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Key Studies at ESMO 2019
Preview of ESMO 2019: Key Expert-Selected Studies

Released: September 26, 2019

Expiration: September 24, 2020

Axel Grothey
Axel Grothey, MD
Sara Hurvitz
Sara Hurvitz, MD
Sandip P. Patel
Sandip P. Patel, MD
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At the 2019 ESMO annual meeting, important results from many clinical trials will be reported. Below, oncology experts have highlighted their most anticipated abstracts in breast cancer, gastrointestinal cancers, gynecologic cancers, and thoracic malignancies, which we will cover online as a part of CCO’s Independent Conference Coverage of ESMO 2019. After the ESMO annual meeting concludes, remember to check the CCO Web site for a downloadable slideset summarizing the data from these studies and more.

Top Picks: Breast Cancer
Sara Hurvitz, MD, FACP:
Clinical data from several important trials in breast cancer will be presented at ESMO 2019. The randomized phase II monarcHER trial is exploring abemaciclib plus trastuzumab with or without fulvestrant vs trastuzumab plus standard-of-care chemotherapy in women with hormone receptor–positive, HER2-positive metastatic breast cancer (MBC). Although preclinical data suggest that CDK4/6 inhibition may be effective in some HER2-positive breast cancers, this study is the first to evaluate whether the addition of a CDK4/6 inhibitor to standard HER2-targeted therapy improves outcomes for hormone receptor–positive/HER2-positive MBC. The results, if positive, may change clinical practice and open the use of CDK4/6 inhibitors for patients with HER2-positive disease.

The MONALEESA-7 trial presented at ASCO was the first study to demonstrate an OS benefit with the use of a CDK4/6 inhibitor in combination with standard endocrine (aromatase inhibitor) therapy in hormone receptor–positive/HER2-negative MBC. Now, 2 studies evaluating the use of a CDK4/6 inhibitor in combination with fulvestrant for the first-line (MONALEESA-3) or second-line (MONALEESA-3, MONARCH2) settings will be presented at ESMO 2019. If positive, these trials would be the first to demonstrate improved survival with the use of a CDK4/6 inhibitor in combination with fulvestrant in both the endocrine-sensitive and endocrine-resistant setting.

The KEYNOTE-522 trial will be the first phase III trial to evaluate whether the addition of immune checkpoint therapy to standard neoadjuvant chemotherapy improves pathologic response rates for patients with early-stage triple-negative breast cancer (TNBC). If this study is positive, this could be practice changing for the management of patients with early-stage TNBC. The relative benefit of checkpoint inhibition on tumors based on PD-L1/PD-1 expression will be an important feature of this study.

Also anticipated are the results from the phase III trial of the PARP inhibitor veliparib with carboplatin and paclitaxel in HER2-negative and germline BRCA-mutated MBC. Currently, there are 2 PARP inhibitors approved for deleterious germline BRCA-mutated MBC: olaparib and talazoparib. When compared as single agents with single-agent chemotherapy in the OlympiAD and EMBRACA registrational trials, respectively, both of these PARP inhibitors were associated with an approximately 3-month improvement in median PFS. However, neither agent was compared with platinum-based therapy and in neither of these studies was the PARP inhibitor combined with chemotherapy. This study being presented at ESMO 2019 will be the first phase III trial to show data addressing whether the addition of a PARP inhibitor to a platinum-based doublet improves outcomes for germline BRCA-mutated patients with MBC.

Top Picks: Gynecologic Cancers
Bradley J. Monk, MD, FACS, FACOG:
At ESMO 2019, 3 studies of significant interest will be reported, with the potential to define a new standard of care in ovarian cancer. The phase III VELIA trial is exploring the addition of veliparib to frontline platinum-based chemotherapy and then as maintenance therapy. Data from the phase III PRIMA trial of niraparib as maintenance therapy following frontline platinum-based chemotherapy will also be presented. Finally, the phase III PAOLA-1 trial will explore the combination of olaparib plus bevacizumab as frontline maintenance therapy following platinum-based chemotherapy. In addition, the phase III FORWARD I trial of the folate receptor alpha (FRa)-targeting antibody-drug conjugate mirvetuximab soravtansine vs chemotherapy in platinum-resistant ovarian cancer will be presented. According to recent press releases, FORWARD I did not meet its primary endpoint but data from this presentation may highlight promising efficacy and safety in the pre-specified subgroup of patients with high FRa expression.

In endometrial cancer, the combination of lenvatinib plus pembrolizumab may be an expansion of immune checkpoint inhibitor–based therapy for patients with recurrent disease. Currently, only MSI-high patients with any solid tumor (including endometrial cancer) are eligible for pembrolizumab but this novel combination shows activity in patients with endometrial cancer whose tumor are MMR proficient.

