Lindsay Fischer

Oregovomab (Ovarex) in combination with paclitaxel and carboplatin for patients with advanced epithelial ovarian cancer is being tested in the phase 3 FLORA-5 trial (NCT04498117). Oregovomab is an investigational monoclonal antibody with promising phase 2 data. Oregovomab and the FLORA-5 trial were highlighted during the 2022 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer in March.

“Oregovomab is an investigational monoclonal antibody that has been studied in clinical trials for patients with ovarian cancer whose tumor cells express the tumor-associated antigen CA-125 (MUC16),” the investigators noted in a poster presentation during the meeting. “Oregovomab is a novel immunotherapy that enhances the immune response to CA-125.”

Oregovomab is a murine monoclonal antibody B43.12, an IgG1k subclass immunoglobin that functions by binding to CA-125 with high affinity. The compound’s interactions with circulating and tissue-associated CA-125 induce robust immune responses.

The phase 3 double-blind, placebo-controlled, multicenter study has been designed to compare the safety and efficacy of oregovomab plus chemotherapy with placebo plus chemotherapy. Patients will be randomly assigned 1:1 to receive either 2 mg of intravenous oregovomab or placebo, along with 6 standard cycles of paclitaxel/carboplatin.

Additionally, investigators will seek to confirm the clinical benefit observed in a randomized phase 2 study (NCT01616303), which demonstrated that adding oregovomab to paclitaxel and carboplatin resulted in clinically significant improvements in progression-free survival (PFS) and overall survival (OS).

At a median follow-up of 42 months, the addition of oregovomab yielded a median PFS of 41.8 months (95% CI, 21.8-not estimable [NE]) compared with 12.2 months (95% CI, 10.4-18.6) with standard chemotherapy (HR, 0.46, 95% CI 0.28-0.70; 

 =.0027). Regarding OS, the median was not reached with the oregovomab group (45.2-NE) but was 43.2 months (31.8-NE) in the control group (HR, 0.35; 95% CI, 0.16-0.74; 

Investigators noted that the trial will also seek to evaluate the role of oregovomab as a neoadjuvant chemotherapy option.

To be eligible for enrollment, patients must have already received optimal debulking surgery and be either about to begin chemotherapy (cohort 1) or have completed 3 cycles of neoadjuvant therapy and about to resume 3 additional cycles of chemotherapy (cohort 2). Patients in each cohort will be randomly assigned to both treatment regimens.

Patients in cohort 1 will receive either oregovomab or placebo on cycles 1, 3, 5, and 5+ of chemotherapy for 12 weeks. Meanwhile, patients in cohort 2 will receive oregovomab or placebo on cycles 4, 6, 6+ for 6 weeks, and 6+ for 18 weeks. Both groups will receive post-treatment follow-up and survival assessment.

The primary objective is PFS, with secondary objectives including OS, safety, and uality of life. Stratification factors include FIGO stage (IIIA/IIIB vs IIIC/IV) and residual disease status after surgical debulking.

Key eligibility criteria for enrollment also will include a recent diagnosis of epithelial ovarian, fallopian tube, or peritoneal origin FIGO stage III or IV cancer; optimal debulking surgery to R1 or R0 stage; an ECOG performance status of 0 or 1; serum CA-125 levels greater or equal to 50 U/mL prior to surgery or chemotherapy; and adequate bone marrow liver, or renal function.

 1/2 germ-line gene mutations, have carcinoma, or previously received treatment with other immune-suppressive drugs are excluded from enrollment. Furthermore, if patients are expected to require additional treatment with PARP inhibitors, bevacizumab (Avastin) or any other investigational agents; or if they harbor active autoimmune diseases, serious illness, clinically significant infections; or if they have a history of more than 1 debulking surgery, they will not be able to enroll.

1. Secord AA, Barroilhet L, Gupta S, et al. FLORA-5/GOG-3035: a phase III double blind placebo controlled multicenter clinical study of front-line chemo-immunotherapy (paclitaxel and carboplatin +/- ore- govomab) in patients with advanced epithelial ovarian cancer. Present- ed at: SGO Annual Meeting on Women’s Cancer; March 18-21, 2022; Phoenix, AZ. Abstract 298.

