Platinum-refractory Disease Research Articles

High pre-treatment NLR and PLR predict poor prognosis of patients with recurrent/metastatic head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.

e18001 Background: The treatment landscape of unresectable recurrent and/or metastatic (R/M) Head and Neck Squamous cell Carcinoma (HNSCC) has profoundly changed with the introduction of Immune checkpoint inhibitors (ICIs). High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with poor outcome in several tumor types. The aim of the present study was to investigate the role of pre-treatment NLR and PLR in predicting overall survival (OS) of patients treated with ICIs. Materials and Methods: We retrospectively reviewed the clinical records of 106 consecutive patients with R/M-HNSCC who received ICIs (single-agent or ICIs-based treatment) between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Patients were grouped into platinum-refractory (patients progressed within 6 months from the last platinum dose) and platinum-sensitive. The cut-off values of pre-treatment NLR and PLR were determined based on percentile distribution (75th percentile). OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used to compare survival outcomes. Results: A total of 102 patients were analyzed. Four patients were excluded because of incomplete data. Primary tumor sites were oropharynx (37%), oral cavity (24%), hypopharynx (19%), larynx (15%), nasopharynx (5%) and nasal cavity (1%). 63 patients (62%) with platinum-refractory disease received nivolumab single-agent. All 39 patients (38%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab-based treatment. Median OS was 8.0 months (95% CI 5.8-10.1) in the platinum-refractory cohort and 13.3 months (95% CI 7.3-19.3) in the platinum-sensitive cohort. At the univariate analysis high NLR (≥7) and PLR (≥345) correlated with poor OS in the overall population and in both the platinum-refractory and the platinum-sensitive cohorts (Table1). At the multivariate analysis PLR was an independent predictor of OS. Conclusions: The efficacy results reported in this retrospective series were in line with the literature data. High PLR was an independent predictor of poor outcome regardless of the platinum sensitivity. Prospective studies are needed to better explore the predictive role of easily obtainable blood biomarkers in this poor prognostic population. Univariate analysis for OS [Table: see text]

REJOICE-Ovarian01: A phase 2/3 study of raludotatug deruxtecan (R-DXd) in patients with platinum-resistant ovarian cancer (OVC).

TPS5625 Background: Platinum resistance develops in most patients with OVC. Prognosis is poor and therapeutic options are limited, illustrating the significant unmet need in these patients. R-DXd is an antibody–drug conjugate comprising a humanized immunoglobulin G1 antibody targeting cadherin 6 (CDH6), a stable linker selectively cleaved within tumor cells, and a membrane-permeable topoisomerase I inhibitor (DXd) payload. In the first-in-human study of R-DXd (NCT04707248) in patients with advanced/metastatic OVC who had prior systemic therapy, doses of 4.8–8.0 mg/kg showed an objective response rate (ORR) of 46% (95% confidence interval [CI]: 32, 61) and a median duration of response (DOR) of 11.2 months (95% CI: 3.0, not estimable). At doses currently being evaluated for RP2D (or dose optimization), R-DXd exhibited a positive benefit/risk profile, with manageable toxicities for further clinical development. Given these promising data, a Phase 2/3 study in patients with platinum-resistant OVC is underway. Methods: REJOICE-Ovarian01 (NCT06161025; ENGOT-ov77; GOG-3096) is a global, randomized, open-label Phase 2/3 study in patients with platinum-resistant OVC who have not been selected for CDH6 expression. Eligible patients are adults with high-grade serous or endometrioid OVC, primary peritoneal cancer, or fallopian tube cancer with acquired platinum resistance and 1–3 prior systemic lines of therapy (LOT) including prior bevacizumab treatment (unless ineligible) and prior mirvetuximab soravtansine treatment for patients whose tumors are folate receptor alpha-positive (unless ineligible or not available). Patients with primary platinum-refractory disease are not eligible. In the Phase 2 dose-optimization part, approximately 105 patients will be randomized 1:1:1 to receive R-DXd at 4.8, 5.6, or 6.4 mg/kg intravenously every 21 days. In the Phase 3 part, approximately 450 patients will be randomized 1:1 to receive either R-DXd or treatment of physician’s choice (TPC: paclitaxel, pegylated liposomal doxorubicin, gemcitabine, or topotecan). Randomization will be stratified by number of prior LOT (1 vs 2–3) and tumor CDH6 expression (high vs low) in both parts, and additionally by TPC (paclitaxel vs others) in the Phase 3 part. The Phase 2 primary endpoint is ORR by blinded independent central review (BICR). Key secondary endpoints include investigator-assessed ORR and DOR. No hypothesis testing will be performed in the Phase 2 part. The dual primary endpoints in Phase 3 are ORR and progression-free survival (PFS) by BICR; key secondary endpoints are OS and quality of life (QoL). ORR will be analyzed using a Cochran-Mantel-Haenszel test at a 2-sided 1% alpha level, and PFS will be analyzed using a stratified log-rank test at a 2-sided 4% alpha level. OS and one QoL subscale will be tested hierarchically after PFS. Study enrollment is planned to start in February 2024. Clinical trial information: NCT06161025 .

