial comparing the antibody-drug conjugate datopotamab deruxtecan to docetaxel in previously treated patients with NSCLC. Dr Peters explains the trial showed a statistically significant improvement in progression-free survival, including in the pre-planned non-squamous subgroup analysis, and nearly doubled response rate compared to docetaxel. She feels these efficacy findings along with a different toxicity profile support datopotamab deruxtecan as a new competitor to docetaxel likely to be adopted into clinical practice.

Dr Garon, who led the REVEL trial of docetaxel/ramucirumab, agrees the toxicity profile appears slightly better than single-agent docetaxel. However, he notes the efficacy improvements over docetaxel are modest and don’t reflect the “leaps better” outcome hoped for. Dr Sabari concurs the PFS benefit is small and questions whether the toxicity shift is worthwhile. Dr Levy states that overall survival data could change perspectives, especially if particular subgroups derive greater benefit. Dr Garassino emphasizes collecting real-world toxicity data and patient-reported outcomes. In conclusion, the panel agrees this antibody-drug conjugate represents the first advance over docetaxel in the second-line NSCLC setting, constituting a new treatment option, but its ultimate impact remains to be defined.

The expert panel reviews the results from the TROPION-Lung01 study and discusses how the data can inform treatment decisions for patients with previously treated NSCLC.

Solange Peters, MD, PhD, reviews key data from TROPION-Lung01 investigating Dato-DXd in patients with previously treated advanced non–small cell lung cancer.

TROPION-Lung01: Dato-DXd in Previously Treated Advanced NSCLC

Dr Levy notes that while immunotherapy has improved first-line NSCLC [non–small cell lung cancer] outcomes, there remains only 1 approved second-line regimen: docetaxel with or without ramucirumab. Many trials have tried unsuccessfully to outperform docetaxel. Dr Peters concurs, stating recent failed trials with various immunotherapies and chemotherapies highlight docetaxel’s ongoing role as the second-line standard of care.

They discuss promising data from an abstract of the TROPION-Lung01 trial comparing the antibody-drug conjugate datopotamab deruxtecan to docetaxel in previously treated patients with NSCLC. Dr Peters explains the trial showed statistically significant improvement in progression-free survival from 3.7 to 4.4 months overall, and 3.7 to 5.6 months in the pre-planned non-squamous subgroup analysis. Response rate also nearly doubled from 13% to 26%. Toxicity profiles differ, but serious adverse events were lower with datopotamab deruxtecan.

In summary, Dr Peters feels these efficacy and toxicity findings support datopotamab deruxtecan as a new competitor to docetaxel in the second-line NSCLC setting that is likely to be adopted into clinical practice. Dr Levy agrees this is an important advance for patients progressing after first-line therapy.

Solange Peters, MD, PhD, reviews key data from TROPION-Lung01 investigating datopotamab deruxtecan (Dato-DXd) in patients with previously treated advanced non–small cell lung cancer.

Clinical insights on how the level of PD-L1 expression informs treatment decisions for patients with non–small cell lung cancer.

NSCLC: PD-L1 Expression and Treatment Decision-Making

The panel discussed whether to use immunotherapy alone or chemoimmunotherapy for patients with stage IV NSCLC [non–small cell lung cancer] with PD-L1 expression above 50%. Dr Garon said higher PD-L1 levels correlate with greater likelihood of benefit from immunotherapy, so he may use pembrolizumab monotherapy more for levels above 70% to 90% versus 50%. He is cautious using monotherapy in never-smokers, who seem to derive less benefit from PD-1 inhibitors alone per the data.

Dr Sabari agreed, noting he often adds chemotherapy for squamous histology and uses clinical factors to personalize first-line treatment. Dr Peters cautioned that a third of patients progress on pembrolizumab monotherapy in trials, so ensuring fitness for subsequent chemotherapy is important if not using upfront chemoimmunotherapy. Dr Levy remarked that chemoimmunotherapy and pembrolizumab alone have similar outcomes for PD-L1 greater than 50% patients in subset analyses from KEYNOTE-024 and KEYNOTE-189.

In conclusion, the experts emphasized that patient factors like smoking status, gender, histology, and disease burden help guide optimal first-line regimen in PD-L1–positive NSCLC. If not using initial chemoimmunotherapy, sequencing to chemotherapy after progression on PD-1 inhibitors remains critical.

Experts on non–small cell lung cancer discuss the role of CTLA-4 inhibitors in the NSCLC treatment landscape.

