Skip to main content
PMC home page
Gynecologic Oncology Reports logoLink to Gynecologic Oncology Reports
. 2023 Mar 31;46:101171. doi: 10.1016/j.gore.2023.101171

Combination lenvatinib plus pembrolizumab in the treatment of ovarian clear cell carcinoma: A case series

Corinne A Calo a,1, Monica D Levine a,1, Morgan D Brown a,b, David M O'Malley a, Floor J Backes a,⁎
PMCID: PMC10090985  PMID: 37065539

Highlights

  • •

    Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma are limited.

  • •

    This case series demonstrated a response rate of 100% among three patients treated with lenvatinib and pembrolizumab.

  • •

    Response was durable with median PFS of 18 months achieved.

Abstract

Effective second-line treatment options for patients with recurrent ovarian clear cell carcinoma (OCCC) are limited. This case series sought to report tumor characteristics and oncologic outcomes in a small group of patients treated with combination lenvatinib and pembrolizumab.

A retrospective analysis of patients with ovarian clear cell carcinoma treated with combination lenvatinib and pembrolizumab at a single institution was performed. Patient and tumor characteristics were collected including demographics and germline/somatic testing. Clinical outcomes were also evaluated and reported.

Three patients with recurrent OCCC were included in the study. The median age of patients was 48 years old. All patients had platinum-resistant disease and had received 1–3 prior lines of therapy. The overall response rate was 100% (3/3). Progression-free survival ranged from 10 months to not-yet-reached. One patient remains on treatment, while the other two died of disease with overall survival of 14 and 27 months.

Combination lenvatinib-pembrolizumab demonstrated favorable clinical response in these patients with platinum-resistant, recurrent, ovarian clear cell carcinoma.

1. Introduction

The treatment of ovarian clear cell carcinoma (OCCC) presents several challenges for clinicians. While historically included in many large epithelial ovarian cancer clinical trials, they compose only a small fraction of enrolled patients, with clinical decision-making for these patients often limited to small sub-group analyses or retrospective studies. It is well-established that the clinical-pathologic behavior of OCCC is distinct from its more commonly diagnosed high-grade serous carcinoma counterpart. While ovarian clear cell carcinoma is more likely to present at an earlier stage, it is often resistant to standard platinum-based therapy and in advanced stage disease is associated with a poorer prognosis (Sugiyama et al., 2000).

In addition, OCCC tumors utilize distinct molecular pathways. While TP53 mutations are relatively ubiquitous in the HGSOC population, they are infrequent in OCCC. Conversely, approximately 40–50% of OCCC tumors harbor ARID1A and/or PIK3CA mutation (Wiegand et al., 2010).

In patients with recurrent, platinum-resistant OCCC, there is a paucity of effective second-line therapies with response rates to traditional cytotoxic therapy reported as low as 1% (Crotzer et al., 2007). The lack of effective treatments in this setting as well as the increasing availability of molecular data has shifted interest towards molecularly-targeted therapy. While there are currently no FDA-approved targeted agents for OCCC, targeted agents are often employed in the presence of actionable mutations (Oda et al., 2018). However, in the absence of known targetable mutations, data-driven, effective treatment options are extremely limited, and response rates are low.

In this setting, off-label treatments are sometimes employed in our practice, such as combination therapy with lenvatinib, a multi kinase inhibitor with strong anti-angiogenic effects, and pembrolizumab, a monoclonal antibody that blocks programmed death-1 (PD-1) receptor. The rationale for utilizing this combination in OCCC patients is based on data from both endometrial and renal cell carcinoma populations.

In patients with advanced endometrial cancer, the single-arm KEYNOTE-146/Study-111 included five evaluable patients with clear cell adenocarcinoma histology. Among these patients, the response rate was 80% (2 complete, 2 partial, 1 stable disease). A durable response was noted with a duration of response ranged from 6.3 to 19.5+ months (Makker et al., 2020). Subsequent phase 3 data evaluating lenvatinib plus pembrolizumab for the treatment of recurrent mismatch repair proficient endometrial cancer was published in Keynote-775/Study-309 and demonstrated improved progression-free and overall survival compared to standard cytotoxic therapy (Colombo, 2021).

