Sintilimab (Tyvyt) plus standard-of-care chemotherapy failed to demonstrate a significant improvement in overall survival (OS) and progression-free survival (PFS) vs standard-of-care chemotherapy alone but did result in an improved objective response rate (ORR) in patients with metastatic or recurrent pancreatic adenocarcinoma (PDAC), according to findings from the phase 3 CISPD3 trial that were presented during the 2022 Gastrointestinal Cancers Symposium.

The standard of care for PDAC is the chemotherapy combination FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin) or modified-FOLFIRINOX (mFFX [folinic acid, irinotecan, oxaliplatin followed by fluorouracil]). Researchers in this study investigated whether sintilimab, a human immunoglobin G4 monoclonal antibody that binds to PD-1 and has shown efficacy in other cancer types, could improve outcomes for patients with PDAC in the first or second line.

“Pancreatic cancers are resistant to PD-1 [and] to PD-L1 used as monotherapy, so the chemotherapy may expand the efficacy of immunotherapy,” said Tingbo Liang, chairman of The First Affiliated Hospital at Zhejiang University School of Medicine, in his presentation.

The single-center, open-label phase 3 CISPD3 trial randomized patients 1:1 to receive either 200 mg of sintilimab every 3 weeks plus mFFX (irinotecan 85 mg/m

) every 2 weeks versus mFFX alone. Of the study population of 110 total patients, only 3 patients on the sintilimab arm and 5 on the mFFX-alone arm had previous chemotherapy.

Patients were treated until disease progression, unacceptable toxicity, or other reasons for discontinuation. The primary end point was OS, while secondary end points included ORR, PFS, and disease control rate (DCR).

Twenty-one patients receiving sintilimab had a partial response (PR) and 1 had a complete response (CR), while 11 had a PR and none had a CR when receiving mFFX alone. In the sintilimab arm, 11 patients were not evaluable compared with 9 in the mFFX arm. The ORR for sintilimab was 50.0% compared with 23.9% with mFFX alone (

 = .05). The duration of response was 7.85 months for sintilimab compared with 4.63 months for mFFX, but this was not statistically significant (

 > .05). The DCR was 84.0% and 71.7% for sintilimab and mFFX, respectively (

However, the median OS was similar between the 2 arms for the intention-to-treat population: 10.9 months for sintilimab and 10.8 months for mFFX alone with a hazard ratio (HR) of 1.09 (95% CI, 0.70-1.690; 

 > .05). The median PFS was 5.9 months for sintilimab and 5.73 months for mFFX with a HR of 0.93 (95% CI, 0.62-1.41), showing no improvement in survival outcomes based on these data.

In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 45 patients (84.9%) in the sintilimab arm compared with 40 (74.1%) in the mFFX-alone arm. The most common grade 3 or higher AE was neutropenia, which was reported in 31 patients (58.5%) given sintilimab and 24 patients (44.4%) given mFFX alone. Other AEs included thrombocytopenia, anemia, vomiting, and increased aminotransferase. Immune-related AEs of grade 3 or higher occurred in 3 patients in the sintilimab arm (5.7%) and pulmonary AEs occurred in 3 patients (5.7%) as well.

“From the study we conclude that from addition of the sinitilimab to the mFFX, we improved the ORR significantly for metastatic pancreatic cancer, but no superior OS and PFS were observed. The toxicity was manageable and acceptable until growth. These data suggest that a combination with PD-1 antibody may expand the benefit of the chemotherapy protocol,” said Liang.

Fu Q, Chen Y, Huang D, Guo C, et al. Randomized phase III study of sintilimab in combination with modified folfrinox versus folfrinox alone in patients with metastatic and recurrent pancreatic cancer in China: The CISPD3 trial. Presented at: 2022 ASCO Gastrointestinal Cancers Symposium. January 20-22, 2022. Abstract 560. 

Articles

Sintilimab plus standard-of-care chemotherapy failed to demonstrate a significant improvement in overall survival and progression-free survival vs standard-of-care chemotherapy alone but did result in an improved objective response rate in patients with metastatic or recurrent pancreatic adenocarcinoma, according to findings from the phase 3 CISPD3 trial.