2. Brewer M, Angioli R, Scambia G, et al. Front-line chemo-immunotherapy with carboplatin-paclitaxel using oregovomab indirect immunization in advanced ovarian cancer: a randomized phase II study. 

l. 2020;156(3):523-529. doi:10.1016/j.ygyno.2019.12.024

Articles

A new murine monoclonal antibody B43.12 is under investigation in combination with paclitaxel and carboplatin as a treatment option for patients with advanced epithelial ovarian cancer.

Investigators Hope Oregovomab Combo Will Show Benefit in Advanced Epithelial Ovarian Cancer

Simultaneous treatment with chemotherapy and intravenous vitamin C shows benefit in cisplatin-ineligible patients with locally advanced muscle-invasive bladder cancer, according to findings presented at the 2022 American Urological Association Annual Meeting.

These data demonstrated that patients who received vitamin C had more success with gemcitabine and carboplatin (GCa).

Overall, investigators observed a 30% rate of pathological downstaging (n = 4) among patients who underwent simultaneous treatment with GCa and IV vitamin C, which met the continuation criteria for a stage 2 study. Furthermore, among those who experienced a pathological response, 25% achieved a complete response.No treatment related adverse events were reported.

Of those 12 patients who underwent simultaneous treatment with gemcitabine and carboplatin plus IV vitamin C, 11 underwent cystectomy following treatment, and 1 patient is pending surgery.

The standard of care for patients with locally advanced disease is neoadjuvant cisplatin-based chemotherapy. However, this treatment strategy is not appropriate for all patients; an estimated 40% to 50% of patients have either renal insufficiency, hearing loss, or poor performance status and are therefore ineligible for cisplatin.

The GCa regimen has demonstrated limited success as an alternative treatment for these patients. However, many patients progress directly to cystectomy without realizing the potential survival effect associated with neoadjuvant chemotherapy.

In other models, the IV administration of vitamin C has been found to safely and feasibly enhance outcomes with chemotherapy. For example, a phase 1 trial (NCT00954525) which assessed vitamin C in conjunction with gemcitabine, or gemcitabine plus erlotinib (Tarceva), elicited unexpected stable disease and prolonged survival in patients with advanced pancreatic cancer.

The regimen was also reported to have good tolerability.

Similarly, a phase 1/2a trial (NCT00772798) not only reported that vitamin C substantially decreased grade 1/2 toxicities in patients with ovarian cancer who were receiving paclitaxel plus carboplatin, but also showed that the combination resulted in prolonged median progression-free survival (PFS). The difference in median PFS between those who did and did not receive IV vitamin C was 25.5 months vs 16.75 months, respectively.

This first-stage analysis (NCT04046094) enrolled 16 and ultimately treated 12 patients with muscle-invasive bladder cancer who were at least 18 years old.

 To be eligible, patients needed to have an ECOG performance status between 0 and 2, as well as adequate organ and marrow functions. Women of child-bearing potential and men whose partners had child-bearing potential needed to consent of prespecified forms of birth control.

Patients were ineligible for enrollment if they were enrolled in any other clinical trials, were currently or anticipating undergoing another investigational agent during the course of the study, diagnosed with any psychiatric or social illness which would inhibit their ability to comply with study requirements, pregnant or breast feeding, had a histology of pure adenocarcinoma, pure squamous cell carcinoma, or pure small cell carcinoma in a TURBT sample, had an uncontrolled or intercurrent illness, or had any prior systematic chemotherapy—not including priori intravesical therapy—or prior radiation to the urinary bladder.

In addition, current tobacco product consumption, as well as a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency, were criteria for exclusion.

Treatment consisted of a single cycle of GCa and IV vitamin C titrated to peak plasms concentration of 350 to 400 mg/dL (~20 mM) for 21 days followed by cystectomy. Patients underwent cystectomy about 4 to 6 weeks following treatment initiation.

Following therapy, patients were followed in accordance with National Comprehensive Cancer Network guidelines. This consisted of standard-of-care bloodwork, physical exams, and imaging studies until either progression or death. Quality of life is being evaluated by Functional Assessment of Cancer Therapy-Bladder (FACT-Bl).

At a mean follow-up of 10.8 months, 3 patients had experienced a recurrence, and 2 patients had died. FACT-BI analysis and clinical follow-up is still ongoing and will be reported at study completion.

