Immunotherapy May Improve Tumor Sensitivity to Palliative Chemotherapy in Platinum Resistant Ovarian Cancer

Abstract

Ovarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Platinum-resistant disease carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%. We hypothesize that in patients with platinum-resistant ovarian cancer, treatment with immunotherapy followed by cytotoxic chemotherapy with antiangiogenic therapy results in prolonged survival without compromising quality of life. Our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulted in progression-free survival durations significantly above previously published averages. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum-resistant ovarian cancer.

Platinum-resistant ovarian cancer carries a particularly poor prognosis and leaves patients with limited therapeutic options. This brief report summarizes the experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy, which resulted in progression-free survival durations significantly above previously published averages.

Introduction

Ovarian cancer is the second most common gynecologic cancer in the US and ranks among the top 10 causes of female cancer-related deaths. Due to the presence of non-specific cancer-related symptoms, 75%-80% of patients have advanced stage ovarian cancer at the time of diagnosis.¹ Although the majority of high grade serous ovarian cancer is responsive to initial platinum-based doublet chemotherapy, 70%-85% of patients will recur within 3 years.²

The 5-year relative survival rate for advanced ovarian cancer is ~30%, in part due to the development of platinum-resistant disease.³ Platinum-resistant ovarian cancer is defined as tumor progression within 6 months of completion of a taxane- or platinum-based regimen.⁴ It carries a particularly poor prognosis and leaves patients with limited remaining therapeutic options. Patients with platinum-resistant disease have significantly lower response rates to additional chemotherapy, with estimates as low as 10%-25%.⁵ The median progression-free survival for platinum-resistant disease is 3.6 months with a median overall survival of only 11.1 months.⁶

Given the dismal prognosis of platinum-resistant ovarian cancer, trials have aimed to improve patient outcomes specifically in this setting. Anti-vascular endothelial growth factor (anti-VEGF) therapy with bevacizumab and pazopanib have been studied, though neither provided significant advances in outcomes.^7-9 More recently, immunotherapy has been studied both alone and in combination with other drugs. However, the only FDA-approved indication for immunotherapy in ovarian cancer is in the setting of high microsatellite-instability (MSI-H), deficient mismatch repair (dMMR), or in the setting of a high tumor-mutation burden (TMB).³ The first study of immunotherapy in platinum-resistant ovarian cancer was a phase II trial that included 20 patients who were treated with nivolumab every 2 weeks for up to 6 cycles until disease progression occurred. The best overall response was 15% including 2 patients who had a durable complete response. However, median progression-free survival remained dismal at 3.5 months.¹⁰ In follow-up to their original study, the authors published a second paper after they noted several cases of unexpected responses to palliative chemotherapy following immunotherapy in the platinum refractory setting, raising the possibility that nivolumab may improve tumor sensitivity to chemotherapy despite prior platinum resistance.¹¹

We share are our experience of 3 patients with recurrent, metastatic platinum-resistant ovarian cancer treated with immunotherapy followed by anti-angiogenic treatment plus chemotherapy resulting in progression-free survival durations significantly above previously published averages.

Case 1

Patient #1 was a 69-year-old female diagnosed with FIGO stage IIIC clear cell ovarian cancer. She was initially treated with neoadjuvant taxotere and carboplatin for 3 cycles followed by total abdominal hysterectomy, right salpingo-oophorectomy and interval debulking surgery. This was followed by 3 additional cycles of adjuvant taxotere and carboplatin, at which point she had no evidence of disease and normalization of her CA-125. She then received single-agent maintenance bevacizumab for 5 months until progression of disease was noted. This was followed by 3 cycles of liposomal doxorubicin until progression was again seen with liver, lung and retroperitoneal lymph node metastases. Due to her platinum-resistant disease, she was enrolled in the phase II National Cancer Institute (NCI)-NRG clinical trial GY003 of nivolumab with or without ipilimumab and was randomized to the combination therapy arm of nivolumab plus ipilimumab. Her treatment was complicated by grade 4 lipase elevation after cycle 1 and she was continued on nivolumab alone for cycles 2-4. Surveillance imaging after 4 cycles of immunotherapy showed a partial response with an interval decrease in both the size of retroperitoneal lymph nodes and number hepatic lesions with no new metastatic lesions in the chest, abdomen, or pelvis (Fig. 1a, b).

