A translational analysis of the ongoing TRASNSCEND CLL 004 study (NCT03331198) revealed that patients with relapsed/refractory chronic lymphocytic leukemia (CLL) experienced positive enrichment of gene sets following receipt of concurrent ibrutinib (Imbruvica) and lisocabtagene maraleucel (liso-cel; Breyanzi).

A presentation at the 2021 SITC Annual Meeting showed that the impact of these combine agents resulted in cell proliferation, metabolism, and interferon response, as well as a negative enrichment of inflammation-associated gene sets, across CAR+ and endogenous T cells.

Data within a gene set enrichment analysis showed that there was positive enrichment of gene sets linked with cell proliferation, metabolism, and interferon response, as well as a negative enrichment of inflammation-associated gene sets.

“These results suggest that ibrutinib may potentiate the efficacy of liso-cel therapy in patients with relapsed/refractory CLL,” lead study author Jerill Thorpe, a senior scientist at Bristol Myers Squibb, said in a virtual presentation during the meeting.

CAR T-cell therapies have demonstrated potential in CLL; however, Thorpe noted that T-cell dysfunction that is inherent to CLL, including reduced proliferative and cytotoxic capacities, limits the efficacy of this approach. Preclinical data have shown that ibrutinib improves the function of liso-cel that is independent of its antitumor effects.

The phase 1 TRANSCEND CLL 004 trial is evaluating the efficacy and safety of liso-cel monotherapy or with concurrent ibrutinib in patients with relapsed/refractory CLL. Most recently, in data presented at the International Workshop on CLL, the combination was associated with a manageable safety profile for patients with relapsed/refractory CLL or small lymphocytic lymphoma.

At a median follow-up of 17 months, no grade 5 adverse events (AEs) or grade 4/5 cytokine release syndrome (CRS) or neurological events were reported. Of the 23 evaluable patients, all-grade CRS events occurred in 18 patients (78%), with only 1 (4%) having grade 3 CRS. All-grade neurologic events were reported for 7 patients (30%); 4 of these (17%) had grade 3 events. Eleven of these patients (48%) required tocilizumab (Actemra) and/or corticosteroids.

Efficacy findings showed that the overall response rate was 95%, which included a 59% complete response (CR) rate and a 36% partial response rate. Moreover, patients who received liso-cel at 100 x 106 CAR T cells had a more pronounced CR (61%) and a 29% PR rate, compared with 50% and 25%, respectively, for those who received 50 x 106 CAR T cells.

At the 2021 SITC Annual Meeting, investigators presented the data from translational analyses from those who received liso-cel alone (n = 16) or plus ibrutinib (n = 19) from the trial. Liso-cel pharmacokinetics were assessed via flow cytometry.

Further data showed that gene set enrichment analyses through hallmark gene sets demonstrated that CAR+ and endogenous T cells had similar expression profiles in response to ibrutinib in patients on this study. Data showed that at peak CAR+ T-cell expansion, increased expression of pathways were associated with T-cell proliferation and metabolism as well as decreased expression of pathways linked with inflammatory signaling.

Additionally, Thorpe noted that treatment with ibrutinib led to increased liso-cel expansion and reduced serum interleukin-6.

An independently derived CLL ibrutinib-response gene signature score was increased and sustained over time in CAR+ and endogenous T cells following the liso-cel/ibrutinib combination, but this was not the case with liso-cel alone.

Also, a higher ibrutinib gene signature score in CAR+ T cells at Tmax was linked with associated with increased probability of undetectable minimal residual disease in the bone marrow (0.1) and in the peripheral blood (0.092) regardless of treatment arm. When the ibrutinib score was higher in endogenous T cells at 2 months posttreatment was linked with longer progression-free survival (

Additional findings showed that a T-cell exhaustion gene signature was significantly reduced and associated with improved PFS with both liso-cel alone and in combination with ibrutinib.

However, Thorpe cautioned that the small sample size of the analysis should be taken into consideration when interpreting the ibrutinib gene expression score and T-cell exhaustion–related gene signature data.

“Work is under way to extend this analysis to a larger cohort,” Thorpe said.

Also, a lower CAR+ T-cell exhaustion score after 1 month of treatment (≤0.8 vs >0.8) was linked with a longer PFS (

Thorpe J, Rytlewski JA, Gillenwater HH, et al. Concurrent ibrutinib enhances T cell function in patients with chronic lymphocytic leukemia (CLL) treated with liscabtagene maraleucel (liso-cel), a chimeric antigen receptor (CAR) T cell therapy. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 449.