Taylor J, Parikh R, Chen Q, et al. Interim analysis NCT04046094: IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients (CI-MIBC). Presented at: 2022 American Urological Association Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract LBA01-09. https://bit.ly/3FPQ99n

Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. 

. 2012;7(1):e29794. doi:10.1371/journal.pone.0029794

Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. 

. 2014;6(222):222ra18. doi:10.1126/scitranslmed.3007154

Intravenous (IV) vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients. ClinicalTrials.gov. Updated May 4, 2021. Accessed May 15, 2022. https://clinicaltrials.gov/ct2/show/NCT0404609

Chemotherapy plus intravenous vitamin C shows benefit in cisplatin-ineligible patients with locally advanced muscle-invasive bladder cancer.

Benefit of Co-Treatment Chemotherapy and Vitamin C in Cisplatin-Ineligible MIBC

Patients with metastatic urothelial carcinoma (mUC) who were given pembrolizumab (Keytruda) achieved both prolonged median progression-free (PFS) and overall survival (OS) after experiencing an immune-related adverse effect (irAE), according to findings presented at the 2022 AUA Annual Meeting.

Ultimately, patients who experienced an irAE while receiving pembrolizumab achieved a median PFS of 28 months (95% CI, 11.7-not reached [NR]) compared with 5.4 months (95% CI, 4.0-8.9) among those who did not experience such an event (

 <.0001). Furthermore, the median OS among patients who experienced an irAE was 44.3 months (95% CI, 15.9-44.3; 

 = .0002) compared with 10.4 months (95% CI, 6.9-19.6) among those who did not (

“PFS was significantly longer in patients with irAEs than [in those] without irAEs,” Kazutaka Nakamura, Department of Urology, Tokiwakai Jyoban Hospital, said in a poster presentation of the findings. “In addition, OS was also significantly longer in patients with irAEs than [in those] without irAEs.”

Study authors noted that the relationship between irAE occurrence and disease prognoses in patients undergoing immune checkpoint inhibition has been observed across various cancer types. Furthermore, multiple studies have reported a positive relationship between irAE incidence and favorable prognoses in patients with mUC receiving pembrolizumab. However, there remains insufficient evidence regarding the prognostic impact of irAEs in this patient population.

Therefore, investigators conducted a retrospective analysis of 95 patients with mUC who received treatment with pembrolizumab as second-line or later-line therapy between January 2018 and February 2022. Patients received pembrolizumab at a dose of either 200 mg every 3 weeks or 400 mg every 6 weeks. Evaluable patients were classified according to their irAE development. Median PFS, OS, overall response rate (ORR), and disease control rate (DCR) were analyzed once the patients began treatment.

Among the 95 evaluable patients, 31 experienced an irAE (32%). Among these patients, a total of 43 irAEs occurred. Notably, there was a significant difference in ECOG performance status greater than 0 between those who did and did not experience an irAE (32% vs 56%, respectively; 

At a median follow-up of 15.1 months (interquartile range, 6.1-22.9), 62 patients (65%) had experienced disease progression and 52 (55%) had died.

Overall, univariate and multivariate analysis demonstrated that irAEs is an independent factor contributing to PFS (HR, 0.33; 95% CI, 0.17-0.62; 

 = .0006). Poor performance status greater than 0 (HR, 2.06; 95% CI, 1.22-3.46; 

 = .0065) and metastases across multiple organs (HR, 1.75; 95% CI, 1.04-2.94; 

 = .0343) were also predictive factors for PFS.

Similarly, these factors were also found to be independent factors for OS as well. The hazard ratio for irAEs was 0.32 (95% CI, 0.16-0.66; 

 = .0018) compared with 2.83 for poor performance status greater than 0 (95% CI, 1.59-5.05; 

 = .0004), 2.04 for modified Glasgow prognostic score greater than 0 (95% CI, 1.09-3.84; 

 = .0267), and 1.90 for multiple metastatic organs (95% CI, 1.07-3.39; 

Lastly, patients who experienced irAEs achieved significantly higher overall response rates than those who did not experience these events (35% vs 9%, respectively; 

 = .0019). The difference in disease control rates were significant as well (61% vs 21%, respectively; 

“This multi-institutional study showed that [the] presence of irAE[s] was significantly associated with PFS, OS, ORRs, and DCRs in patients [with mUC] treated with pembrolizumab,” the study authors concluded. Moving forward they noted irAE occurrence may be used as a surrogate prognostic factor for pembrolizumab.