Figure 1.

Patient #1, imaging prior to immunotherapy on the left and after treatment on the right showing decrease in the size and number of hepatic metastases.

She was continued on nivolumab alone for an additional 12 months with stability on her surveillance scans. After 17 cycles of nivolumab, she had increasing lymphadenopathy in the abdomen and pelvis, consistent with disease progression. A right groin lymph node biopsy was performed and confirmed metastatic ovarian cancer. Extended gene sequencing was performed and showed the following mutations: PIK3CA H1047R mutation, AR1D1AQ1397fs*84 mutation, and BRAFK483e mutation. The tumor was microsatellite-stable (MSS) with a low tumor-mutation burden (TMB) of 4 mutations/Mb. She went on to receive low-dose single-agent ipilimumab for 2 cycles but it was discontinued due to grade 4 hepatitis. She was subsequently enrolled in the Memorial Sloan Kettering (MSK) 17-181 FOCUS trial with paclitaxel, bevacizumab and either placebo or the experimental drug Combretastatin A4-Phosphate (CA4P). CA4P is a synthetic phosphorylated prodrug of CA4, a naturally occurring derivative of the South African willow tree, that targets tumor vasculature and results in an acute, reversible reduction in tumor blood flow which then leads to central necrosis within a tumor. The CA-125 level improved in response to chemotherapy (Fig. 2). Surveillance scans after 3 cycles of therapy showed a response to treatment with an overall decrease in the size and number of pulmonary metastases and decreased lymphadenopathy within the chest, abdomen and pelvis. Due to termination of the trial after 3 cycles due to lack of efficacy of the investigational drug, she was started on standard paclitaxel plus bevacizumab and continued on maintenance paclitaxel plus bevacizumab for 6 cycles. Unfortunately, imaging after 6 cycles showed progression of disease. Shortly thereafter she had a declining performance status and cancer-directed therapy was discontinued. She transitioned to hospice 50 months after the initial diagnosis of stage IIIC ovarian cancer and 36 months after becoming platinum resistant.

Figure 2.

Graph of CA-125 trend for patient #1.

Case 2

Patient #2 was a 55-year-old female diagnosed with FIGO stage IIIC high grade, serous ovarian cancer. Expanded genomic testing revealed somatic p53 and FGFR3 mutations as well as a low mutation rate (0 mutations/Mb). She underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy with optimal debulking followed by 6 cycles of cisplatin and paclitaxel. The patient’s tumor marker decreased from a baseline of 6130 U/mL to 632 U/mL but did not return to normal. Due to persistently elevated tumor markers, she was treated with an additional 6 cycles of carboplatin, paclitaxel and bevacizumab followed by an additional 4 months of bevacizumab alone with improvement in her CA-125 to 59 U/mL. However, within 2 months of completion of therapy, the CA-125-level rose to 113 U/mL and restaging scans revealed prominent paraaortic lymph nodes measuring up to 17 mm × 10 mm, consistent with recurrent disease. Exploratory laparotomy, lymphadenectomy, and secondary tumor debulking were performed followed by treatment with liposomal doxorubicin and gemcitabine, which was poorly tolerated. Due to a rising CA-125 and poor tolerance, therapy was changed to cyclophosphamide and bevacizumab with improvement in her CA-125 level. This was continued for a total of 6 cycles followed by 10 cycles of maintenance bevacizumab alone. The patient’s CA-125 again began to rise and imaging confirmed disease progression. She was then restarted on carboplatin and taxotere. At the completion of 6 cycles of therapy, she had stable disease on imaging though her CA-125 was rising. She was briefly placed on olaparib with CA-125 stabilization but developed worsening ascites requiring monthly paracentesis drainage.