The Role of CTLA-4 Inhibitors in NSCLC

Dr Levy asked Dr Peters about her perspective on incorporating CTLA-4 inhibitors like ipilimumab. She responded that while the data is not high-level evidence, the most consistent finding across multiple trials is benefit in PD-L1–negative patients when adding CTLA-4 inhibitors to chemotherapy/immunotherapy regimens, with similar magnitude as in PD-L1–positive patients. Since PD-L1–negative patients derive little benefit from IO [immuno-oncology] alone, adding CTLA-4 blockade could address this unmet need. Dr Peters also noted possible extra benefit in patients with brain metastases and tumors with 

 alterations that limit immunogenicity, though prospective data is needed.

Dr Sabari agreed on the rationale but prefers prospective trial data before adding CTLA-4 inhibitor toxicity. He mentioned an ongoing study evaluating chemoimmunotherapy with durvalumab/tremelimumab versus chemotherapy in difficult-to-treat patients with NSCLC [non–small cell lung cancer], including those with 

 co-mutations. Dr Garassino concurred that more research focus is still needed on improving outcomes for PD-L1–negative patients, even if CTLA-4 inhibitors provide some benefit.

In summary, the expert panel discussed current evidence and rationale for CTLA-4 inhibitors in first-line NSCLC, particularly for PD-L1–negative patients, while noting the need for further randomized trial data given the added toxicity with CTLA-4 blockade.

A panel of thoracic medical oncologists provide an overview of first-line treatment strategies for advanced non–small cell lung cancer (NSCLC).

First-Line Treatment Strategies for Advanced Non–Small Cell Lung Cancer

Dr Levy opened by remarking on the rapid pace of new data and practice-changing developments in lung cancer coming out of recent ESMO and WCLC meetings, which will require interpretation to optimize clinical application.

Regarding first-line treatment for patients without targetable genomic alterations, Dr Sabari said most oncologists now obtain next-generation sequencing and PD-L1 expression analysis to guide immunotherapy options. Patients receive immunotherapy (anti–PD-1 or anti–PD-L1 agents) with or without chemotherapy, though some are reluctant to use pembrolizumab monotherapy below 50% PD-L1 expression. The major decision point is whether to incorporate a CTLA-4 inhibitor like ipilimumab. For PD-L1–positive patients, pembrolizumab, cemiplimab, and atezolizumab are approved options.

Dr Sabari stated we likely have most major first-line data now, with mainly incremental annual trial updates going forward. Dr Levy remarked on the incredible progress from the days when carboplatin-paclitaxel was standard treatment. He stated we can now offer personalized approaches leveraging precision medicine and targeted therapies. Dr Sabari said the biggest difference in first-line practices now is whether to incorporate a CTLA-4 inhibitor with various chemotherapy regimens.

In conclusion, Dr Levy characterized this as an era of tremendous scientific disruption and rapid innovation in lung cancer that will continue to push the field forward and improve patient outcomes.

Edward B. Garon, MD, professor of medicine, Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles (UCLA), thoracic medical oncologist, UCLA Health, discusses the potential impact of the ongoing, phase 3 TROPION-LUNG01 trial (NCT04656652) in non–small cell lung cancer (NSCLC).

Although the phase 2 TROPION-Lung05 (NCT04484142) trial is also ongoing, the TROPION-LUNG01 study has the most potential to impact clinical care in NSCLC, Garon explains. The study is comparing datopotamab deruxtecan (DS-1062a) with docetaxel in patients with previously treated advanced or metastatic NSCLC without actionable genomic alterations.  

Docetaxel is not the preferred comparator arm to datopotamab deruxtecan because the chemotherapy is associated with substantial toxicity and limited efficacy, Garon expands. However, there are some docetaxel-containing regimens that have shown improved outcomes for patients with NSCLC in the United States, such as the addition oframucirumab (Cyramza) plus docetaxel has led to permanent outcomes, Garon adds.

Moreover, if the duration of response data from the TROPION-LUNG01 trial demonstrate positive results with datopotamab deruxtecan and the pulmonary toxicity is found to be mitigated with decreased dosing, the antibody-drug conjugate has the potential to change second-line treatment for patients with NSCLC, Garon concludes.

Edward B. Garon, MD, discusses the potential impact of the ongoing, phase 3 TROPION-LUNG01 trial in non–small cell lung cancer. 


Dr. Garon on the Potential Clinical Implications of the TROPION-Lung01 Trial in NSCLC 

Edward B. Garon, MD, an associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles, discusses immunotherapy treatment considerations for patients with non–small cell lung cancer (NSCLC).