Sintilimab Plus Standard Chemotherapy Misses OS End Point in Metastatic Pancreatic Cancer

Acalabrutinib (Calquence) demonstrated an advantage in quality-adjusted survival compared with other standard treatments for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), according to findings from a post-hoc risk-benefit analysis that were presented during the 2021 ASH Annual Meeting and Exposition.

Acalabrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, showed progression-free survival (PFS) benefit in phase 3 trials versus previous approved treatments for CLL as well as tolerable toxicity.

 Investigators applied Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis, a quality-adjusted life-year (QALY) method that assesses the risks and benefits of treatment based on drug efficacy and toxicity profile, to the results of these studies. The findings demonstrated that acalabrutinib offers significant quality-adjusted survival gains compared with immunotherapy or a PI3K inhibitor, as well as clear benefit over ibrutinib (Imbruvica), a first-generation BTK inhibitor.

The Q-TWiST analysis focused on a pair of phase 3 studies, the ASCEND trial (NCT02970318) and ELEVATE-RR trial (NCT02477696). The ASCEND trial compared acalabrutinib with either bendamustine (Bendeka) plus rituximab (Rituxan) or idelalisib (Zydelig) plus rituximab in patients with R/R CLL. The ELEVATE-RR trial compared acalabrutinib with ibrutinib in patients with R/R CLL with high-risk genomics.

For this analysis, investigators looked at patients from the trials in 3 states: duration with toxicity before disease progression, duration without progression or toxicity, and duration from disease progression to death or end of follow-up. Toxicity was defined based on grade 3 and 4 adverse events (AEs), and when comparing acalabrutinib to ibrutinib, it was also measured by grade 2 to 4 AEs and the occurrence of AEs of any grade that occurred frequently.

“We also applied definitions of grade 2 to 4 AEs and any-grade AEs occurring in 10% or more patients because a significant clinical burden is associated with persistent low-grade adverse events in BTK inhibitor treatment,” John F. Seymour, AM, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation.

Investigators created Kaplan-Meier survival curves for time from toxicity to disease progression, PFS, and overall survival. The Q-TWiST analysis was based on the total of the weighted restricted mean durations of each of the 3 states.

When comparing acalabrutinib with bendamustine/rituximab or idelalisib/rituximab, patients spent an average 3.58 more months without progression or toxicity with acalabrutinib (95% CI, 2.42-4.74) and 2.51 fewer months between disease progression and death (95% CI, −3.50 to −1.60) and 0.73 fewer months with toxicity but before disease progression. The Q-TWiST with acalabrutinib was 17.48 months compared with 15.52 months with immunotherapy or PI3K inhibitors, a difference of 1.96 months (95% CI, 1.13-2.81).

In the acalabrutinib versus ibrutinib comparison, patients who received acalabrutinib had an average 0.37 months more between disease progression and death or relapse (95% CI, −1.82 to 2.60; 

 = .749). When analyzing toxicity by counting all AEs that affected at least 10% of patients, their Q-TWiST was 33.02 months with acalabrutinib versus 30.46 months with ibrutinib, an increase of 2.56 months (95% CI, 0.19-4.83). When considering grade 2, 3, and 4 AEs, the Q-TWiST difference was 2.58 months (95% CI, 0.22-4.89). When only considering grade 3 and 4 AEs, the difference was 1.28 months, which was not statistically significant (95% CI, −1.34 to 3.80).

A sensitivity analysis based on utility measures from the study did not find statistically significant improvement in Q-TWiST for acalabrutinib in either study population regardless of toxicity definition; however, the investigators noted in their presentation that the 2 studies were not designed to collect EuroQol-5 Dimension quality of life data from patients after treatment discontinuation.

“Overall, acalabrutinib demonstrated a favorable benefit-risk profile compared with idelalisib or B/R [bendamustine plus rituximab] in ASCEND or ibrutinib in ELEVATE-RR among patients with relapsed/refractory CLL,” Seymour concluded.