Correlation between irAEs and treatment efficacy of anti-PD-1 single agent in patients with recurrent/metastatic head and neck squamous cell carcinoma: A monocentric real-world observational study.

6029 Background: Immune-related adverse events (irAEs) are associated with efficacy of ICIs-based treatment in various cancer types. The aim of this retrospective study was to assess the relationship between irAEs and outcomes in patients with recurrent/metastatic Head and Neck squamous cell carcinoma (R/M-HNSCC) treated with immune checkpoint inhibitors (ICIs) monotherapy. Methods: We retrospectively reviewed data from patients with R/M HNSCC treated with ICIs single-agent between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Common Terminology Criteria for Adverse Events v.5.0 was used to assess irAEs evaluation. Patients were stratified into irAEs (any grade) and non-irAEs groups. Overall survival (OS) and progression free survival (PFS) were assessed using the Kaplan-Meier method. Univariate and multivariate Cox-regression were used to compare survival outcomes. The chi-square test was used to assess the association between irAEs and objective responses (ORR). Results: A total of 89 patients were eligible for the analysis. Patients with platinum-refractory disease received nivolumab (64 patients, 72%). All the 25 patients (28%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab as first line treatment for R/M disease. Median follow-up was 8.7 months. IrAEs (any grade) were observed in 60 patients (67%), including 9 patients (10%) with grade ≥3 AEs. The most common irAEs were endocrinopathies (35%), skin events (15%), hepatic events (13%), diarrhea/colitis (10%) and lipase/amylase elevation (10%). The ORR was higher in the irAEs group than in the non-irAEs group (19.5% vs 2%, p=0.017). PFS and OS were also significantly longer in the irAEs group: median PFS was 3.9 months vs 2.1 months (HR 0.48 95% CI 0.30-0.77; p=0.003) and median OS was 12.5 months vs 4.3 months (HR 0.36 95% CI 0.21-0.60; p=0.000). The statistically significant benefit for both PFS and OS was confirmed at the multivariate analysis (Table1). Patients who experienced endocrine-related irAEs (p=0.004), diarrhea/colitis (p=0.040) and lipase/amylase increase (p=0.005) had significantly longer OS than those without the corresponding toxicity. A positive trend was observed for skin toxicity (p=0.051). Conclusions: The occurrence of irAEs was a predictor of response and survival outcomes in patients with R/M HNSCC treated with ICIs single-agent.[Table: see text]

A phase II, multicenter, open-label study of abemaciclib and letrozole in patients with estrogen receptor-positive rare ovarian cancer: ALEPRO trial

BackgroundLow-grade serous and endometrioid ovarian cancers and adult-type granulosa cell tumors are rare ovarian malignancies that show high estrogen receptor positivity. Recurrences of these subtypes of ovarian cancer are often...

Current outstanding challenges in germ cell tumors.

Despite the remarkable advances in the treatment of germ cell tumors (GCT), several challenges remain. This review aims to highlight some of these challenges and provide guidance on how to navigate through them. Patients with International Germ Cell Cancer Collaborative Group poor risk disease have worse prognosis and investigating novel therapeutic interventions are warranted in this population. Patients with brain metastases require a multidisciplinary approach by a group of clinicians experienced in the management of germ cell tumors. Patients with platinum refractory disease have poor prognosis and development of novel treatment options is urgently needed. Conventional tumor markers including alpha fetoprotein and human chorionic gonadotropin remain standard. Development of novel biomarkers to detect minimal residual disease or teratoma is needed. Management of patients with GCT requires a multidisciplinary approach. Patients should preferably be evaluated at tertiary care centers with expertise in the management of this disease.

The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are cancers with very good prognosis, even in the metastatic setting, with high curative potential mainly attributed to the introduction of cisplatin-based chemotherapy. However, approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses. Therefore, there is an unmet need for novel therapeutic agents with improved efficacy and minimal long-term side effects. Recent advances in the development of immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have offered an opportunity to test their activity in various tumor types, including GCTs. This review aims to analyze the immune microenvironment of these tumors and present the most recently available data from studies that have tested immunotherapeutic agents against GCTs. The majority of the available knowledge derives from case reports or small cohort studies, particularly those involving ICIs of the PD-1/PD-L1 axis alone or in combination with anti-CTLA-4 monoclonal antibodies. Other immunotherapeutic targeted approaches, including antibody-drug conjugates, antibody prodrugs, vaccines, tyrosine kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapy, have biological rationales and have shown preliminary activity or are currently being tested. Growing evidence on these and other approaches will assist in broadening the currently limited treatment armamentarium against platinum-refractory TGCTs.

A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.