Given her platinum refractory disease, several therapeutic options were discussed, all with estimated response rates of <20%. Based on prior success at our institution with immunotherapy followed by chemotherapy and antiangiogenic therapy in patient #1 described above, she was started on niraparib with pembrolizumab. After 2 cycles of niraparib and pembrolizumab she had progression of disease on imaging as well as increasing paracenteses requirements, on average requiring weekly therapeutic drainage. She was then started on paclitaxel and bevacizumab with rapid improvement in her abdominal ascites and stabilization and then improvement in her CA-125 level (Fig. 3). She continued to have disease stability and maintained a 5-month interval without the need for therapeutic paracentesis, affording her a dramatic improvement in her quality of life. Unfortunately, she once again developed worsening ascites and went on to receive several more lines of therapy including topotecan, low-dose weekly paclitaxel and carboplatin, pemetrexed and finally pembrolizumab with bevacizumab and low-dose metronomic Cytoxan. The patient was then maintained on pembrolizumab and bevacizumab with ongoing disease stability for several months. However, due to symptomatic disease progression, she ultimately opted to proceed with hospice care and died 71 months (nearly 6 years) after her original diagnosis and 23 months after developing platinum refractory disease.

Figure 3.

Graph of CA-125 trend for patient #2.

Case 3

Patient #3 was a 51-year-old female diagnosed with stage IIIC ovarian cancer. She underwent open total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, bilateral salpingo-oophorectomy and tumor debulking followed by 6 cycles of cisplatin/paclitaxel with complete resolution of her disease and normalization of CA-125. Six months after the completion of therapy she relapsed and was treated with liposomal doxorubicin/gemcitabine x 6 cycles again with a complete response.

Five months after completion of liposomal doxorubicin and gemcitabine she had disease recurrence and was taken for secondary debulking surgery. Her tissue was sent for genomic sequencing which identified the following mutations: TP53, TNF, DICER, and KDM. She also had germline testing performed that revealed a BRCA 1 mutation. The patient was treated with 6 cycles of carboplatin and cyclophosphamide followed by PARP-inhibitor maintenance. Within 5 months of completion of chemotherapy she had a rapidly rising CA-125 with evidence of progression of disease on imaging. At this time, she was diagnosed with platinum resistant disease. fourth line chemotherapy was considered—however, due to known poor response rates in the platinum resistant setting, she was treated with pembrolizumab and PARP inhibitor. After 4 cycles, imaging showed disease progression and therapy was switched to paclitaxel and bevacizumab. Her tumor CA-125 level dropped dramatically after 1 cycle (see Fig. 4). Imaging after 2 cycles of paclitaxel and bevacizumab revealed a significant decrease in the pelvic mass and retroperitoneal adenopathy along with complete resolution of right hydronephrosis (see Fig. 5). The previously noted lymphadenopathy along the common iliac chains and in the paraaortic retroperitoneum also normalized in size. She went on to receive an additional 4 cycles of paclitaxel and bevacizumab to complete 6 cycles total. She progressed shortly after the completion of cycle 6 with extensive lymphadenopathy noted on imaging, went on to receive 1 cycle of combination ipilimumab and nivolumab but developed grade 3 autoimmune side effects and therapy was stopped. Shortly thereafter, she continued to have further progression of disease and died, 51 months after her initial diagnosis and 15 months after developing platinum resistant disease.

Figure 4.

Graph of CA-125 trend for patient #3.

Figure 5.

A. CT prior to taxol + avastin showing 84.1 × 45.8 mm right pelvis mass B. CT after taxol + avastin showing right pelvic mass that has decreased in size to 41.3 mm × 22.9 mm.

Discussion

Platinum resistant ovarian cancer remains a difficult-to-treat malignancy without any published advances in meaningful survival. It is well established that in high-grade serous ovarian cancer, metastases occur through pro-angiogenic pathways. This led to the targeting of anti-vascular endothelial growth factor (anti-VEGF) in both platinum-sensitive and platinum-refractory tumors. The most well-known anti-VEGF therapy is bevacizumab, which has been evaluated in several phase III clinical trials and was found to prolong progression-free survival among patients with platinum-sensitive advanced ovarian cancer.¹² For platinum-resistant ovarian cancer, several studies have also demonstrated statistically significant improvements in progression-free survival with the use of antiangiogenic therapy, though none have shown advances in overall survival. The most notable include the TRIAS, AURELIA, and MITO-11 trials, with improvements of only ~2 months in PFS^7-9