Nakamura K, Ishiyama Y, Nemoto Y, et al. Association between immune-related adverse events and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab. Presented at: 2022 AUA Annual Meeting; May 13-16; New Orleans, LA. Abstract MP03-19. 

Immune-related adverse effects may show significantly longer progression-free survival and overall survival in patients with metastatic urothelial carcinoma who are receiving pembrolizumab.

Association Between irAEs and Prolonged Survival With Pembrolizumab in Metastatic Urothelial Carcinoma

Study results show that belimumab (Benlysta) may aid in the prevention of chronic graft-vs-host-disease (cGVHD) in patients undergoing allogeneic hematopoietic transplantation, according to findings presented during the 2022 Transplantation & Cellular Therapies Meetings.

A large confirmatory clinical trial is needed to confirm these early data, according to investigators lead by Iskra Pusic, MD, MSCI, of the Division of Oncology at Washington University School of Medicine in St. Louis.

Belimumab (Benlysta) may be a useful treatment for the prevention of chronic graft-vs-host-disease (cGVHD) in patients undergoing allogeneic hematopoietic transplantation, although a larger confirmatory trial is still warranted, according to study results presented at the 2022 ASTCT Meeting.

Overall, 2 out of the 9 patients who received belimumab on study developed moderate to severe cGVHD. One patient died and the other did have an initial response to therapy.

“These data describe, for the first time, [the] use of belimumab for chronic GVHD prophylaxis,” Pusic noted in a presentation of the findings. “Belimumab was very well tolerated, and the absence of severe infections and myelosuppression is very reassuring.”

Belimumab is a human monoclonal antibody that functions by preventing B-cell activating factor (BAFF) from binding to its receptors on B cells, thus preventing aforeactive B cells from surviving. Because B cells play an important role in cGVHD pathophysiology and because BAFF plays a substantiated role in cGVHD by promoting BCR signaling, investigators hypothesized that belimumab could be effective at prevention of this disease.

“The coordinated interaction and response between T cells and B cells are required for further perpetuation of chronic GVHD,” Pusic explained. “We know that selective modulation of this alloreactive response rather than general immunosuppression would be a promising mechanism for prevention of GVHD, while still allowing and preserving [the] graft-vs-leukemia effect.”

To that end, this single-center, investigator-initiated phase 1 trial enrolled 9 patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndromes (MDS), and lymphoma to evaluate whether targeting BAFF early after allogenic hematopoietic transplant would have a favorable effect on the incidence or severity of cGVHD.

Enrolled patients were adults in complete remission and tested negative for minimal residual disease 30 days after transplant. Patients had received mobilized peripheral blood stem cells from 10/10 haploidentical-matched related or unrelated donors. Cells received either myeloablative or non-myeloablative conditioning, and tacrolimus, methotrexate, and antithymocyte globulin were allowed. Seven out of the 8 patients were treated with ATG and 1 was treated with posttransplant cyclophosphamide.

Patients received belimumab at 10 mg/kg every 2 weeks for 3 doses followed by 4 more doses at monthly intervals. Treatment initiation began 50 to 80 days following allogeneic hematopoietic cell transplantation.

Patients who received at least 1 dose were evaluable for safety, and patients who received at least 2 doses were evaluable for both safety and efficacy.

The median follow-up time after transplant was 28 months (range, 12-43); the median time since belimumab completion was 23 months (range, 4-29).

Eight of 9 patients successfully received all 7 of the preplanned doses of belimumab. After more than 20 months of follow-up (range, 20-29 months), 5 are alive with no evidence of cGVHD.

Two patients developed cGVHD of the skin, eye, mouth, and liver. For 1 patient, this occurred following their fifth cycle of belimumab; however, their condition improved through treatment with tacrolimus, ruxolitinib (Jakafi), and steroids administered via a tapered schedule. Unfortunately, the other patient died from pneumonia complications after cGVHD occurred 2 months beyond their last belimumab cycle.

Another patient completed all 7 cycles but relapsed with AML 1 month later and was treated with enasidenib (Idhifa) and donor lymphocyte infusion. This patient is now 16 months posttreatment and receiving prednisone for mild oral and upper gastrointestinal cGVHD.