Low free triiodothyronine and immune-related hyperthyroidism are associated with overall and progression-free survival in head and neck squamous cell carcinoma treated with pembrolizumab

IntroductionThyroid function is frequently impaired in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). In patients treated with pembrolizumab, immune-related adverse events (irAEs) of the thyroid are common. However, the prognostic significance of baseline and on-treatment thyroid dysfunction is currently unclear. MethodsThis study included 95 patients who received pembrolizumab for R/M HNSCC between 2016 and 2022. Baseline thyroid status, according to serum hormone levels, and irAEs were assessed. Univariable and multivariable Cox regression analyses were performed for overall survival (OS) and progression-free survival (PFS). Furthermore, the best overall response according to the prognostic groups was examined. ResultsLow fT3 (HR: 2.52, p = 0.006), immune-related hyperthyroidism (HR: 0.11, p = 0.038), ECOG performance status ≥2 (HR: 3.72, p = 0.002), and platinum-refractory disease (HR: 3.29, p = 0.020) were independently associated with OS. Furthermore, immune-related hyperthyroidism was associated with longer PFS (HR: 0.13, p = 0.007), a higher objective response rate (83% vs. 31%, p = 0.018), and a higher disease control rate (100% vs. 43%, p = 0.008). Thyroid-related autoantibodies were elevated in 40% of thyroid irAEs cases with available measurements. Out of 16 thyroid irAEs, 15 occurred in patients with fT3 above the lower limit of normal. ConclusionLow fT3 was associated with worse OS. Immune-related hyperthyroidism was correlated with both improved OS and PFS. Baseline fT3 assessment and close on-treatment monitoring of serum thyroid levels may be valuable for risk stratification in R/M HNSCC patients receiving pembrolizumab.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (GOG-3063; ENGOT-OV68).

TPS5612 Background: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Ovarian cancer (OC) is the 8th most common cause of cancer mortality in women. OC is an area of high unmet need, as many pts become resistant/refractory to frontline platinum-based chemotherapy. In the platinum-resistant setting, standard of care chemotherapy and anti-PD-1 therapy in clinical trials have modest response rates ranging from ~6% to 20% and ~7% to 12%, respectively. Nemvaleukin was designed to selectively bind to the intermediate-affinity interleukin-2 (IL-2) receptor, preferentially activating antitumor CD8+ T and natural killer cells with minimal regulatory T cell expansion. This selectivity may provide enhanced tumor killing and improved safety/tolerability vs high-dose IL-2. In clinical studies, nemvaleukin, as monotherapy and in combination with pembrolizumab, has shown clinical benefit in multiple tumor types, including OC. In ARTISTRY-1, in 14 evaluable patients with OC, 4 responses were observed with nemvaleukin + pembrolizumab, including 2 complete responses and 2 partial responses (ORR 28.6%; DCR 71.4%; median DOR 53.4 wks). Nemvaleukin monotherapy activity was also observed (6 melanoma and 4 renal cell carcinoma responses). Methods: ARTISTRY-7 (NCT05092360) is an ongoing phase 3, multicenter, randomized study of nemvaleukin and/or pembrolizumab vs chemotherapy. Eligible pts are women (≥18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have had ≥1 prior line of systemic therapy (platinum-sensitive setting), ≤5 prior lines (platinum-resistant setting), and prior bevacizumab, with radiographic progression on most recent therapy. Pts with primary platinum-refractory disease (progression on first-line platinum therapy) or primary platinum resistance (progression <3 months after first-line platinum therapy completion) are excluded. Approximately 376 pts will be randomized (3:1:1:3) to receive nemvaleukin 6 μg/kg IV (days 1-5) + pembrolizumab 200 mg IV (day 1) of each 21-day cycle, pembrolizumab or nemvaleukin monotherapy, or chemotherapy, and stratified by PD-L1 status, histologic subtype, and chemotherapy (paclitaxel vs other). Pts will continue treatment until disease progression or intolerable toxicity (maximum 35 pembrolizumab cycles; nemvaleukin can be continued). The primary endpoint is investigator-assessed PFS (RECIST v1.1) in the nemvaleukin + pembrolizumab vs chemotherapy arms. Secondary/exploratory endpoints include overall survival, other antitumor measures, safety, health-related quality of life, and PK/PD effects. Clinical trial information: NCT05092360 .

CINOVA: a phase II study of CPC634 (nanoparticulate docetaxel) in patients with platinum resistant recurrent ovarian cancer

ObjectiveRecurrent platinum-resistant ovarian cancer has a poor prognosis with limited therapeutic options. Sub‐therapeutic intra-tumoral drug concentrations may add to therapy resistance. CPC634 (docetaxel entrapped in CriPec nanoparticles) was designed to...