Although clear cell renal cell carcinoma (RCC) and OCCC can have distinct genomic alterations, important genomic similarities have been demonstrated in driver mutations such as the PI3K and SWI-SNF pathways (Ji et al., 2018). In patients with RCCC, the combination of lenvatinib plus pembrolizumab has demonstrated encouraging antitumor activity in both the first-line and recurrent settings (Motzer et al., 2021, Lee et al., 2021).

To our knowledge, there is limited to no data regarding the use of this combination regimen in patients with OCCC. Here we report the outcomes of patients with OCCC treated with combination lenvatinib and pembrolizumab.

2. Methods

A retrospective review was conducted at a single institution. This review was approved by the institutional review board (IRB#2020C0176). All patients with OCCC treated with a combination of lenvatinib and pembrolizumab were included in the analysis. No patients were excluded. Patient demographic data was collected as well as tumor characteristics and germline/somatic genetic testing when available. Clinical outcomes such as response rate, progression free survival, and overall survival were calculated and reported descriptively given the small number of patients included.

3. Results

Patients with platinum-resistant (defined as progression <6 months from receiving platinum-based therapy) recurrent clear cell ovarian cancer treated with a combination of lenvatinib and pembrolizumab between September 2019 to December 2021 were identified through chart review. A total of three patients met inclusion criteria. Patients included had an ECOG performance status of 0–1 and had received 1–3 prior lines of therapy. One patient received prior immunotherapy (combination ipilimumab/nivolumab). The two patients who had not received immunotherapy prior each had only one prior line of standard systemic chemotherapy. The overall response rate was 100% (3/3) with a PFS ranging from 10 months to not yet reached (Table 1).

Table 1.

Patient demographics and clinical outcomes.

Patient Histology Race Previous lines of therapy Previous radiation Response rate PFS (months) OS (months)
1 OCCC White 1 No PR 25* 25*
2 OCCC Black 1 No PR 10 13
3 OCCC White 3 Yes PR 18 26



OCCC = ovarian clear cell carcinoma; PR = partial response; SD = stable disease; *remains on treatment ongoing response
Open in a new tab

No germline pathogenic variants were identified in any patient. All patients had MSI-stable tumors with low tumor mutational burden. Table 2 provides germline and somatic testing information for each patient.

Table 2.

Germline and somatic tumor testing.

Patient Germline Somatic Testing
MSI TMB (Muts/Mb) LOH PDL1 Somatic gene mutations
1 Negative Stable 0 3.30% <1% ARID1A, PPP2R1A
2 Negative Stable 3.7 NA <1% TP53, NCOR1, MCL1
3 Negative Stable 4 <16% NA PIK3CA, ARID1A, TERT



MSI = microsatellite instability; TMB = tumor mutational burden; LOH = loss of heterozygosity; NA = not performed
Open in a new tab

4. Discussion

This small case series demonstrated a favorable response to combination therapy with lenvatinib plus pembrolizumab in patients with recurrent, platinum-resistant OCCC. While this study is limited by a very small sample size, the response rate in all three patients compares favorably with the historically quoted response rates of 1–33% for patients with platinum-resistant, recurrent disease (Crotzer et al., May 2007, Esposito, 2014, Gien et al., 2022). Due to the nature of this small case series, this study is certainly limited by potential for significant selection bias as it is likely patients in relatively good health with an appropriate functional status were selected to undergo treatment with a regimen associated with potential for significant toxicity. Additionally, because this study included only those patients treated with immunotherapy combination, a comparison group of other patients with clear cell ovarian cancer treated during the same time frame is not available for reference.

Limited data support the biologic rationale for targeting angiogenesis/VEGF pathways in patients with OCCC. It has been demonstrated that VEGF is strongly expressed in a vast majority of OCCC and expression has been inversely correlated with prognosis (Mabuchi et al., 2010). There is also limited retrospective data to suggest PFS benefit for patients with advanced OCCC with the addition of bevacizumab in the first-line setting (Tate et al., 2021). Targeting this pathway alone may be insufficient, as seen in the phase 2 trial (GOG 254) evaluating sunitinib (combined VEGF/PDGF tyrosine kinase inhibitor) in the treatment of recurrent/persistent OCCC, which demonstrated a response rate of only 6.7% with a median PFS of 2.7 months and a median OS of 12.8 months (Chan et al., 2018).

