Rebecca C. Arend, MD
Unlike PARP inhibitors, which are showing extensive utility in a broader group of patients with advanced ovarian cancer, the impact of immunotherapy will likely be seen on a smaller scale. The onus, explained Rebecca C. Arend, MD, will lie in defining the patient subset in which this approach will provide the most benefit.
In a presentation during the 2019 OncLive®
State of the Science Summit™ on Ovarian Cancer, Arend, an assistant professor and associate scientist, University of Alabama Comprehensive Cancer Center, discussed several ongoing trials exploring the use of immunotherapy in patients with advanced ovarian cancer.
For immunotherapy to be effective, T cells have to infiltrate the tumor and recognize the cancer cells before they can kill the malignant cells, explained Arend. Although 55% of ovarian cancers have tumor-infiltrating lymphocytes (TILs) at diagnosis, increased expression of immune checkpoints such as PD-1/PD-L1 can inhibit anticancer activity.
Given the centrality of PD-1/PD-L1 to immune inhibition, checkpoint inhibitors have been the focus of research, said Arend. However, initial investigations of single-agent inhibition showed modest activity in this space.
"What we need to recognize in developmental therapeutics is that it's not black and white," said Arend.
Although PD-L1 has been posited as a logical biomarker of response to immunotherapy, it has shown variable predictive capacity, she added.
For example, in the KEYNOTE-100 trial,1
patients with higher PD-L1 expression, defined as a combined positive score (CPS) of ≥10, had a higher objective response rate (ORR) with single-agent pembrolizumab (Keytruda) than those with lower expression. However, responses were still observed in patients with low PD-L1 expression, indicating that a stronger biomarker is needed, said Arend.
In the KEYNOTE-028 trial,2
investigators evaluated the use of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Relationships between T-cell inflamed gene expression profile (GEP), PD-L1 expression, and tumor mutational burden (TMB) were also analyzed.
Results showed that response rates were higher and PFS was longer in those whose tumors had higher T-cell inflamed GEP, PD-L1 expression, and/or TMB. Specifically, patients whose tumors had a higher T-cell inflamed gene expression profile experienced a better response to pembrolizumab than a lower T-cell inflamed gene expression profile (P = .012) as well as longer progression-free survival (PFS; P = .017). The investigators concluded that all three biomarkers—either alone or in combination—could potentially help identify patients who have a higher likelihood of response to anti–PD-1 agents across several tumor types.
"The bottom line is ovarian cancer has the lowest TMB of all gynecologic cancers, with low levels of PD-L1 expression, and extremely low levels of high microsatellite instability," said Arend.
Building off of the single-agent activity seen with immune checkpoint inhibitors, researchers have turned to combination strategies to increase T-cell activity and transform "cold" tumors into "hot" ones. Specifically, these agents are being paired with other immune checkpoint inhibitors, VEGF inhibitors, and PARP inhibitors, as well as chemotherapy.
The rationale for chemoimmunotherapy combinations stems from the knowledge that chemotherapy can upregulate the immune system's ability to respond to immunotherapy, explained Arend. Such synergy has been demonstrated with nab-paclitaxel (Abraxane) and anti–PD-L1 therapy in preclinical models.
"Agents that we give to patients with ovarian cancer, such as taxanes and platinum, increase TILs," added Arend.
However, such synergy has yet to translate to upfront clinical trials. In the phase III JAVELIN Ovarian 100 trial, for example, investigators tested the combination of chemotherapy and avelumab (Bavencio) followed by avelumab maintenance therapy in combination with talazoparib (Talzenna) in treatment-naïve patients.
The trial was terminated in December 2018, after data from a planned interim analysis indicated that the study would not meet its primary endpoint of PFS.3
Moreover, in March 2019, these data served as a reason to also terminate the JAVELIN Ovarian PARP 100 trial, which was evaluating the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance avelumab in combination with talazoparib (Talzenna) in patients with locally advanced or metastatic ovarian cancer.
The phase III JAVELIN Ovarian 200 trial4
was subsequently launched to determine whether the combination of avelumab and pegylated liposomal doxorubicin could induce responses in the platinum-resistant setting. However, this too failed to demonstrate an improvement in PFS and overall survival.
However, in an exploratory analysis, investigators showed that patients with PD-L1–positive immune cells or tumor cells had an 18.5% ORR versus 3.4% in PD-L1–negative patients.5
"It's hypothesis-generating for how we can design the next study better," said Arend.