Efficacy and Safety of Nivolumab Plus Ipilimumab vs Nivolumab Alone for Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN. The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from October 20, 2016 (first patient, first visit), to March 8, 2019 (primary database lock), and April 6, 2020 (overall survival database lock). Patients were randomized 2:1 to receive nivolumab (3 mg/kg intravenously [IV] every 2 weeks) plus ipilimumab (1 mg/kg IV every 6 weeks) or nivolumab (3 mg/kg IV every 2 weeks) plus placebo for up to 2 years or until disease progression, unacceptable toxic effects, or consent withdrawal. The primary end points were objective response rate (ORR) and duration of response between treatment arms by blinded independent central review in the population with platinum-refractory R/M SCCHN. Exploratory end points included safety. Of 425 included patients, 241 (56.7%; median age, 59 [range, 24-82] years; 194 males [80.5%]) had platinum-refractory disease (nivolumab plus ipilimumab, n = 159; nivolumab, n = 82) and 184 (43.3%; median age, 62 [range, 33-88] years; 152 males [82.6%]) had platinum-eligible disease (nivolumab plus ipilimumab, n = 123; nivolumab, n = 61). At primary database lock, the ORR in the population with platinum-refractory disease was 13.2% (95% CI, 8.4%-19.5%) with nivolumab plus ipilimumab vs 18.3% (95% CI, 10.6%-28.4%) with nivolumab (odds ratio [OR], 0.68; 95.5% CI, 0.33-1.43; P = .29). Median duration of response for nivolumab plus ipilimumab was not reached (NR) (95% CI, 11.0 months to NR) vs 11.1 months (95% CI, 4.1 months to NR) for nivolumab. In the population with platinum-eligible disease, the ORR was 20.3% (95% CI, 13.6%-28.5%) with nivolumab plus ipilimumab vs 29.5% (95% CI, 18.5%-42.6%) with nivolumab. The rates of grade 3 or 4 treatment-related adverse events with nivolumab plus ipilimumab vs nivolumab were 15.8% (25 of 158) vs 14.6% (12 of 82) in the population with platinum-refractory disease and 24.6% (30 of 122) vs 13.1% (8 of 61) in the population with platinum-eligible disease. The CheckMate 714 randomized clinical trial did not meet its primary end point of ORR benefit with first-line nivolumab plus ipilimumab vs nivolumab alone in platinum-refractory R/M SCCHN. Nivolumab plus ipilimumab was associated with an acceptable safety profile. Research to identify patient subpopulations in R/M SCCHN that would benefit from nivolumab plus ipilimumab over nivolumab monotherapy is warranted. ClinicalTrials.gov Identifier: NCT02823574.

Efficacy and Safety of Weekly Paclitaxel Plus Vistusertib vs Paclitaxel Alone in Patients With Platinum-Resistant Ovarian High-Grade Serous Carcinoma

Patients with platinum-resistant or refractory ovarian high-grade serous carcinoma (PR-HGSC) have a poor prognosis and few therapeutic options. Preclinical studies support targeting PI3K/AKT/mTOR signaling in this setting, and a phase 1 study of the dual mTORC1/mTORC2 inhibitor vistusertib with weekly paclitaxel showed activity. To evaluate whether the addition of vistusertib to weekly paclitaxel improves clinical outcomes in patients with PR-HGSC. This phase 2, double-blind, placebo-controlled multicenter randomized clinical trial recruited patients from UK cancer centers between January 2016 and March 2018. Patients with PR-HGSC of ovarian, fallopian tube, or primary peritoneal origin and with measurable or evaluable disease (Response Evaluation Criteria in Solid Tumors version 1.1 and/or Gynecological Cancer Intergroup cancer antigen 125 criteria) were eligible. There were no restrictions on number of lines of prior therapy. Data analysis was performed from May 2019 to January 2022. Patients were randomized (1:1) to weekly paclitaxel (80 mg/m2 days 1, 8, and 15 of a 28-day cycle) plus oral vistusertib (50 mg twice daily) or placebo. The primary end point was progression-free survival in the intention-to-treat population. Secondary end points included response rate, overall survival, and quality of life. A total of 140 patients (median [range] age, 63 [36-86] years; 17.9% with platinum-refractory disease; 53.6% with ≥3 prior therapies) were randomized. In the paclitaxel plus vistusertib vs paclitaxel plus placebo groups, there was no difference in progression-free survival (median, 4.5 vs 4.1 months; hazard ratio [HR], 0.84; 80% CI, 0.67-1.07; 1-sided P = .18), overall survival (median, 9.7 vs 11.1 months; HR, 1.21; 80% CI, 0.91-1.60) or response rate (odds ratio, 0.86; 80% CI, 0.55-1.36). Grade 3 to 4 adverse events were 41.2% (weekly paclitaxel plus vistusertib) vs 36.7% (weekly paclitaxel plus placebo), and there was no difference in quality of life. In this randomized clinical trial of weekly paclitaxel and dual mTORC1/2 inhibition in patients with PR-HGSC, vistusertib did not improve clinical activity of weekly paclitaxel. isrctn.org Identifier: ISRCTN16426935.