One patient experienced thrombocytopenia and consequently had to reduce their dose to 3 cycles—3 months later, this patient relapsed with lymphoma. Three patients developed stage 1 skin acute GVHD; 2 cases resolved completely with a steroid pulse, and 1 case developed into overlap cGVHD.

No adverse events equal to or greater than grade 3 were reported. There were also no signification infections or myelosuppression, although 1 patient had cytomegalovirus reaction. No patients demonstrated any infusion reactions or hypersensitivity.

“While the result of our study really needs further validation in a larger trial to further assess the impact of belimumab on incidences of chronic GVHD, these preliminary results are encouraging,” Pusic said.

Furthermore, risk stratification should be an important consideration in future studies, she concluded, noting that correlative studies have been launched because B-cell reconstitution was delayed.

Pusic I, Johanns T, Sarantopoulos S, et al. Use of belimumab for prophylaxis of chronic graft-versus-host disease. Presented at: 2022 Tandem Meetings Transplantation & Cellular Therapy Meetings of ACTCT and CIBMTR; April 23-26, 2022; Salt Lake City, UT. Abstract 34.

The majority of patients treated in a phase 1 trial of belimumab used as chronic graft-vs-host-disease prophylaxis showed no evidence of the disease after 20 months of follow-up.

Belimumab May Be a Prophylaxis Option for cGVHD After Allogenic Transplant

An exploratory analysis from the phase 3 CASPIAN trial showed that patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease harbors inflamed T-cell or 

 molecular subtypes may be more likely to derive a superior overall survival (OS) benefit from treatment with durvalumab (Imfinzi) and chemotherapy compared with those who have other overexpressed biomarkers, according to a presentation given during the AACR Annual Meeting 2022.

An analysis of 2 different RNA sequencing-based SCLC subtyping methods applied within the context of the CASPIAN data demonstrated that patients with these subtypes experienced the longest OS following treatment with the immunotherapy combination compared with patients expressing 

Overall, the highest median OS were observed in patients with 

 or T-cell inflamed signature expression who received durvalumab/EP. In these patients, the median OS were 17.3 months (95% CI, 12.8-NE) and 17.6 months (95% CI, 11.4-NE), respectively.

These data are consistent with previous findings, although further research is warranted to determine the relationship between these biomarkers and immunotherapy response, the study authors noted. 

“When the 2 RNA-based subtyping methods were applied to the CASPIAN data, we found that the 2 methods were consistent in differentiating neuroendocrine from non-neuroendocrine subtypes, and showed highest concordance within the non-neuroendocrine subtypes,” lead study author Yashaswi Shrestha, PhD, director of Oncology Translational Medicine and clinical biomarkers at AstraZeneca, said in a presentation of the findings. “Among the 4 subtypes, the inflamed subtype determined by Gay et al and the 

subtype [determined] by Rudin et al showed the longest overall survival in the durvalumab/[chemotherapy] arm, suggesting that [this] subgroup of patients that have an inflamed phenotype are primed to respond to immunotherapy.”

Investigators on the phase 3 CASPIAN study enrolled 805 patients with treatment-naïve ES-SCLC and a World Health Organization performance status of either 0 or 1, a life expectancy of 12 weeks or greater, and measurable disease per RECIST v1.1 criteria. Patients with asymptomatic or treated and stable brain metastases were permitted to enroll.2

The enrolled patients were randomized 1:1:1 to undergo either durvalumab plus etoposide with either carboplatin or cisplatin (EP) for 4 cycles followed by single-agent durvalumab until disease progression, EP for up to 6 cycles followed by optional prophylactic cranial irradiation, or tremelimumab added to durvalumab plus EP for 4 cycles, followed by durvalumab until disease progression.

EP was administered in a dose ranging from 80 to 100 mg/m2 of etoposide along with either area under the curve 5-6 of carboplatin or 75 to 80 mg/m2 of cisplatin. Durvalumab was administered at 1500 mg and tremelimumab was administered at 75 mg.

The coprimary end points of CASPIAN were OS; progression-free survival, overall response rate, safety and tolerability, and patient reported outcomes (PROs) represented secondary end points. Biomarker analysis (tTMB; PD-L1) was an exploratory outcome measure.