Qin JS, Johnstone TG, Baturevych A, et al. Antitumor potency of an Anti-CD19 chimeric antigen receptor t-cell therapy, lisocabtagene maraleucel in combination with ibrutinib or acalabrutinib. 

. 2020;43(4):107-120. doi:10.1097/CJI.0000000000000307

Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory CLL/SLL. Presented at: 2021 International Workshop on Chronic Lymphocytic Leukemia; September 17-20, 2021; virtual. Abstract 1084088.

This was originally published on OncLive as “Liso-Cel/Ibrutinib Combo Improves Efficacy in Relapsed/Refractory CLL”

Articles

Patients with relapsed/refractory chronic lymphocytic leukemia experienced positive gene set enrichment after receiving ibrutinib in addition to lisocabtagene maraleucel.

Liso-Cel Plus Ibrutinib Increases Potency in Relapsed/Refractory CLL Treatment

Health-related quality of life (HRQoL) was similar between placebo and surufatinib among patients with advanced neuroendocrine tumors (NETs), according to pooled findings from the phase 3 SANET-p and SANET-ep studies presented at the 2021 NANETS Virtual Symposium.

Specifically, results showed that surufatinib was found to significantly decrease the risk of deterioration in dyspnea vs placebo (HR, 0.0058; 95% CI, 0.39-0.86). However, the agent also significantly increased the risk of deterioration in diarrhea (HR, 2.91; 95% CI, 1.66-5.10; 

 = .0001) vs placebo via the QLQ-C30 scales. There were no significant differences observed in time until definite deterioration (TuDD) between the 2 arms in other scales, including global health status/QoL, physician functioning, cognitive functioning, fatigue, nausea and vomiting, pain, constipation, and insomnia, among others.

Surufatinib is a novel, angio-immuno kinase inhibitor designed to simultaneously target both VEGFR 1/2/3, FGFR, and CSF-1R. In the phase 3 SANET-p (NCT02589821) and SANET-ep (NCT02588170) trials, surufatinib was found to significantly improved progression-free survival (PFS) vs placebo in patients with advanced pancreatic NETs and extra-pancreatic NETs, respectively.

In SANET-p, the median follow-up in the investigative and control arms was 19.3 months (95% CI, 9.3-19.4) and 11.1 months (95% CI, 5.7-35.9), respectively. The median PFS per investigator assessment was 10.9 months (95% CI, 7.5-13.8) with surufatinib vs 3.7 months (95% CI, 2.8-5.6) with placebo (HR, 0.49; 95% CI, 0.32-0.76; 

In SANET-ep, the median follow-up in the investigative and control arms was 13.8 months (95% CI, 11.1-16.7) and 16.6 months (95% CI, 9.2–not calculable), respectively. The investigator-assessed median PFS was 9.2 months (95% CI, 7.4-11.1) vs 3.8 months (95% CI, 3.7-5.7) with placebo (HR, 0.33; 95% CI, 0.22-0.50; 

In July 2021, the FDA accepted the filing of a new drug application for surufatinib as a potential therapeutic option for patients with pancreatic and extra-pancreatic NETs, based on the SANET-p and SANET-ep findings.

For the pooled analysis of the phase 3 studies, investigators sought to examine the HRQoL of surufatinib in this patient population.

In the pooled analysis, investigators evaluated patients with advanced, well-differentiated (grade 1/2) pancreatic NETs or extra-pancreatic NETs with disease progression in the past year, and progression on up to 2 prior systemic anticancer therapies. Patients, who must have had an ECOG performance status of 0 or 1, were randomized 2:1 to receive 300 mg of surufatinib daily (n = 242) or placebo (n = 128) until disease progression. At this point, patients on surufatinib were followed for survival and those on placebo went onto open-label surufatinib.

The primary end point was investigator-assessed PFS; secondary end points were objective response rate, disease control rate, duration of response, time to response, overall survival, and safety and tolerability. Quality of life was an exploratory end point.

Patient-reported HRQoL was measured at various timepoints: baseline, day 15 of cycle 1, day 1 of each subsequent cycle, and at the time of treatment discontinuation using the European Organization of Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET-21.

The TuDD was defined as the time from randomization to the first deterioration of at least 10 points in domain score vs baseline score or death due to any cause. TuDD was tested with Kaplan-Meier estimators and unstratified Cox models, and 

 values were derived from unstratified log rank test.