Comparison of real-world outcomes following immunotherapy in recurrent or metastatic head and neck squamous cell carcinoma with outcomes of randomized controlled trials.

Evaluate outcomes of patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with immunotherapy (IO). Among patients with R/M HNSCC treated with IO in this retrospective single-institution cohort, Cox regression was used to compare overall survival (OS) for those with platinum-refractory disease and those treated in the first-line setting with OS from KEYNOTE-040/048, respectively. Multivariable Cox regression was used to identify predictors of OS. There was no significant OS difference for those treated in the platinum-refractory setting when compared to patients on KEYNOTE-040 (HR=1.22, p=0.27), nor for the first-line setting compared to KEYNOTE-048 (HR=1.23, p=0.19). ECOG-PS 1 (HR=2.00, p=0.02) and ECOG-PS 2 (HR=3.13, p < 0.01) were associated with worse OS. Higher absolute lymphocyte count (ALC) was associated with improved OS (HR=0.93 per 100 cells/μL, p=0.03). Real-world outcomes of IO in R/M HNSCC are similar to outcomes in randomized control trials, with performance status and ALC correlating with OS.

The microtubule inhibitor eribulin demonstrates efficacy in platinum-resistant and refractory high-grade serous ovarian cancer patient-derived xenograft models.

Despite initial response to platinum-based chemotherapy and PARP inhibitor therapy (PARPi), nearly all recurrent high-grade serous ovarian cancer (HGSC) will acquire lethal drug resistance; indeed, ~15% of individuals have de novo platinum-refractory disease. To determine the potential of anti-microtubule agent (AMA) therapy (paclitaxel, vinorelbine and eribulin) in platinum-resistant or refractory (PRR) HGSC by assessing response in patient-derived xenograft (PDX) models of HGSC. Of 13 PRR HGSC PDX, six were primary PRR, derived from chemotherapy-naïve samples (one was BRCA2 mutant) and seven were from samples obtained following chemotherapy treatment in the clinic (five were mutant for either BRCA1 or BRCA2 (BRCA1/2), four with prior PARPi exposure), recapitulating the population of individuals with aggressive treatment-resistant HGSC in the clinic. Molecular analyses and in vivo treatment studies were undertaken. Seven out of thirteen PRR PDX (54%) were sensitive to treatment with the AMA, eribulin (time to progressive disease (PD) ⩾100 days from the start of treatment) and 11 out of 13 PDX (85%) derived significant benefit from eribulin [time to harvest (TTH) for each PDX with p < 0.002]. In 5 out of 10 platinum-refractory HGSC PDX (50%) and one out of three platinum-resistant PDX (33%), eribulin was more efficacious than was cisplatin, with longer time to PD and significantly extended TTH (each PDX p < 0.02). Furthermore, four of these models were extremely sensitive to all three AMA tested, maintaining response until the end of the experiment (120d post-treatment start). Despite harbouring secondary BRCA2 mutations, two BRCA2-mutant PDX models derived from heavily pre-treated individuals were sensitive to AMA. PRR HGSC PDX models showing greater sensitivity to AMA had high proliferative indices and oncogene expression. Two PDX models, both with prior chemotherapy and/or PARPi exposure, were refractory to all AMA, one of which harboured the SLC25A40-ABCB1 fusion, known to upregulate drug efflux via MDR1. The efficacy observed for eribulin in PRR HGSC PDX was similar to that observed for paclitaxel, which transformed ovarian cancer clinical practice. Eribulin is therefore worthy of further consideration in clinical trials, particularly in ovarian carcinoma with early failure of carboplatin/paclitaxel chemotherapy.

Nivolumab for Platinum-refractory and -sensitive Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Nivolumab has antitumor efficacy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) who relapse within 6 months after platinum-based therapy; however, the efficacy of nivolumab for platinum-sensitive R/M HNSCC has not been shown. Therefore, this study compared the efficacy and safety of nivolumab for platinum-refractory and platinum-sensitive R/M HNSCC. This was a retrospective study of patients who received nivolumab for R/M HNSCC who had been previously treated with platinum-based anticancer drugs. Patients were divided into a platinum-sensitive and a platinum-refractory group, and progression-free survival (PFS), overall survival (OS), the overall response rate (ORR) [complete response (CR) + partial response (PR)], the disease control rate (DCR) (CR + PR + stable disease), and the incidence of immune-related adverse events (irAEs) were compared between the two groups. We included 88 patients with squamous cell carcinoma: 60 with platinum-refractory disease and 28 with platinum-sensitive disease. The median PFS in the platinum-refractory and platinum-sensitive groups were 2.7 months and 5.3 months, respectively (p=0.03), and the median OS were 8.8 months and 17.1 months, respectively (p=0.06). There were no significant differences in the ORR, DCR, or incidence of irAEs between the two groups (p>0.99, p=0.11, and p>0.99, respectively). Nivolumab is a safe and effective treatment for platinum-sensitive R/M HNSCC.