Similarly, the use of pembrolizumab monotherapy in patients with recurrent, platinum-resistant epithelial ovarian cancer has not demonstrated significant clinical benefit in the overall population. A recent analysis by Gordhandas et al. demonstrated that a majority of OCCC are copy number low and would not be expected to respond to checkpoint inhibitors (Gordhandas et al., 2022). A subgroup analysis of patients treated with single-agent pembrolizumab with OCCC, however, did demonstrate an overall response rate of 15.8% (95% CI 3.4–39.6%), which compares favorably to historic controls (Matulonis, 2019). Furthermore, NRG-GY003 evaluated nivolumab +/- ipilimumab with a majority of responses noted in patients with OCCC (Zamarin et al., 2020). Combination anti-PD-L1 therapy with avelumab plus pegylated liposomal doxorubicin did not demonstrate clinical benefit over PLD monotherapy in the overall population or OCCC subgroup (Pujade-Lauraine et al., 2021).

More recent data from a trial combining pembrolizumab with epacadostat (NRG GY016) demonstrated ORR 21% in OCCC population (Gien et al., 2022). Using pembrolizumab in combination with Lenvatinib or epacadostat may be important for effectiveness of IO in this population. Extrapolating from the clinical evidence from the endometrial literature it is reasonable to consider the combination of an anti-vascular therapy to pembrolizumab may improve responses in OCCC (Makker et al., 2020).

When considering lenvatinib/pembrolizumab in this patient population, it is important to weigh the side effect profile and potential for significant toxicity, particularly when the use of this regimen is palliative in nature. Only one patient in the current case series experienced a grade 3 or greater adverse event (rectovaginal fistula) and none of the patients discontinued therapy due to toxicity. However, it is reasonable to assume, that in a larger population, rates of grade 3 or greater adverse events would likely approach those reported in larger studies of other disease sites with grade 3 or greater AE rates as high as 89% (Makker et al., 2020).

As tumor genetic information becomes more commonplace, there are increasing opportunities for targeting potential drivers in rare tumors. Guided by data from histologic clear cell counterparts in both endometrial and renal cell carcinoma as well as initial clinical activity among patients with OCCC presented here, the authors feel that there is rationale to support the use of the regimen of lenvatinib plus pembrolizumab in these patients with extremely limited effective treatment options available.

5. Conclusion

Lenvatinib plus pembrolizumab appears to have favorable clinical activity among patients with OCCC with responses noted among all three patients included and durable responses achieved. In a patient population with very limited treatment options available, this combination warrants further investigation in this patient population.

Dr. Backes reports grants and personal fees from Clovis, Eisai, Merck, grants from Immunogen, personal fees from Agenus, AstraZeneca, Genentech, GlaxoSmithKline, all outside the submitted work. Dr. O'Malley reports personal fees for consulting and/or advisory boards from AstraZeneca, Tesaro/GSK, BBI, Immunogen, Ambry, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, GOG Foundation, Iovance Biotherapeutics, Myriad Genetics, Eisai, Agenus, Tarveda, Merck, SeaGen, Novartis, Mersana, Clovis, Rubius, Elevar; Research funding (all funding to institution): AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, AbbVie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto, Ludwig Cancer Research, Stemcentrx, CERULEAN PHARMA, GOG Foundation, NCI, BMS, Serono Inc., Yale University, New Mexico Cancer Care Alliance, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, PRA International, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, and Clovis; leadership or fiduciary role for BOD – GOG Foundation, and Editorial Board for Gynecologic Oncology.

None of the authors have a significant conflict of interest related to the current study.