The completion rate was determined as the proportion of patients among the intent-to-treat population who completed at least 1 scale of QLQ-C30 at each visit; the compliance rate was the proportion of patents who completed at least one scale of QLQ-C30 at each visit among those who were expected to complete the instruments at each visit. The change of scores from baseline were evaluated with the use of longitudinal method.

Investigators noted that the compliance rate of QLQ-C30/GI.NET21 was greater than 90% in both groups at all time points.

When TuDD was evaluated on the EORTC QLQ-C30 scales, surufatinib improved the reduction of the risk of deterioration in treatment-related symptoms (HR, 0.77; 95% CI, 0.31-1.93) and information/communication function (HR, 0.73; 95% CI, 0.45-1.19). Placebo performed slightly better in gastrointestinal symptoms (HR, 1.02; 95% CI, 0.68-1.54) and sexual function (HR, 1.12; 95% CI, 0.64-1.96).

Furthermore, least-squares mean differences from baseline to week 40 highlighted a trend toward benefit with surufatinib vs placebo at most visits except for diarrhea on the QLQ-C30 scale (increase of 14.9 vs 1.1 points; 

 <.0001) and muscle/bone pain symptoms on the QLQ-GI.NET21 scale (increase of 9.3 vs 3.9 points; 

Bai C, Xu J, Shen L, et al. Health-related quality-of-life analysis of surufatinib versus placbo for advanced neuroendocrine tumors: poled results from two phase 3 studies (SANET-p and SANET-ep). Presented at: 2021 NANETS Virtual Symposium; November 3-6, 2021; virtual. Abstract 150.

Xu J, Shen L, Bai C, et al. Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study. 

. 2020;21(11):1489-1499. doi:10.1016/S1470-2045(20)30493-9

Xu J, Shen L, Zhou Z, et al. Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study. 

. 2020;21(11):1500-1512. doi:10.1016/S1470-2045(20)30496-4

US FDA accepts filing of HUTCHMED’s NDA for surufatinib for the treatment of advanced neuroendocrine tumors. News release. July 1, 2021. Accessed July 1, 2021. https://bit.ly/3ycuQdd

This article was originally published on OncLive as “Surufatinib Shows Comparable HRQoL Vs Placebo in Advanced Neuroendocrine Tumors”

Pooled findings indicate that the quality of life in patients receiving surufantinib for advanced neuroendocrine tumors was comparable to that of placebo.  

Comparable Quality of Life with Surufatinib for Neuroendocrine Tumors Appears Manageable

Endometrial cancer is a molecularly driven malignancy with 4 distinct subtypes. In a presentation during the 

 Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow® (CFS®),Bhavana Pothuri, MD, MS, explained how recent regulatory approvals of checkpoint blockade has significantly progressed the management of this cancer type.

Moreover, Pothuri added that phase 3 trials of other immune-based combinations with chemotherapy, PARP inhibitors, and other novel agents are on the horizon to target some of these select subsets.

“The endometrial cancer treatment paradigm has changed significantly and will continue to evolve,” said Pothuri, a professor in the Department of Obstetrics and Gynecology and Medicine at NYU Grossman School of Medicine, and director of Gynecologic Oncology Clinical Trials at NYU Langone Health’s Laura & Isaac Perlmutter Cancer Center.

Pothuri dedicated her CFS® presentation to the late Franco M. Muggia, MD, a leader in the field of gynecologic oncology who died on September 8, 2021. Pothuri called Muggia her “dear friend and mentor,” and was most recently involved with him on endometrial cancer research.

Endometrial cancer is comprised of 4 distinct subtypes: 

-mutant, microsatellite instability–high (MSI-H)/mismatch repair deficient (dMMR), copy number (CN) low, and CN high/

-mutant disease tend to have the best prognosis compared with CN-low and MSI/dMMR disease (intermediate outcomes), and CN-high/

Up until 2017, the sole FDA-approved therapy in the endometrial cancer armamentarium was megestrol acetate. Now, clinical practice has benefitted from 3 new regimens that are available based on patients’ molecular profiles: pembrolizumab (Keytruda), dostarlimab-gxly (Jemperli), and pembrolizumab plus lenvatinib (Lenvima).

Recent Regulatory Advances in Endometrial Cancer Treatment

The PD-1 inhibitor pembrolizumab was explored in the open-label, nonrandomized, phase 2 KEYNOTE-158 trial (NCT02628067), which comprised previously treated patients with advanced MSI-H/dMMR tumors, including endometrial cancer. Patients received either pembrolizumab at 200 mg every 3 weeks, or at 10 mg/kg every 2 weeks.

Preliminary findings from all-comers showed that the objective response rate (ORR) was 39.6% (95% CI, 31.7%-47.9%), and responses lasting at least 6 months occurred in 78% of responders.