ARTISTRY-7: A phase 3, multicenter study of nemvaleukin alfa, a novel engineered cytokine, in combination with pembrolizumab versus chemotherapy in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (326)

Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected. Objectives: ARTISTRY-7 will evaluate the novel engineered cytokine nemvaleukin alfa (nemvaleukin, ALKS 4230) in patients (pts) with gynecologic cancers. Nemvaleukin was designed to selectively bind to the intermediate-affinity IL-2 receptor, preferentially activating and expanding antitumor CD8+ T and NK cells with minimal expansion of Tregs. This selectivity may enhance tumor killing and improve safety/tolerability compared with high-dose IL-2. In clinical studies, nemvaleukin monotherapy and combination with pembrolizumab have shown evidence of clinical benefit in multiple tumor types. In ARTISTRY-1, four responses are observed in pts with ovarian cancer (OC), including one complete response in a pt with platinum-resistant OC and five prior lines of therapy who remains on treatment. Epithelial OC is the 7th most common cause of cancer mortality in women. The standard frontline treatment is platinum-based chemotherapy, to which many pts become resistant or are refractory. There is a high unmet medical need for platinum-resistant OC. Methods: ARTISTRY-7 is a phase III, multicenter, open-label randomized study of nemvaleukin and/or pembrolizumab versus chemotherapy (ClinicalTrials.gov registration forthcoming). Eligible pts included females (>18 y) with histologically confirmed epithelial OC (high-grade serous, endometrioid, clear cell), fallopian tube cancer, or primary peritoneal cancer. Pts must have received >1 prior line of systemic anticancer therapy in the platinum-sensitive setting, ≤5 prior lines in the platinum-resistant setting, and prior bevacizumab, with evidence of radiographic progression on most recent therapy. Primary platinum-refractory disease (progression during first-line platinum-based therapy) or primary platinum resistance (progression <3 months after completion of first-line platinum-based therapy) is exclusionary. Pts must have an ECOG performance status of 0 or 1, an estimated life expectancy of >3 months, and adequate hematologic reserve and hepatic and renal function. Approximately 376 pts will be randomized (3:1:1:3) to receive intravenous nemvaleukin (6 μg/kg) on days 1-5 and pembrolizumab (200 mg) on day 1 of each 21-day cycle, pembrolizumab monotherapy, nemvaleukin monotherapy, or investigator’s choice chemotherapy (pegylated liposomal doxorubicin, paclitaxel, topotecan, or gemcitabine) and stratified according to PD-L1 status, histologic subtype (high-grade vs non-high-grade serous), and chemotherapy (paclitaxel vs other). Pts will continue treatment in the absence of disease progression or intolerable toxicity (maximum 35 cycles for pembrolizumab; nemvaleukin can be continued). Investigator-assessed progression-free survival (RECIST v1.1) in pts treated with nemvaleukin/pembroli- zumab versus chemotherapy (primary endpoint), characterization of antitumor activity of nemvaleukin and pembrolizumab in combination and as monotherapy, safety, HRQOL, and pharmacokinetic/ pharmacodynamic effects will be collected.

Overall survival data from a 3-arm, randomized, open-label, phase 2 study of relacorilant, a selective glucocorticoid receptor modulator, combined with nab-paclitaxel in patients with recurrent platinum-resistant ovarian cancer.

LBA5503 Background: Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that glucocorticoid receptor (GR) modulation with relacorilant (RELA) reverses the anti-apoptotic effects of cortisol and restores the efficacy of cytotoxic agents. We report overall survival (OS) results from a randomized, controlled phase 2 study of RELA + nab-paclitaxel (NP) compared to NP only in patients with ovarian cancer (NCT03776812). The primary analysis showed improved progression-free survival (PFS) and a favorable safety profile with intermittent RELA + NP vs NP only, despite overrepresentation of primary platinum-refractory patients in the intermittent RELA + NP (n = 7) vs the NP-only arm (n = 1). Methods: A phase 2, open-label, randomized, 3-arm study of 2 RELA dosing schedules + NP compared with NP only was performed. 178 women with recurrent, platinum-resistant/refractory, high-grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma with ≤4 prior chemotherapeutic regimens were enrolled. Patients were randomized 1:1:1 to: a) NP (80 mg/m2) + intermittent RELA (150 mg QD the day before, of, and after NP) (n = 60); b) NP (80 mg/m2) + continuous RELA (100 mg QD) (n = 58); or c) NP only (100 mg/m2) (n = 60). NP was administered on days 1, 8, and 15 of each 28-day cycle. The primary endpoint was PFS; OS was a secondary endpoint. OS data for the intermittent and continuous arms were compared to NP only using a 2-sided log-rank test, stratified by presence of ascites and relapse within 6 months on previous taxane, at a 0.05 level of significance without multiplicity adjustment. Results: At the pre-defined OS analysis (128 OS events), hazard ratios (HRs) were 0.67 (95% CI [0.43, 1.03], P= 0.066) and 0.85 (95% CI [0.56, 1.29], P= 0.447) for intermittent and continuous RELA + NP vs NP only. Median OS was 13.9 (95% CI [11.1, 18.4]), 11.3 (95% CI [7.5, 16.4]), and 12.2 (95% CI [7.7, 15.3]) months in the intermittent RELA + NP, continuous RELA + NP, and NP-only arms. In the subgroup of patients without primary platinum-refractory disease, a statistically significant improvement in OS was observed with HR 0.63 (95% CI [0.39, 0.99], P= 0.045) and median OS of 13.9 (95% CI [11.1, 18.4]) vs 12.2 (95% CI [7.7, 15.3]) months for intermittent RELA + NP vs NP only. Conclusions: In addition to the improved PFS and DOR observed at the primary analysis, the OS analysis confirmed the survival benefit of intermittent RELA + NP compared to NP only, particularly in patients who were not primary platinum refractory. A phase 3 trial evaluating intermittent RELA + NP vs investigator’s choice of chemotherapy in patients without primary platinum-refractory disease is ongoing (NCT05257408). Clinical trial information: NCT03776812.