Seymour JF, Gaitonde P, Emeribe U, Cai L, Mato AR. A quality-adjusted survival (Q-TWiST) analysis to assess benefit-risk of acalabrutinib versus idelalisib/bendamustine plus rituximab or ibrutinib among relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3722.

Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia

. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. 

 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

Acalabrutinib demonstrated an advantage in quality-adjusted survival compared with other treatments for relapsed/refractory chronic lymphocytic leukemia.

Acalabrutinib Shows Superior PFS, Safety Over Other Treatments in Relapsed/Refractory CLL

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to a lower rate of minimal residual disease (MRD) compared with fludarabine, cyclophosphamide, and rituximab (Rituxan; [FCR]) in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to preliminary findings from the phase 2 ERADIC trial (NCT04010968) that were presented at the 2021 ASH Annual Meeting and Exposition.

The randomized phase 2 ERADIC trial, a French Innovative Leukemia Organization (FILO) trial presented by co-principal investigator Anne-Sophie Michallet, MD, of the department of hematology at the Centre Léon Bérard, compared ibrutinib plus venetoclax with the standard FCR regimen in medically fit, previously untreated patients with intermediate-risk CLL. These patients had either unmutated 

, 11q deletion, or complex karyotype in the absence of 

The investigators’ goal was to evaluate whether ibrutinib in combination with venetoclax, a BCL2 inhibitor, could lead to a lower MRD. However, at the 9-month interim follow-up, FCR showed a greater rate of reduced MRD in patients than ibrutinib/venetoclax. This result may not be indicative of the full trial length of 27 months.

Participants in the study were randomized 1:1 between receiving 6 cycles of FCR versus ibrutinib 420 mg and 400 mg venetoclax each daily, with 60 patients in each arm. Patients in the ibrutinib/venetoclax arm received ibrutinib monotherapy as a lead-in for the first 3 months. Treatment was either continued or discontinued after the results of bone marrow (BM) MRD assessment using flow cytometry at 9 months from the start of treatment. If BM MRD was below 0.01%, patients would continue treatment for 6 more months, for a total of 15 months. If BM MRD was above 0.01%, treatment would continue for 18 months instead, for a total of 27 months.

The trial’s primary end point in both arms was the percentage of patients at 27 months with BM MRD of 0.01%, while secondary end points included progression-free survival, overall survival, complete response (CR) rate at 27 months, and safety of both arms.

According to Michallet, at the ninth month of treatment, patients received evaluations including CT scans, bone marrow biopsies, and both peripheral blood (PB) MRD and BM MRD assessment. The interim results she presented had a median follow up of 11 months (95% CI, 2.9-19.8).

Of the 120 patients, 103 had reached 9 months of treatment at the data cut-off. There were 56 evaluable patients in the FCR arm. One of the 4 who were not evaluable experienced early disease progression. In this arm, 90% of patients received the full 6 cycles of FCR.

There were 47 evaluable patients in the ibrutinib/venetoclax arm. Ibrutinib was discontinued for 4 patients permanently and 3 patients stopped but were able to resume at a lower dose, while 4 patients discontinued taking venetoclax permanently due to digestive toxicities and grade 4 neutropenia.

Of the evaluable patients, 71% in the FCR arm and 42% of patients in the ibrutinib/venetoclax arm achieved BM MRD of below 0.01% at 9 months. In the FCR arm, 75.5% had PB MRD of below 0.01% compared with 48% in the ibrutinib/venetoclax arm.

This was also consistent for more detailed analysis of the sensitivity level of the MRD. “When we look at the sensitivity of the MRD responses, the result is also very clear, with a higher rate and higher depth of minimum residual disease undetectable in the blood and the marrow for the FCR compared to the IV [ibrutinib/venetoclax],” Michallet stated in her presentation.

In the FCR arm, 50% had a CR and 48% had a partial response (PR), while in the ibrutinib/venetoclax arm, 64% had a CR and 32% had a PR.