The FDA granted a tissue-agnostic approval in May 2017 to pembrolizumab based on the preliminary KEYNOTE-158 data, making it the first regulatory approval based on a biomarker regardless of tumor type.

Longer follow-up of the endometrial cancer cohort was presented at the 2021 ESMO Congress, which had a data cutoff date of October 5, 2020.4 In the efficacy-evaluable population of the endometrial group (cohorts D and K; n = 79), the ORR was 48% (95% CI, 37%-60%), which included a 14% complete response (CR) rate and a 34% partial response rate; 18% of patients had stable disease.

The median time to response was 2.3 months (range, 1.3-10.6). Additionally, the median duration of response (DOR) had not been reached, but 68% of patients were still in response at 3 years. The median progression-free survival (PFS) and overall survival (OS) was 13.1 months (95% CI, 4.3-34.4) and not reached (NR; 95% CI, 27.2-NR), respectively.

Safety with pembrolizumab was consistent with that of other checkpoint inhibitors. Treatment-related adverse events (TRAEs) occurring in at least 10% of patients included pruritus (24%), fatigue (21%), diarrhea (16%), arthralgia (14%), nausea (14%), hypothyroidism (13%), and rash (11%). Immune-related AEs (irAEs) at any grade occurred in 28% of patients, but 7% of patients experienced these as grade 3/4 events, including colitis (n = 1), severe skin reactions (n = 2), type 1 diabetes mellitus (n = 1), hepatitis (n = 1), and adrenal insufficiency (n = 1).

The multicenter, single-arm, multiple parallel-cohort, open-label, phase 1b GARNET trial (NCT02715284) evaluated single-agent dostarlimab, a PD-1 inhibitor, in expansion cohorts across multiple tumor types, including endometrial cancer. Patients were treated with dostarlimab at 500 mg of intravenous (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until disease progression.

The trial featured dose-finding (part 1), fixed-dose safety run-in (part 2A), and expansion cohorts (part 2B). In the expansion cohort, there were 5 groups: dMMR endometrial cancer, MMR proficient (pMMR) endometrial cancer, non–small cell lung cancer, nonendometrial dMMR/MSI-H cancer, and platinum-resistant ovarian cancer.

Dostarlimab elicited a 42.3% ORR in 71 patients with dMMR recurrent or advanced endometrial cancer, which included a 12.7% CR rate and a 29.6% PR rate.

 The DOR was at least 6 months for 93.3% of responders, and the median DOR was not reached at a median follow-up of 14.1 months (range, 2.6-22.4+).

At a median follow-up of 16.5 months, the ORR via investigator-assessed irRECIST criteria was 45.5% in patients with dMMR endometrial cancer (n = 110).

Based on the GARNET findings, the FDA granted an accelerated approval in April 2021 to dostarlimab for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are dMMR, as determined by an FDA-approved test.

The safety profile with dostarlimab was also found to be manageable. Any-grade treatment-emergent AEs (TEAEs) occurred in 69.9% of patients; grade 3 or higher irTRAEs had an incidence of 1.6% or lower. Additionally, increased alanine aminotransferase led to discontinuation in 1.4% of patients, but no TRAEs led to death.

Microsatellite Stable/pMMR: Pembrolizumab/Lenvatinib

The combination of pembrolizumab and lenvatinib was tested in patients with advanced endometrial cancer who received prior platinum-based chemotherapy in the phase 3 Study-309/KEYNOTE-775 trial (NCT03517449).

At a median follow-up of 11.4 months and in those with microsatellite stable (MSS)/pMMR disease, the median OS was 17.4 months (95% CI, 14.2-19.9) with pembrolizumab/lenvatinib vs 12.0 months (95% CI, 10.8-13.3) with chemotherapy (HR, 0.68; 95% CI, 0.56-0.84; 

Results showed that the median PFS in patients with pMMR status was 6.6 months (95% CI, 5.6-7.4) and 3.8 months (95% CI, 3.6-5.0) with pembrolizumab/lenvatinib and chemotherapy, respectively (HR, 0.60; 95% CI, 0.50-0.72; 

 <.0001). Here, the ORR was 30.3% (95% CI, 25.5%-35.5%) with pembrolizumab/lenvatinib vs 15.1% (95% CI, 11.5%-19.3%) with physician’s choice; the median DOR was 9.2 months (range, 1.6-23.7) vs 5.7 months (range, 0.0-24.2), respectively.