Taxanes plus cetuximab with or without platinum chemotherapy after progression on immune checkpoint inhibitors in patients with squamous cell carcinoma of the head and neck.

6036 Background: Salvage chemotherapy after progression on immune checkpoint inhibitors (ICIs) was associated with an objective response rate (ORR) of 30% in patients (pts) with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We aimed to investigate the efficacy of taxanes + cetuximab (TC) +/- platinum chemotherapy in pts with R/M SCCHN who failed ICIs in palliative setting. Methods: A retrospective study was conducted at 7 French university hospitals. Eligibility criteria were pts treated with ICI for R/M SCCHN, who progressed after treatment with ICI and received TC +/- platinum salvage chemotherapy between August 2017 and December 2021. Clinical and radiological data and outcome were collected from review of medical records. Results: Ninety-nine pts met eligibility criteria: 63 pts received TC and 36 pts received triplet regimen (TR). The median age was 61 years (range 24-78) and 79% of pts were male. Forty-two pts (42%) had platinum-refractory disease (PRD) after multimodal treatment, 13 pts received prior taxanes and 24 pts received prior cetuximab. The median PS at salvage chemotherapy was 1 (range 0-3). ICIs were given as first-line treatment in 70% of pts including those with PRD. The ORR of the entire cohort was 62% (61/99) including 5 complete responses (CR) and the disease control rate was 79% (78/99). The median progression-free survival of the entire cohort was 4.4 months and the median overall survival (OS) was 7.5 months. The 5 pts who had CR as best response are still in remission after a median follow-up of 24 months (range 8-58). The ORR of TC subgroup was 57% (36/63) and the ORR of TR subgroup was 69% (25/36). Furthermore, the ORR in the PRD subgroup of pts was 54% (39/72), and the ORR in the subgroup of pts who were not chemo naïve was 54% (39/72). The ORR in pts who previously received cetuximab was 50% (12/24) vs 75% (49/75) in those who did not. The ORR in pts who previsouly received taxanes was 38% (5/13) vs 65% in those who did not. Finally, the ORR in PRD pts and treated with TR was 50% (7/14) and the ORR in pts who previously received platinum-based treatment or PRD and treated with TR was 55% (11/20). Conclusions: TC +/- platinum chemotherapy was highly effective in pts R/M SCCHN who progressed on ICIs with an ORR of 62% and DCR of 79%. Further investigations are warranted.

Salvage high-dose chemotherapy (HDCT) for relapsed primary mediastinal nonseminomatous germ-cell tumors (PMNSGCT).