There was a wide range of serious adverse events (SAEs) in both arms; 31 patients were evaluated for SAEs in the FCR arm and 25 patients in the ibrutinib/venetoclax arm. SAEs included tumor lysis syndrome, infections, neutropenia, and digestive issues. Notably, investigators observed more frequent hematological and infectious toxicities in the FCR arm. However, they observed 8 cardiovascular disorders in the ibrutinib/venetoclax arm, including 3 cases of atrial fibrillation and 2 sudden deaths. According to Michallet, the patients who died had no known cardiovascular issues in the past and had no predictive factors for cardiovascular risk.

While the ibrutinib/venetoclax arm showed significantly lower BM MRD, this could change as the trial period continues. “The BM MRD rate should improve after longer exposure to the IV combination, and the analysis of the primary end point at 27 months will be decisive in determining the best therapeutic strategy,” Michallet concluded.

Michallet AS, Quinquenel A, Letestu R, et al. Preliminary results of the Filo phase 2 trial for untreated fit patients with intermediate risk chronic lymphocytic leukemia comparing ibrutinib plus venetoclax (IV) versus FCR. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 641

The combination of ibrutinib and venetoclax led to a lower rate of minimal residual disease compared with fludarabine, cyclophosphamide, and rituximab in patients with treatment-naïve chronic lymphocytic leukemia, according to preliminary findings from the phase 2 ERADIC trial.

Ibrutinib Plus Venetoclax Induces Lower MRD Rate Vs FCR in Previously Untreated CLL

Significant outcome differences were observed in premenopausal vs postmenopausal patients with hormone receptor (HR)–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes and received adjuvant chemotherapy as well as endocrine therapy, according to the updated results of SWOG S1007 RxPONDER trial (NCT01272037), presented at the 2021 San Antonio Breast Cancer Symposium.

 Results from the study were also published in the 

The investigators found a statistically significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in premenopausal women who received adjuvant chemotherapy, while no improvement was observed in postmenopausal patients. Kevin Kalinsky, MD, MS, director of Emory University Winship Cancer Institute’s Glenn Family Breast Center, also reported on post hoc analyses of subgroups among premenopausal patients and observed benefit for chemotherapy in premenopausal patients in terms of disease recurrence-free interval (DRFI), a more informative measure than DRFS.

“As opposed to DFRS, DRFI excludes death from non–breast cancer or unknown cause, and only includes distant recurrence or death from breast cancer,” Kalinsky said in his presentation. “This is a clinically important outcome given its relevance to long-term breast cancer–related survival.”

The randomized phase 3 RxPONDER trial enrolled approximately 5000 patients with HR-positive, HER2-negative breast cancer with 1 to 3 positive lymph nodes, no distant metastasis, and a 21-gene Oncotype DX Recurrence Score (RS) lower than 25. Those with a higher RS were treated off study and recommended to receive both endocrine therapy and chemotherapy, according to Kalinsky. Patients with a score of 25 or below were randomized to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone. Among the 4983 patients evaluated in the updated results were 1654 premenopausal women and 3329 postmenopausal women.1

Patients in the endocrine therapy group received adjuvant endocrine therapy consisting of tamoxifen citrate, 1 of the aromatase inhibitors anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin), or both tamoxifen citrate and an aromatase inhibitor. Patients in the chemotherapy group received an endocrine therapy in addition to systemic chemotherapy.

The primary end point of the study was IDFS and a secondary end point was DRFS. The 

 showed differences in IDFS and DRFS between premenopausal and postmenopausal patients who received chemotherapy. At a median follow-up of 6.1 years, the updated results contained 553 IDFS events. The results showed that in patients who were premenopausal, there was a 5-year absolute benefit of 4.9% for IDFS with chemotherapy (adjusted HR, 0.64; 95% CI, 0.47-0.87; 2-sided 

 = .004). There was a 5-year absolute benefit of 2.5% for DRFS with chemotherapy (adjusted HR, 0.66; 95% CI, 0.45-0.97; 2-sided 