It is important to know whether a patient has an 

 rearrangement, as this indicates whether they should receive a targeted therapy; however, how this applies to other mutations is less clear, according to Garon. 

Aside from mutational status, PD-L1 status is another consideration that must be made when selecting an immunotherapy agent in this patient population, Garon adds. PD-L1 is a marker that is widely available and able to be assessed through immunohistochemistry testing, the results of which come back fairly quickly, Garon notes. There are 3 classifications of PD-L1: no expression, expression of less than 50%, and expression of 50% or more, Garon notes.

New data indicate that even with these strata, there are advantages to having a high PD-L1 status rather than having an expression of 50%, Garon concludes.

Edward B. Garon, MD, discusses immunotherapy treatment considerations for patients with non–small cell lung cancer.

Dr. Garon on Immunotherapy Treatment Considerations in NSCLC

Edward B. Garon, MD, MS, associate professor of medicine, David Geffen School of Medicine, University of California, Los Angeles, discusses the KEYNOTE-001 study, which examined the 5-year long-term overall survival (OS) in patients with non—small cell lung cancer (NSCLC) treated with pembrolizumab (Keytruda).

The KEYNOTE-001 study was the original study of pembrolizumab, according to Garon. However, it was unlike other first-in-human studies because it enrolled over 1000 patients and led to the initial approvals in melanoma and NSCLC, explained Garon. It also led to approval for an assay to look at PD-L1 expression.

The study showed that the 5-year OS rate was 23.2% in treatment-naïve patients and 15.5% in previously treated patients. The study also showed that the clinical benefit appeared to correlate well with PD-L1 expression, particularly with the best outcomes being amongst patients who had PD-L1 expression in at least half of their tumor cells, according to Garon. The 5-year OS rate in patients with high levels of PD-L1 expression was 29.6% in treatment-naïve patients and 25% in previously treated patients.

Edward B. Garon, MD, MS, discusses the KEYNOTE-001 study, which examined the 5-year long-term overall survival in patients with non–small cell lung cancer treated with pembrolizumab.

Dr. Garon on the KEYNOTE-001 Study in NSCLC

	at the University of California, Los Angeles

The role of immunotherapy is emerging as an effective, and in some cases, dramatic treatment in the non-small cell lung cancer (NSCLC) landscape. The programmed cell death 1 (PD-1) inhibitor pembrolizumab (Keytruda) is approved for the treatment of previously treated patients with metastatic NSCLC and was originally approved to treat patients with advanced melanoma in 2014.

PD-1 is a negative costimulatory receptor expressed primarily on the surface of activated T cells.

 Binding of PD-1 to one of its ligands, PD-L1, can inhibit T cell cytotoxic responses. Tumors have been hypothesized to utilize this pathway to escape immune surveillance.

Lung cancer is the leading cause of cancer deaths in the United States with NSCLC being responsible for approximately 85% of all cases. According to the National Cancer Institute, in 2015 an estimated 158,040 deaths will result from 221,200 diagnosed lung cancers.

 Despite several available targeted therapies, most patients do not have mutations for which FDA-approved treatments exist.

The large international phase I KEYNOTE-001 trial recently led to accelerated approval for pembrolizumab in NSCLC.

 This study evaluated the efficacy and safety of pembrolizumab in patients with advanced NSCLC. Of the 495 patients reported, 394 had experienced disease progression after undergoing platinum-based chemotherapy. The remaining 101 patients had not been previously treated. Patients received pembrolizumab at a dose of either 2 mg/kg or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks.

The anti—PD-L1 antibody clone 22C3 was utilized in an immunohistochemical assay to determine each patient’s PD-L1 expression. Two groups were created, a training group made up of 182 patients and a validation group made up of the remaining 313. During the course of the study, computed tomography or magnetic resonance imaging was performed every 9 weeks and the resultant images were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. In the training group, patients with staining for PD-L1 in at least half of their cells were more likely to clinically respond to pembrolizumab. There were no clear differences between patients with staining in a minority of their cells versus no PD-L1 staining in this training set.

The objective response rate was 19.4%—18.0% in the 394 previously treated patients, and 24.8% in the 101 untreated patients. The best overall response was stable disease in 21.8% of patients. In contrast to current or former smokers who had a response rate of 22.5%, patients who had never smoked cigarettes had a response rate of 10.3%. The response rate for patients with PD-L1 expression in at least half of their cells was 45.2%.