5032 Background: Patients with PMNSGCT have high relapse rates after first-line therapy. Historical outcomes in this subset with standard-dose salvage chemotherapy or HDCT+bone marrow transplant (BMT) have been poor. The use of peripheral-blood stem-cell transplant (PBSCT) has allowed for more rapid engraftment and the ability to start the 2nd course 3-4 weeks after the 1st course of HDCT. We report survival outcomes of salvage HDCT+PBSCT in relapsed PMNSGCT. Methods: Between 2004-January 2021, 32 pts with relapsed PMNSGCT were treated with HDCT+PBSCTx2 utilizing our institutional regimen: carboplatin 700 mg/m2 + etoposide 750 mg/m2, for 3 consecutive days, followed by PBSCT. Median time between cycle1 day1 to cycle2 day1 was 3.2 wks (range, 2.6-4.6). Kaplan-Meier methods were used for progression-free (PFS) and overall survival (OS) analysis. Results: Median age was 30. At the start of HDCT, median AFP was 192 (range, 4-17130) and hCG 1.5 (range, 0.6-15711). First-line therapy was standard germ cell tumor chemotherapy such as bleomycin-etoposide-cisplatin (BEP) or etoposide-ifosfamide-cisplatin (VIP). HDCT was 2nd line in (26, 81.3%) and 3rd line in (6, 18.8%). Eighteen (56.3%) pts had platinum-refractory disease defined as progression within 4 weeks of 1st line chemo. Twenty-three (72%) patients had extra mediastinal metastases (mets) at the start of HDCT. Metastatic sites included pulmonary (17), lymph nodes (2), liver (3), bone (2), brain (1). Median follow-up time from start of HDCT was 1 yr (range, 0.02-14.1). Twenty-six (81%) pts completed both cycles, while 6 (19%) completed only one cycle due to toxicity or progression. The estimated 2-yr PFS was 30.7 (95% CI, 15.8-46.9) and 2-yr OS was 35.2 (95% CI, 18.9-51.9). At the most recent follow-up, 9 (28%) pts were continuously no evidence of disease (NED), including 2 pts who had surgical resection of teratoma following HDCT. Median follow-up from the start of HDCT for the NED pts was 4.6 yrs (range, 1-14.1). Five of the NED pts had extra mediastinal mets, and 2 had platinum-refractory disease. Among the 9 NED pts, HDCT was 2nd line in 7 (77.8%) and 3rd line in 2 (22.2%). These results compare favorably to historical data with standard-dose chemotherapy or HDCT+BMT in relapsed primary mediastinal GCT with salvage rates &lt; 10% (Hartmann et al., JCO 19:1641-1648, 2001). Grade ≥3 toxicity, as previously described in our study (Adra et al., JCO 35:1096-1102, 2017), occurred in 8 (25%) pts. There were two treatment-related deaths. Conclusions: HDCT+PBSCT is a safe and effective salvage therapy in pts with relapsed PMNSGCT with curative potential. In our opinion, these complicated patients are best managed at tertiary centers with expertise in medical oncology, stem cell transplantation, and thoracic surgical oncology.

ROSELLA: A phase 3 study of relacorilant in combination with nab-paclitaxel versus investigator’s choice in advanced, platinum-resistant, high-grade epithelial ovarian, primary peritoneal, or fallopian-tube cancer.

TPS5620 Background: Chemotherapy resistance is a major concern in the treatment of advanced platinum-resistant and platinum-refractory ovarian cancer. One mechanism of resistance is driven by cortisol, which can suppress the apoptotic pathways that chemotherapy agents rely upon, eg, suppression of BCL2 and FOXO3a pathways. Preclinical and clinical data indicate that glucocorticoid receptor (GR) antagonism may reverse the anti-apoptotic effects of cortisol, thereby restoring the efficacy of cytotoxic agents. Relacorilant is a selective GR modulator that has shown promise in overcoming resistance when combined with taxanes (particularly nab-paclitaxel) in preclinical models (Greenstein &amp; Hunt 2021) and early-phase clinical studies (Munster et al. 2019) in various solid tumors. A randomized, controlled phase 2 study of relacorilant + nab-paclitaxel found clinically meaningful improvements in progression-free survival (PFS) and duration of response (DOR) without increased side effect burden in patients with recurrent, platinum-refractory and platinum-resistant ovarian cancer (Colombo et al. 2021). The aim of this phase 3 study is to confirm these phase 2 findings in a larger patient population. Methods: ROSELLA (EudraCT 2022-000662-18, NCT pending) is a phase 3, randomized, 2-arm, open-label, multicenter study of relacorilant + nab-paclitaxel compared to investigator’s choice of chemotherapy agents in patients with confirmed high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer. The trial is being conducted at multiple sites in North America and Europe and has a planned enrollment of 360 patients. Patients are randomized 1:1 to either relacorilant (150 mg the day before, day of, and day after nab-paclitaxel infusion) + nab-paclitaxel (80 mg/m2 on days 1, 8, and 15 of each 28-day cycle) or investigator’s choice of chemotherapy (liposomal doxorubicin, paclitaxel, topotecan, or nab-paclitaxel). Randomization is stratified by prior lines of therapy (1 vs &gt; 1), region of world (North America vs Europe), and prior bevacizumab (yes/no). Adult female patients with platinum-resistant disease (progression within 6 months of completion of platinum-containing therapy), excluding patients with primary platinum refractory disease, who have received 1–3 lines of prior systemic anticancer therapy and at least 1 prior line of platinum therapy are being enrolled. Life expectancy ≥3 months, adequate organ function, and ECOG performance status of 0 or 1 are required. The primary study endpoint is PFS by blinded independent central review. Key secondary endpoints include overall survival, PFS by investigator, overall response rate, best overall response, DOR, clinical benefit rate, safety, quality of life, CA-125, pharmacodynamics, and pharmacokinetics. Clinical trial information: 2022-000662-18.