Prior findings from CASPIAN revealed that durvalumab/EP significantly improved OS vs EP alone in this patient population, a benefit that was sustained for over 3 years of median follow-up. In the intent-to-treat population, the median OS was 12.9 months (95% CI, 11.3-14.7) with durvalumab/EP and 10.5 months (95% CI, 9.3-11.2) with EP alone (HR, 0.71; 95% CI, 0.60-0.86; 

These results established durvalumab/EP as the global standard of care in ES-SCLC.2 The combination is FDA approved for the first-line treatment of patients with ES-SCLC.

Notably, the association between predictive biomarkers and improved outcomes with immune checkpoint inhibitors are still not well understood for patients with SCLC. However, investigators recently identified 4 SCLC molecular subtypes with distinct therapeutic vulnerabilities using 2 different differential gene expression methods.3,4

Investigators in the exploratory analysis therefore evaluated the concordance between the 2 methods and their link to improved OS using RNA sequencing data from the phase 3 CASPIAN study.

Formalin-fixed paraffin-embedded (FFPE) tumor samples previously collected at baseline were used to create whole-transcriptome RNA sequencing data.

Overall, the biomarker-evaluable population (BEP) consisted of 57 out of 268 patients on durvalumab/EP and 47 out of 269 patients on EP monotherapy arm.

For the BEP population, the data cutoff date was March 2021, and the median number of months follow-up was 39.4 months (range, 0.1–47.5). In the BEP population, the median OS was 11.8 months (95% CI, 8.6-14.9) with durvalumab/EP and 9.1 months (95% CI, 7.7-11.3) with EP alone (HR, 0.61; 95% CI, 0.40-0.92).

The Rudin et al. 2019 SCLC subtyping method3 found that 

 was commonly expressed in all subtypes, though at a relatively low level. Therefore, a sample was labeled as 

. Among the 4 transcription factors determined to be a subtype of the sample, 

 were classified as neuroendocrine while 

The Gay et al. 2021 SCLC subtyping method4 used a 1300 gene signature to arrange the subtypes into 4 hierarchical clusters, each of which were assigned a subtype based on the highest expressed gene of 

 The fourth cluster, which had a low expression of all 3 of the gene signatures was designated as the inflamed subtype because of its inflamed gene signature.

The T-cell inflamed signature was identified through assessment of RNA baseline tumor samples from pembrolizumab (Keytruda)-treated patients. The 18-gene T-cell inflamed gene expression signature comprised IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance.

The methods revealed high agreement in distinguishing neuroendocrine tumors from non-neuroendocrine subtypes. The highest levels of concordance were identified between non-neuroendocrine subtypes: the prevalence of Rudin 

 was 8% and the prevalence of Gay inflamed was 11%.

An OS analysis of the Rudin et al method revealed that, among patients treated with durvalumab/EP, the median OS with 

was 17.3 months. In patients treated with EP alone, the median OS with 

An analysis of the Gay et al. method showed that, among patients treated with durvalumab/EP, the median OS with 

was 17.6 months. In patients treated with EP alone, the median OS with 

Specifically, patients with high T-cell inflamed signature had numerically longer OS when receiving durvalumab/EP treatment than with EP alone. Patients in the former arm had a median top quartile OS of 15.8 months (10.4-NE), and a low median OS of 11.3 months (7.3-14.6; HR, 0.64; 95% CI, 0.31-1.32). Patients receiving EP alone had a median top quartile OS of 9.4 months (95% CI, 7.3-15.9), and a low median OS of 8.3 month (95% CI, 6.1-11.4), leading to a 13% reduction in the risk of disease progression or death (HR, 0.87; 95% CI, 0.45-1.66).

“This finding is consistent with previous observations,” Shrestha concluded. “[However], further analysis is necessary for us to gain confidence on the response and resistance biomarkers for immunotherapy and small cell lung cancer.”

Because of the limited sample size of eligible RNA sequencing data, these findings should be considered hypothesis generating, Shrestha noted.

1. Xie M, Chugh P, Broadhurst H, et al. Durvalumab + platinum-etoposide in first-line extensive-stage small cell lung cancer (ES-SCLC): exploratory analysis of SCLC molecular subtypes in CASPIAN. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT024. 

2. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6. 

3. Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data [published correction appears in Nat Rev Cancer. June 7, 2019]. 

. 2019;19(5):289-297. doi:10.1038/s41568-019-0133-9.

4. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. 

. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014.

Two Subtypes Linked to Improved Response to Durvalumab Plus Chemotherapy in ES-SCLC

Nivolumab (Opdivo) plus cabozantinib (Cabometyx) was associated with more sustainable health-related quality of life (HRQOL) compared with sunitinib (Sutent) in patients with advanced renal cell carcinoma, according to longer follow-up of the CheckMate 9ER trial (NCT03141177).

In the 32.9-month follow-up, PRO scores revealed that patients receiving nivolumab/cabozantinib had maintained or improved HRQOL compared with patients in the sunitinib arm. The longitudinal changes from baseline consequently showed statistical significance (

 < .05) in favor of the experimental regimen for all scores except for FKSI-19 functional well-being (FWB).

The findings, which were presented during the 2022 Genitourinary Cancers Symposium, demonstrated that this benefit was derived across multiple definitions of deterioration.

In the 151 weeks following baseline, patients receiving nivolumab/cabozantinib experienced a –0.47 least square (LS) mean change from baseline FKSI-19 total score compared with a –2.84 decline with those in the sunitinib arm (overall difference in mean change, 2.37; 

 < .0001). For the FKSI-19 DRS score, patients receiving nivolumab/cabozantinib experienced an LS mean change from baseline of 0.71 compared with –0.46 in the sunitinib arm (1.17; 

Similarly, patients receiving nivolumab/cabozantinib experienced an EQ-5D-3L health status score of 2.73 compared with –0.95 in the sunitinib group (3.68; 

 = .0001). The EQ-5D-3L UK utility index score demonstrated that patients receiving nivolumab/cabozantinib experienced an LS mean change from baseline of –0.01 compared with –0.06 in the sunitinib arm (0.05; 

At baseline, both arms demonstrated a high PRO completion rate of at least 90%. By week 151, the rates were over 75% and 73% in the nivolumab plus cabozantinib and sunitinib arms, respectively. At baseline, both arms demonstrated relatively low symptom burden.

“At nearly 3 years of follow-up, patients continued to report improved HRQOL with nivolumab/cabozantinib compared with sunitinib,” David Cella, FASCO, PhD, of Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and coinvestigators, wrote in a poster presentation of the findings. “Treatment with [nivolumab/cabozantinib] was observed to reduce the risk of clinically meaningful deterioration in HRQOL scores in comparison with sunitinib, regardless of definition of deterioration.”

The CheckMate 9ER trial enrolled 651 patients with advanced RCC who were randomized 1:1 to receive either intravenous nivolumab at a dosage of 240-mg intravenously every 2 weeks plus oral cabozantinib at 40-mg daily or 50 mg of oral sunitinib in 4-weeks-on/2-weeks-off cycles. Treatment continued until either disease progression or unacceptable toxicity occurred.

Patients could not have received nivolumab beyond 2 years from cycle 1; however, they were able to receive cabozantinib and sunitinib beyond 2 years, provided no disease progression or unacceptable toxicity occurred. If the investigator determined there may be benefit, patients could continue treatment beyond progression as well.

At an initial follow-up of 18.1 months, nivolumab/cabozantinib was associated with improved progression-free survival (HR, 0.51; 95% CI, 0.41-0.64; 

 < .001) and overall survival (HR, 0.60; 95% CI, 0.40-0.89; 

In this long-term analysis, FKSI-19 instruments were used to evaluate disease-related symptoms (DRS) while the EQ-5D-3L visual analogue scale (VAS) was utilized to assess HRQOL.

FKSI-19 and EQ-5D-3L were administered at baseline, at the beginning of each treatment cycle (every 2 weeks for nivolumab/cabozantinib and every 6 weeks for sunitinib), and during the 2 subsequent follow-up visits (30 and 100 days from last dose). The EQ-5D-3L were also administered every 3 months during survival follow-up. Of note, although PRO instruments were more frequently administered to the nivolumab/cabozantinib arm, the current analysis only included assessment time points that were concurrent in both treatment arms.

Investigators noted longitudinal changes from baseline that were assessed these changes via a mixed-model repeated measures (MMRM), which adjusted for baseline scores and stratification factors, and measured common timepoints every 6 weeks for 151 weeks. Kaplan-Meier estimates and Cox proportional hazards models were used to conduct time to first deterioration (TTFD), confirmed deterioration (TTCD), and definitive deterioration (TTDD) analysis.