While immunotherapy has led to improvements in MSI-H or dMMR ovarian tumors, its role in MSI-S or pMMR tumors remains limited. This is because ovarian cancer is considered an immunologically “cold” tumor. Proposed mechanisms for cold tumors include a low burden of tumor neoantigens and gene silencing among others.¹³ Additionally, in chronic conditions such as cancer, T cells become dysfunctional, display defective proliferation and upregulate inhibitory receptors, a phenomenon known as T-cell exhaustion.¹⁴ Based on pre-clinical models, T-cell exhaustion can be overcome by PD-1 blockade, thereby restoring tumor sensitivity to chemotherapy with antiangiogenic therapy, which we propose as a potential mechanism for the improvement in survival presented above.^15,16 Immunotherapy is postulated to cause a priming effect for subsequent therapies and thereby change an immunologically “cold” tumor microenvironment into a “hot” microenvironment. This then results in high response rates to subsequent chemotherapy, particularly with a combination of taxane-plus antiangiogenic therapy. A similar treatment strategy studied and published by Zsiros, et al the single-arm, phase II non-randomized trial looked at patients with recurrent ovarian cancer (platinum-sensitive and platinum-refractory) and patients received a 3-drug combination of pembrolizumab with bevacizumab and oral metronomic cyclophosphamide. This combination was well-tolerated and provided clinical benefit in 95% of patients with durable treatment responses.¹⁷

Our case series illustrates our observation that by treating patients with platinum resistant ovarian cancer with PD1 inhibition followed by cytotoxic plus antiangiogenic therapy, we were able to prolong both progression-free and overall survival. This observation was also demonstrated by Inayama et al.¹¹ Importantly, the prolongation in survival did not come at the cost of a decrease in quality of life. Conversely, our patients had subjective improvements in their quality of life. The etiology is multifactorial but included among others minimal toxicities associated with immunotherapy and a decreased need for therapeutic paracenteses due to improved disease control systemic therapy for patients 1, 2, and 3 is provided in Tables 1-3, respectively.

Table 1.

Systemic therapy for patient #1.

1	Neoadjuvant taxotere + carboplatin
2	Taxotere + carboplatin
3	Bevacizumab
4	Liposomal doxorubicin
5	Nivolumab plus ipilimumab (on NCI NRG clinical trial GY003)
6	Nivolumab
7	Low-dose ipilimumab
8	Taxol + bevacizumab + CA4P (on MSK 17-181 FOCUS trial)
9	Taxol + bevacizumab

Table 3.

Systemic therapy for patient #3.

1	Cisplatin + taxol
2	Doxil + gemcitabine
3	Carboplatin + cyclophosphamide
4	PARP inhibitor (olaparib) inhibitor maintenance
5	Pembrolizumab + PARP inhibitor (niraparib)
6	Taxol + Avastin
7	Ipilimumab + nivolumab

Table 2.

Systemic therapy for patient #2.

1	Cisplatin + paclitaxel
2	Carboplatin + paclitaxel + bevacizumab
3	Bevacizumab
4	Doxil + gemcitabine
5	Cyclophosphamide + bevacizumab
6	Bevacizumab
7	Carboplatin + taxotere
8	Olaparib
9	Niraparib + pembrolizumab
10	Paclitaxel + bevacizumab
11	Topotecan
12	Low-dose weekly paclitaxel + carboplatin
13	Pemetrexed
14	Low dose metronomic cyclophosphamide with pembrolizumab and bevacizumab
15	Pembrolizumab + bevacizumab

These observations shed light on the interactions between chemotherapy and immunotherapy, a rapidly evolving area of research in the field of oncology. Inhibition of PD-1 may decrease drug resistance in platinum resistant or platinum refractory ovarian cancer which then allows chemotherapeutics to induce a state of partial remission, explaining the phenomena seen in the cases presented above. Limitations of our case series include the limited sample size, heavily pretreated population and lack of randomized study design. Further studies evaluating the role of immunotherapy followed by chemotherapy in combination with drugs targeting angiogenesis are needed and may provide a long-sought after breakthrough for advancing survival in platinum- resistant ovarian cancer.

Funding

The author indicated no financial relationships.

Conflict of Interest

The authors indicated no financial relationships.

Author Contributions

Conception/design: all authors. Provision of study material or patients: R.K., S.N., C.K., B.T. Collection and/or assembly of data: all authors. Manuscript writing and final approval of manuscript: all authors.

Data Availability

The data underlying this article will be shared on reasonable request to the corresponding author.