The VEGF pathway is largely responsible for hampering T-cell function, she added. However, dual inhibition of VEGF and PD-L1 could alleviate inhibitory immune activity, leading to synergistic antitumor activity. Preclinically, this approach has already proven to be true and, as such, is now being explored in several clinical trials.
PARP inhibitors are also logical combination partners, explained Arend. By triggering the STING pathway, PARP inhibitors could release a greater load of neoantigens, increasing the likelihood of response to immunotherapy.
Among investigational combination strategies, immunotherapy and PARP inhibitors have been studied the most extensively and have shown synergy regardless of BRCA mutation status or PD-L1 expression.
Most recently, the results of the ovarian cohort of the phase I/II TOPACIO/KEYNOTE-162 trial6
were published. In the trial, patients with recurrent platinum-resistant ovarian cancer (n = 60) received the combination of niraparib (Zejula) and pembrolizumab and experienced an ORR of 18% (90% CI, 11-29).
“We were all pretty enthusiastic about the results, given that the trial included wild-type patients,” said Arend.
The phase I/II MEDIOLA trial (NCT02734004) is similarly designed to evaluate the efficacy of the combination of olaparib (Lynparza) and durvalumab (Imfinzi), but restricted enrollment to patients with platinum-sensitive disease and a germline BRCA mutation.
Moreover, inclusion criteria dictated that patients could not have received a prior PARP inhibitor or immunotherapy agent. To find such a patient in the clinic today would be extremely rare, explained Arend, being that olaparib is approved for use as frontline maintenance therapy in women with BRCA-mutated ovarian cancer per the phase III SOLO-1 trial.
Results presented at the 2018 SGO Annual Meeting showed that the combination induced ORRs in more than 70% of patients.7
Specifically, 23 of 32 patients experienced objective response with olaparib plus durvalumab, including 6 (19%) complete responses.
The question of whether the combination could still serve as a strategy for patients with a germline BRCA mutation and prior PARP exposure remains to be seen, she added.
The third approved PARP inhibitor, rucaparib (Rubraca), is being explored in the ongoing phase III ATHENA trial in combination with nivolumab (Opdivo) in the newly diagnosed setting. Notably, patients will be stratified by their response to platinum-based therapy, germline/somatic BRCA status, loss of heterozygosity, and timing of debulking surgery.
Additional hypothesis-generating research has led to the investigation of dual checkpoint inhibition, specifically with the combination of nivolumab and ipilimumab (Yervoy). The combination is being compared with nivolumab alone in the ongoing phase II NRG-GY003 trial in patients with recurrent ovarian cancer.
“The biggest thing that we're [testing right now] is triplet therapies, both in the upfront and recurrent platinum-sensitive and platinum-resistant settings,” said Arend.
Highly anticipated studies in this space include the phase III IMaGYN050 (NCT03038100) and ATALANTE (NCT02891824) trials of atezolizumab (Tecentriq), bevacizumab, and chemotherapy in the treatment-naïve and platinum-sensitive relapsed settings, respectively.
- Matulonis UA, Shapira-Frommer R, Santin AD. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase 2 KEYNOTE-100 study [published online ahead of print May 2, 2019]. Ann Oncol. doi: 10.1093/annonc/mdz135.
- Ott PA, Bang YJ, Piha-Paul SA, et al. T-cell-inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol. 2019;37(4):318-327. doi: 10.1200/JCO.2018.78.2276.
- Merck KGAA, Darmstadt, Germany, and Pfizer Provide Update on Javelin Ovarian 100 Trial of Avelumab in Previously Untreated Advanced Ovarian Cancer [news release]. Darmstadt, Germany, and New York: Pfizer; December 21, 2018. http://bit.ly/30KkmRV. Accessed August 29, 2019.
- Merck KGaA, Darmstadt, Germany, and Pfizer Provide Update on Avelumab in Platinum-Resistant/Refractory Ovarian Cancer [news release]. Darmstadt, Germany: Merck KGaA. Published November 19, 2018. https://bit.ly/2PGGzPB. Accessed August 29, 2019.
- Pujade-Lauraine E, Fujiwara K, Ledermann JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Presented at: 50th Annual Meeting of the Society of Gynecologic Oncology; March 16 to 19, 2019; Honolulu, HI. Abstract LBA1.
- Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma [published online ahead of print June 13, 2019]. JAMA Oncol. 2019. doi: 10:10.1001/jamaoncol.2019.1048.
- Drew Y, de Jonge M, Hong S-H, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC). Gyn Oncol. 2018;149(Supp 1):246