Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028

Varga, Andréa; Piha-Paul, Sarina A.; Ott, Patrick A.; Mehnert, Janice M.; Berton‐Rigaud, Dominique; Morosky, Anne; Yang, Ping; Ruman, Jane; Matei, Daniela

doi:10.1016/j.ygyno.2018.11.017

Cited by 210 publications

(180 citation statements)

References 33 publications

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“…Only one G3 AE (transaminase elevation) was registered, and no deaths or discontinuations due to AEs were reported. ORR was 11.5% (3 patients) in this cohort [34].…”

Section: Introductionmentioning

confidence: 53%

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

et al. 2020

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Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological cancers. Despite improvements in medical treatments, the prognosis for EOC remains poor, and there is an urgent need for new therapeutic strategies. Immune checkpoint inhibitors (CPIs) have dramatically improved survival of several cancers and are under evaluation in OC. Unfortunately, CPIs have shown globally unsatisfactory results. The aim of this manuscript is to critically review the results from early-phase trials with CPIs in terms of safety and activity, discuss the possible reasons for disappointing results and the new therapeutic approaches to improve patient outcomes. However, despite the success of immunotherapy in other malignancies such as in melanoma, non-small cell lung cancer (NSCLC) and urothelial cancers [25,26], the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of 10% up to 15% [18][19][20]27].Interestingly, the combination of the anti-PD1 nivolumab and the anti-lymphocyte-associated protein 4 (anti-CTLA4) ipilimumab showed promising results in platinum-resistant EOC at six-month interim analyses with an overall response rate (ORR) of 34% (doubling the results of nivolumab monotherapy). However, final results are still awaited [28].As a consequence, no immunotherapeutic agent has obtained regulatory approval for EOC thus far. PD1/PD-L1

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“…Only one G3 AE (transaminase elevation) was registered, and no deaths or discontinuations due to AEs were reported. ORR was 11.5% (3 patients) in this cohort [34].…”

Section: Introductionmentioning

confidence: 53%

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

et al. 2020

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“…[13][14][15][16] In a phase 2 study with 2 dose levels, nivolumab (anti-PD-1) demonstrated 3 responses (2 complete responses [CRs] and 1 partial response [PR]) among 20 patients with platinum-resistant EOC. 16 All these trials shared the following common issues: 1) they were developed in a heavily pretreated population; 2) the ORR was low (10%-15%), but long-term responders were observed [13][14][15] ; and 3) PD-L1 expression was not a clear predictive factor. 13 Treatment with pembrolizumab (anti-PD-1) achieved 3 responses (1 CR and 2 PRs) among 26 patients included in the KEYNOTE-028 trial who were not candidates for standard therapy, and whose tumors expressed PD-L1 in 1%.…”

Section: Role Of Tumor-infiltrating Lymphocytesmentioning

confidence: 99%

“…Data regarding the activity in early phase 1/2 trials with nivolumab, pembrolizumab, avelumab, and atezolizumab have been reported and are summarized in Table 1. [13][14][15][16] In a phase 2 study with 2 dose levels, nivolumab (anti-PD-1) demonstrated 3 responses (2 complete responses [CRs] and 1 partial response [PR]) among 20 patients with platinum-resistant EOC. It is interesting to note that 2 of the responses were long lasting and there was no relationship noted between response and PD-L1 expression.…”

Section: Role Of Pd-l1 Expression In Patients With Ovarian Cancermentioning

confidence: 99%

“…15 Finally, atezolizumab (anti-PD-L1) demonstrated a response in 2 of 8 heavily pretreated patients. 16 All these trials shared the following common issues: 1) they were developed in a heavily pretreated population; 2) the ORR was low (10%-15%), but long-term responders were observed [13][14][15] ; and 3) PD-L1 expression was not a clear predictive factor.…”

Section: Role Of Pd-l1 Expression In Patients With Ovarian Cancermentioning

confidence: 99%

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Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

González-Martín

Sánchez-Lorenzo

2019

Cancer

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Despite advances in surgery and chemotherapy and the integration of antivascular endothelial growth factor therapy as well as poly(adenosine diphosphate-ribose) polymerase inhibitors into daily clinical practice, epithelial ovarian cancer remains the leading cause of death from gynecological cancer. The incorporation of new therapies with the potential to achieve long-term disease remission is a clear need for patients with ovarian cancer. Immunotherapy with checkpoint inhibitors (CPIs) (antiprogrammed cell death protein 1 [anti-PD-1] or antiprogrammed death-ligand 1 [anti-PD-L1]) has been adopted in several malignancies based on improvements shown with regard to progression-free survival and in particular overall survival. Although there is a solid rationale for the use of CPIs in patients with ovarian cancer, to our knowledge the clinical data presented to date are not very convincing. This article reviews the current data regarding CPIs in patients with ovarian cancer along with the future directions and designs of clinical trials aiming to overcome the low efficacy of CPIs in these individuals. Cancer 2019;125:4616-4622.

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“…During the last decade, therapeutic antibodies against PD-1 and PD-L1 were approved for the treatment of various cancer types either as monotherapies or in combination with current standardof-care therapeutic regimens (4,5). However, clinical responses can vary significantly between patients and reflect the heterogeneous nature of individual tumors and their microenvironment (TME) (4,6,7). Ovarian cancer is known to respond poorly to immune checkpoint blockade (ICB) with clinical trials reporting responses ranging from 6%-22% (8,9).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

Miao

Thakkar

Qian

et al. 2020

Preprint

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One Sentence Summary: Dual Inhibition of PD-L1 and PD-L2 using an affinity enhanced sPD-1 decoy molecule delivers superior antitumor activity when compared with αPD-1 and αPD-L1 antibodies in ovarian cancer. Abstract:Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have improved for a number of solid tumors. Unfortunately, ovarian cancer represents a major clinical hurdle for immune checkpoint blockade (ICB) with reported low patient response rates. Using IHC staining, we find that PD-L2 is highly expressed in ovarian cancers and other malignancies with sub-optimal response to ICB, and is expressed at low levels in cancers responsive to ICB. Based on this observation, we hypothesized that the elevated expression of PD-L2 produced by both tumor and surrounding stromal cells contributes to immune-suppression. Since PD-L2 has been reported to have a 6-to10-fold higher native binding affinity to PD-1 compared with PD-L1, we hypothesized that high levels of PD-L2 can lead to insufficient blockade of the PD-1 signaling pathway. To overcome the immune repressive activity of PD-L2, we engineered a soluble PD-1 decoy molecule (sPD-1 mutant) that binds and neutralizes both PD-L1 and PD-L2 with a 10,000-and 200-fold improvement in binding affinity, respectively, when compared to wild-type binding to these same molecules. Such enhancement in binding affinity is facilitated by amino acid mutations both within and outside of the binding interface. Furthermore, this high affinity sPD-1 mutant molecule demonstrates superior in vivo efficacy in multiple cancer models including ovarian cancer where PD-L2 is highly expressed on the cell surface.

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Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: Analysis of KEYNOTE-028

Cited by 210 publications

References 33 publications

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

Immune Checkpoint Inhibitors in Epithelial Ovarian Cancer: An Overview on Efficacy and Future Perspectives

Immunotherapy with checkpoint inhibitors in patients with ovarian cancer: Still promising?

Neutralizing PD-L1 and PD-L2 Enhances the Efficacy of Immune Checkpoint Inhibitors in Ovarian Cancer

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