Analysis of median progression-free survival and overall survival in patients with PD-L1 staining in at least half of their cells was 6.1 months for previously treated patients and 12.5 months for previously untreated patients. The median duration of response exceeded a year among those who responded, without clear differences based on PD-L1 expression.

Pembrolizumab showed modest toxicity with fatigue, pruritus, and anorexia being the most common treatment-related adverse events. Serious adverse events were reported in 9.5% of cases, a proportion that is lower than that anticipated with chemotherapy. More specifically, the most common inflammatory or immune-mediated adverse events were hypothyroidism, infusion- related reactions, and pneumonitis.

No significant differences were observed in efficacy or toxicity among patients receiving 10 mg/kg either every 2 or 3 weeks. There were an insufficient number of patients treated with the 2 mg/kg to draw meaningful conclusions.

The KEYNOTE-010 trial compares pembrolizumab to docetaxel in patients with NSCLC whose tumors express PD-L1 and have progressed after systemic platinum-based treatments. This study will be able to answer the relative efficacy of the 2 mg/kg dose and the 10 mg/kg dose.

In the KEYNOTE-001 study, PD-L1 expression was assessed based on tissue collected contemporaneously to treatment instead of archived tissue. As some patients on KEYNOTE-010 underwent new biopsies while others submitted archival biopsies, the role of a new biopsy to assess likelihood of benefit can also be assessed in this phase II/III study.

In addition to conducting the clinical trial, many patients consented for institutional bio-banking protocols. Data from the analysis of those specimens are beginning to emerge, identifying additional factors associated with response to PD-1 inhibition. To date, these evaluations have focused on mutations in the tumor and infiltrating immune cells.

As the malignancies that have been most sensitive to PD-1 inhibition have been those with the highest mutational load, it was hypothesized that tumors with a larger number of mutations would have a greater likelihood of being recognized by the immune system, leading to a correlation between mutational load and sensitivity to pembrolizumab.

Nonsynonymous mutations lead to the creation of neoantigens in tumors, against which activated T cells could mount a robust immune response.

 Whole exome sequencing was performed on 34 patients treated with pembrolizumab at Memorial Sloan Kettering and UCLA. This analysis showed a correlation between mutational load and response to pembrolizumab.

Previous studies in melanoma tumor specimens revealed that responses to PD-1/L1 blockade rely on pretherapy tumor infiltration of activated cytotoxic T cells.

 Initial studies with samples from patients treated with pembrolizumab have shown pre-treatment accumulation of CD8+ T cells, as well as tumor infiltration of CD4+ T cells, corresponding to enhanced durable clinical response (>6 months).

Further analysis of the KEYNOTE-001 trial data revealed that prior tyrosine kinase inhibitor (TKI) therapy in NSCLC EGFR-mutant patients strongly correlated with a lack of response to PD-1 inhibitor therapy. Among the 29 patients treated at UCLA with the EGFR mutation, 2 of 3 patients who were EGFR TKI naïve had a partial response to pembrolizumab. Among the 26 patients who had been previously treated with an EGFR TKI, only 1 had a partial response.

Laboratory studies have shown cell lines treated with EGFR TKIs have lower PD-L1 expression levels.9 The only patient with a prior EGFR TKI who responded to pembrolizumab had an EGFR mutation that is typically not sensitive to available EGFR TKIs. A study of EGFR-mutant TKInaïve NSCLC patients is planned to gain a better understanding of response to PD-1 inhibition in those individuals.

			Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 

			Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. 

			http://seer.cancer.gov/statfacts/html/lungb.html

			Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP et al.. Pembrolizumab for the treatment of non-small-cell lung cancer. 

			Alexandrov LB, Nik-zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. 

			Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. 

			Garon EB, Wolf B, Lisberg A, et al. Prior TKI therapy in NSCLC EGFR mutant patients associates with lack of response to anti-PD-1 treatment. Presented at: 2015 World Conference on Lung Cancer; September 6-9; Denver, CO. ID 2172.

			Hu-Lieskovan S, Goldman JW, Han M, et al. High intratumoral T cell infiltration correlated with mutational load and response to pembrolizumab in non-small cell lung cancer. Presented at: 2015 World Conference on Lung Cancer; September 6-9; Denver, CO. ID 2728.

			Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. 

Articles

The role of immunotherapy is emerging as
an effective, and in some cases, dramatic
treatment in the non-small cell lung
cancer landscape.

Edward B. Garon, MD, MS