In this analysis, TTFD was defined as the duration from baseline to the date of the first clinically meaningful deterioration in PRO scores. TTCD was defined as the duration from the date of randomization to the date of first clinically meaningful observed deterioration in PRO scores, provided that the deterioration was also confirmed at the next scheduled visit common for both arms or followed by death or dropout.

TTDD was defined as the duration of time from the date of randomization to the date of first clinically meaningful observed deterioration in PRO scores, provided that this deterioration was observed at all following check-ins or if the patient subsequently dropped out or died.

Treatment with nivolumab/cabozantinib induced significantly reduced TTFD in FKSI-19 score (HR, 0.71; 95% CI, 0.57-0.87; 

 = .0011), DRS score (HR, 0.70; 95% CI, 0.56-0.87; 

 = .0017), DRS-P score (HR, 0.73; 95% CI, 0.59-0.91; 

 = .0050), and FWB score (HR, 0.69; 95% CI, 0.54-0.87; 

 = .0019).

This benefit was also observed TTCD in the same scores with FKSI-19 (HR, 0.66; 95% CI, 0.52-0.84; 

 = .0005), DRS (HR, 0.65; 95% CI, 0.50-0.86; 

 = .0020), DRS-P (HR, 0.56; 95% CI, 0.43-0.73; 

 <.0001), and FWB (HR, 0.67; 95% CI, 0.50-.088; 

Similarly, nivolumab/cabozantinib significantly reduced the risk of TTDD compared with sunitinib in FKSI-19 total (HR, 0.68; 95% CI, 0.52-0.90; 

 = .0070), DRS (HR, 0.53; 95% CI, 0.37-0.75; 

 = .0003), and DRS-P scores (HR, 0.52; 95% CI, 0.38-0.72; 

 <.0001). The HR for the FWB was 0.79 (95% CI, 0.37-0.75; 

Finally, nivolumab/cabozantinib was also linked to significantly reduced deterioration in EQ-5D-3L VAS compared with sunitinib across TTFD (HR, 0.74; 95% CI, 0.59-0.92; 

 = .0071), TTCD (HR, 0.74; 95% CI, 0.58-0.95; 

 = .0183), and TTDD (HR, 0.64; 95% CI, 0.48-0.86; 

Treatment-related adverse events (AE) impact were also analyzed. Researchers used generalized estimating equations models to descriptively assess pain-impact with the following ratings:

Treatment-related adverse events (AE) impact were also analyzed. Researchers used generalized estimating equations models to descriptively assess pain-impact with the following ratings: Minimal bother (Not at all? Or a little bit?) or notable bother (Somewhat? Quite a bit? Very much?)

This questioning method is associated with clinician-rated AE measurement and is supported as a valid form of measuring treatment-related toxicity, the study authors noted. Furthermore, this system was recommended in the latest draft of the FDA oncology guidance.

Overall, patients receiving nivolumab/cabozantinib experienced less bothersome adverse effects (AEs) compared with those receiving sunitinib. Findings from a weighted generalized estimating equations revealed that patients in the experimental group were 48% less likely to report bothersome AEs compared with the control group (odds ratio, 0.52; 95% CI, 0.35-0.77).

“Patients treated with [nivolumab/cabozantinib] showed decreased odds of being notably bothered by treatment side effects in contrast to sunitinib,” the authors concluded. “Along with the previously reported superior efficacy of [nivolumab/cabozantinib] versus sunitinib, the results show that the additional benefit of improved HRQOL with [nivolumab/cabozantinib] over sunitinib is maintained with longer follow-up.”

Cella D, Motzer RJ, Blum S, et al. Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC): CheckMate 9ER updated results. J Clin Oncol. 2022;40(suppl 6; abstr 323). doi:10.1200/JCO.2022.40.6_suppl.323

Shah AY, Motzer RJ, Apolo AB, et al. Cabozantinib exposure-response analysis for the phase 3 CheckMate 9ER trial of nivolumab plus cabozantinib versus sunitinib in first-line advanced renal cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4561. doi:10.1200/JCO.2021.39.15_suppl.4561

Health-related quality of life outcomes was more sustainable in patients with advanced renal cell carcinoma on nivolumab plus cabozantinib compared to sunitinib. 