CRediT authorship contribution statement

Corinne A. Calo: Conceptualization, Methodology, Formal analysis, Writing – original draft, Supervision, Data curation. Monica D. Levine: Conceptualization, Methodology, Formal analysis, Writing – original draft, Supervision, Data curation. Morgan Brown: Data curation. David M. O'Malley: Conceptualization, Methodology, Formal analysis, Writing – original draft, Supervision. Floor J. Backes: Conceptualization, Methodology, Formal analysis, Writing – original draft, Supervision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

  1. Chan J.K., et al. A phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell ovarian carcinoma: an NRG Oncology/Gynecologic Oncology Group Study (GOG-254) Gynecol. Oncol. 2018;150(2):247–252. doi: 10.1016/j.ygyno.2018.05.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Colombo N., et al. Outcomes by histology and prior therapy with lenvatinib plus pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer (Study 309/KEYNOTE-775) Ann. Oncol. 2021;32:S725–S772. doi: 10.1016/annonc/annonc703. [DOI] [Google Scholar]
  3. Crotzer D.R., Sun C.C., Coleman R.L., Wolf J.K., Levenback C.F., Gershenson D.M. Lack of effective systemic therapy for recurrent clear cell carcinoma of the ovary. Gynecol. Oncol. 2007;105(2):404–408. doi: 10.1016/j.ygyno.2006.12.024. [DOI] [PubMed] [Google Scholar]
  4. Esposito F., et al. Second-line chemotherapy in recurrent clear cell ovarian cancer: results from the multicenter italian trials in ovarian cancer (MITO-9) Oncology. 2014;86(5–6):351–358. doi: 10.1159/000358730. [DOI] [PubMed] [Google Scholar]
  5. Gien, L., Enseroo, D., Block, M., 2022. Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: an NRG Oncology Study (NRG-GY016). Presented at: 2022 Annual Global Meeting of the International Gynecologic Cancer Society, Sep. 2022.
  6. Gordhandas, S., Manning-Geist, B., Hodgson, A., 2022. Molecular stratification of ovarian clear cell carcinoma predicts clinical outcomes. Presented at: 2022 Annual Global Meeting of the International Gynecologic Cancer Society, Sep. 2022.
  7. Ji J.X., Wang Y.K., Cochrane D.R., Huntsman D.G. Clear cell carcinomas of the ovary and kidney: clarity through genomics. J. Pathol. 2018;244(5):550–564. doi: 10.1002/path.5037. [DOI] [PubMed] [Google Scholar]
  8. Lee C.-H., et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): a phase 1b/2 study. Lancet Oncol. 2021;22(7):946–958. doi: 10.1016/S1470-2045(21)00241-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Mabuchi S., et al. Vascular endothelial growth factor is a promising therapeutic target for the treatment of clear cell carcinoma of the ovary. Mol. Cancer Ther. 2010;9(8):2411–2422. doi: 10.1158/1535-7163.MCT-10-0169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Makker V., et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J. Clin. Oncol. 2020;38(26):2981–2992. doi: 10.1200/JCO.19.02627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Matulonis U.A., et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 2019;30(7):1080–1087. doi: 10.1093/annonc/mdz135. [DOI] [PubMed] [Google Scholar]
  12. Motzer R., et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. New England J. Med. 2021;384(14):1289–1300. doi: 10.1056/NEJMoa2035716. [DOI] [PubMed] [Google Scholar]
  13. Oda K., Hamanishi J., Matsuo K., Hasegawa K. Genomics to immunotherapy of ovarian clear cell carcinoma: unique opportunities for management. Gynecol. Oncol. 2018;151(2):381–389. doi: 10.1016/j.ygyno.2018.09.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Pujade-Lauraine E., et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021;22(7):1034–1046. doi: 10.1016/S1470-2045(21)00216-3. [DOI] [PubMed] [Google Scholar]
  15. Sugiyama T., et al. Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer. 2000;88(11):2584–2589. [PubMed] [Google Scholar]
  16. Tate S., et al. Bevacizumab in first-line chemotherapy improves progression-free survival for advanced ovarian clear cell carcinoma. Cancers (Basel) 2021;13(13):3177. doi: 10.3390/cancers13133177. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Wiegand K.C., et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. New England J. Med. 2010;363(16):1532–1543. doi: 10.1056/NEJMoa1008433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Zamarin D., et al. Randomized Phase II Trial of Nivolumab Versus Nivolumab and Ipilimumab for Recurrent or Persistent Ovarian Cancer: an NRG Oncology Study. J. Clin. Oncol. 2020;38(16):1814–1823. doi: 10.1200/JCO.19.02059. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Gynecologic Oncology Reports are provided here courtesy of Elsevier

RESOURCES