Top Picks: Gastrointestinal Cancers
Axel Grothey, MD:
Several studies of interest on gastrointestinal cancers will be presented at ESMO 2019. Data from the phase III CheckMate 459 trial will help us to understand the role of immune checkpoint inhibitors in hepatocellular carcinoma (HCC). Currently, pembrolizumab and nivolumab are FDA approved for use in HCC based on single-arm studies that showed durable response in approximately 15% to 20% of patients. Unfortunately, in randomized trials, these agents have not yet been shown to improve outcome over best supportive care (pembrolizumab in second line) and over sorafenib (nivolumab in first line). We hope that with translational analyses from the CheckMate 459 trial, we will be able to identify a subgroup of patients who will respond to nivolumab as a first-line treatment for HCC.

In addition, we will see results from the phase III BEACON CRC trial for patients with BRAF V600E–mutated colorectal cancer. Although the initial data of the phase III trial with encorafenib plus cetuximab with or without binimetinib vs FOLFIRI plus cetuximab were already presented at the ESMO World Congress on GI Cancer earlier in 2019, this presentation will further detail the survival benefit with this targeted therapy combination and also elucidate the contribution of the MEK inhibitor to the overall efficacy of the treatment.

Finally, biliary cancers are very aggressive malignancies that represent a heterogenous group of cancers. Intrahepatic cholangiocarcinomas are one type of biliary cancer and have a high prevalence of targetable mutations/alterations like IDH1 mutations. Data from the phase III ClarIDHy trial will be presented looking at the efficacy and safety of the IDH1 inhibitor ivosidenib vs placebo in patients with advanced cholangiocarcinoma with an IDH1 mutation. A press release regarding this phase III trial indicated that the primary endpoint of improvement in PFS was met. Therefore, this agent could represent a potential new treatment option for patients with cholangiocarcinoma and IDH1 mutations.

Top Picks: Thoracic Malignancies
Sandip P. Patel, MD:
At ESMO 2019, several interesting studies in non-small-cell lung cancer (NSCLC), mesothelioma, and metastatic thymic carcinoma are being presented.

In advanced NSCLC, the final analysis of part 1 of the CheckMate 227 trial comparing nivolumab plus low-dose ipilimumab vs platinum-based doublet chemotherapy as first-line therapy will be presented. The use of nivolumab plus ipilimumab vs chemotherapy in this setting has left open questions of optimal integration for immunotherapy and for the utility of ipilimumab in NSCLC. Although data looking at tumor mutational burden as a biomarker have been provocative for PFS, its use has not been shown to predict an OS benefit. At ESMO 2019, data for PD-L1 IHC subsets will be presented, and it has been announced that the combination has improved OS in patients with PD-L1 ≥ 1%. Data showing the magnitude of benefit, outcomes in patients with PD-L1 < 1%, and relationship of outcome to TMB are awaited, although the standard of care in this setting has broadly changed to chemotherapy plus pembrolizumab combinations, as opposed to chemotherapy alone.

Interim OS data from the phase III IMpower110 trial of first-line atezolizumab vs platinum-based chemotherapy for patients with NSCLC and high PD-L1 expression will also be presented. Comparisons of CheckMate 227 and IMpower110 results to KEYNOTE-024 or -042 will likely be difficult due to differences in trial design and PD-L1 assay characteristics. However, at the highest PD-L1 expression levels there may be more comparable performance in assays that may allow for more robust cross-trial therapeutic comparisons of the multiple immunologic agents emerging in first-line NSCLC.

Osimertinib is a third-generation EGFR TKI that has gained widespread adoption in the United States as first-line therapy for EGFR-mutated metastatic NSCLC based on a substantive PFS benefit as well as central nervous system activity and improved toxicity compared with first-generation EGFR TKI. The final analysis of OS data from the FLAURA trial assessing osimertinib vs comparator EGFR TKIs as first-line treatment for advanced EGFR-positive NSCLC will also be reported and is anxiously awaited. The magnitude of the OS benefit in FLAURA may influence adoption of osimertinib worldwide and in those practices in the United States that continue to favor sequential therapy with first-generation EGFR TKI initially, which until recently (April 2018) represented the optimal standard of care.

In addition to these anticipated results in advanced NSCLC, there are several trials in malignant pleural mesothelioma (MPM) that are of interest. Pembrolizumab has been investigated in multiple thoracic tumor types, and the phase III PROMISE-meso trial will present data comparing pembrolizumab with standard single-agent chemotherapy for patients who have progressed after platinum-based chemotherapy. This is a randomized, control study that is not biomarker selected and is powered to look at PFS. Data from this trial will expand on the available evidence for the utilization of pembrolizumab as second-line therapy for patients with MPM.

The phase II SAKK 17/16 trial assessing lurbinectedin as second-line or third-line palliative chemotherapy is also being presented. This novel agent may offer a new treatment alternative for previously treated patients with MPM where there is currently no standard of care.

Finally, early results from the phase II REMORA trial with lenvatinib for patients with advanced or metastatic thymic carcinoma will be presented.

Remember to Check the CCO Web Site Often During and After ESMO!
These are just a few of the interesting and important abstracts from ESMO 2019 selected by the experts. A comprehensive downloadable slideset of these studies and more will be available on our Web site after the conclusion of ESMO 2019.

What studies are you most excited about at ESMO 2019 and why? Leave your comments below to join in the conversation.

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