“In an updated analysis, we report with longer follow-up that postmenopausal women with recurrence scores of 0 to 25 continue to not benefit from adjuvant chemotherapy,” said Kalinsky. In postmenopausal women, the 5-year IDFS rate was 91.2% in those treated with chemotherapy plus endocrine therapy compared with 91.9% in those treated with endocrine therapy alone (adjusted HR, 1.06; 95% CI, 0.87-1.30; 2-sided 

= .55). The 5-year DRFS rate was 94.3% with added chemotherapy vs 94.8% without (adjusted HR, 1.12; 95% CI, 0.88-1.44; 2-sided 

“However, premenopausal women with recurrence scores 0 to 25 do, with a 44% to 46% decrease in IDFS, DRFS, and DRFI events,” Kalinsky added.

For premenopausal patients, those who received chemotherapy demonstrated an improved DRFI of 2.4% (adjusted HR, 0.64; 95% CI, 0.43-0.95; 2-sided 

= .026) over those who only received endocrine therapy. For those with an RS of 0 to 13, the DRFI was 2.3%, while it was 2.8% for those with an RS of 14 to 25. However, postmenopausal patients did not show any DRFI benefit from chemotherapy in addition to endocrine therapy (HR, 1.12; 95% CI, 0.82-1.52; 2-sided 

Post hoc analysis showed that in 206 premenopausal women who had micrometastases of 0.2 to 2 mm in their lymph nodes, a 7.3% absolute benefit in IDFS from chemotherapy was observed with a hazard ratio of 0.44 (95% CI, 0.18-1.08). The absolute benefit in 5-year IDFS for 1403 patients with larger lymph node metastases of over 2 mm was 4.8% (HR, 0.64; 95% CI, 0.46-0.90).

“It does appear that premenopausal women with [only] micrometastases benefit from chemotherapy, though there [was] a limited number of events [n = 22], and there was a wide confidence interval,” Kalinsky noted.

In premenopausal patients who only received endocrine therapy, 50% stopped having periods in the first 6 months, compared with 25% of those who received chemotherapy as well. In the first 24 months, 58.9% of those receiving only endocrine therapy stopped having periods within the first 24 months, while 80.8% of those who also received chemotherapy stopped having periods in the first 24 months. In both arms, patients who stopped having periods also had a higher IDFS rate vs those who continued to have periods, with a hazard ratio of 1.56 (95% CI, 0.85-2.86) in those receiving chemotherapy and endocrine therapy vs a hazard ratio of 1.48 (95% CI, 0.92-2.40) in those receiving only endocrine therapy.

For those only treated with endocrine therapy, a 2-year landmarked analysis of ovarian function suppression (OFS) was meant to determine if it was linked to IDFS. A total 17.2% of premenopausal patients in this group underwent OFS. However, no difference in IDFS was observed based on OFS status (HR, 0.88; 95% CI, 0.47-1.63). The study was not able to establish that the benefit from chemotherapy was related to OFS. OFS rates were low in both treatment arms but were higher in the endocrine therapy–alone arm.

“It remains unclear if ovarian function suppression can replace chemotherapy in premenopausal women with hormone receptor–positive, HER2-negative, node-positive breast cancer,” Kalinsky said. “We conclude that future randomized trials should be considered to address this important clinical question in a genomically-defined population.”

Kalinsky K. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-07.

Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. Published online December 1, 2021. 

Significant outcome differences were observed in premenopausal vs postmenopausal patients with hormone receptor–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes and received adjuvant chemotherapy as well as endocrine therapy.

Jonah Feldman

Articles

Sintilimab Plus Standard Chemotherapy Misses OS End Point in Metastatic Pancreatic Cancer

Acalabrutinib Shows Superior PFS, Safety Over Other Treatments in Relapsed/Refractory CLL

Ibrutinib Plus Venetoclax Induces Lower MRD Rate Vs FCR in Previously Untreated CLL

Addition of Chemo to Endocrine Therapy Yields Survival Benefit in Premenopausal HR+/HER2- Breast Cancer