In all-comers, the median OS was 18.3 months (95% CI, 15.2-20.5) and 11.4 months (95% CI, 10.5-12,9), respectively (HR, 0.62; 95% CI, 0.51-0.75; 

 <.0001). The median PFS was 7.2 months (95% CI, 5.7-7.6) with pembrolizumab/lenvatinib and 3.8 months (95% CI, 3.6-4.2) with chemotherapy (HR, 0.56; 95% CI, 0.47-0.66; 

 <.0001). The ORRs were 31.9% (95% CI, 27.4%-36.6%) and 14.7% (95% CI, 11.4%-18.4%) with pembrolizumab/lenvatinib and physician’s choice, respectively. Finally, the median DOR was 14.4 months (range, 1.6-24.2) and 5.7 months (range, 0.0-24.2).

Results of a subgroup analysis from KEYNOTE-775 demonstrated the improvement of pembrolizumab/lenvatinib over physician’s choice of therapy in patients with dMMR endometrial cancer. The median OS with pembrolizumab/lenvatinib-treated patients was NR (95% CI, NR-NR) compared with 8.6 months (95% CI, 5.5-12.9) for physician’s choice of therapy (HR, 0.37; 95% CI, 0.22-0.62; 

Here, the median PFS was 10.7 months (95% CI, 5.6–not reached [NR]) and 3.7 months (95% CI, 3.1-4.4), respectively (HR, 0.36; 95% CI, 0.23-0.57; 

 <.0001). The ORRs were 40.0% (95% CI, 28.0%-52.9%) and 12.3% (95% CI, 5.5%-22.8%), respectively.

The combination was given accelerated approval in September 2019, followed by a regular approval in July 2021, for use in patients with advanced endometrial carcinoma that is not MSI-H/dMMR, who have disease progression following prior systemic therapy in any setting and are ineligible for curative surgery or radiation.

Regarding safety, toxicities associated with pembrolizumab/lenvatinib were consistent with those observed with each therapy given individually. The most frequent all-grade and grade 3 or higher TEAEs included hypertension (64% and 38%, respectively), hypothyroidism (all-grade, 57%), diarrhea (54% and 8%, respectively), nausea (all-grade, 50%), and decreased appetite (45% and 8%, respectively).

Additional grade 3 or higher TEAEs with the combination included weight decrease (10%), anemia (6%), asthenia (6%), fatigue (5%), and proteinuria (5%). It should be noted that 5.7% of patients on pembrolizumab/lenvatinib died due to grade 5 gastrointestinal disorders (1.2%), cardiac disorders (0.5%), general disorders (1.5%), infections (0.7%), decreased appetite (0.2%), and neoplasms, nervous system, psychiatric, renal, reproductive, or respiratory disorders (0.2% each). This was compared with 4.9% of patients on the physician’s choice arm.

“There are overlapping toxicities to also keep in mind, with the diarrhea and the hypothyroidism. It’s important to sort out: Are those related to the immunotherapy or to the lenvatinib?” Pothuri asked.

Ongoing phase 3 trials are tackling more checkpoint inhibitors alone or in combination in endometrial cancer, including RUBY (NCT03981796) with dostarlimab with carboplatin/paclitaxel, RUBY Part 2 with dostarlimab plus niraparib (Zejula; NCT03981796), AtTEnd (NCT03603184) with atezolizumab (Tecentriq), NRGY018 (NCT03914612) with pembrolizumab plus carboplatin/paclitaxel, KEYNOTE-B21 (NCT04634877) with pembrolizumab plus adjuvant chemotherapy with or without radiotherapy, and LEAP-001 (NCT03884101) with pembrolizumab plus lenvatinib.

Although CN-low endometrial cancer represents a subgroup of patients that has long been treated with chemotherapy, Pothuri admits that this likely not the optimal approach for this subset.

An additional trial of interest is the phase 2 ENGOT-EN3/NSGO-PALEO study (NCT02730429), which enrolled patients with primary stage IV or relapsed measurable/evaluable endometrial cancer who have received at least 1 prior systemic therapy. Patients were randomized 1:1 to receive palbociclib (Ibrance) at 125 mg days 1 to 21 plus letrozole at 2.5 mg on days 1 to 28 vs placebo and letrozole at the same dosage schedule every 28 days until disease progression. The primary end point was investigator-assessed PFS.

Data showed that the median PFS was 8.3 months and 3.0 months for the palbociclib/letrozole and placebo/letrozole arms, respectively (HR, 0.56; 95% CI, 0.32-0.98; 

 Additionally, the disease control rate was 63.6% and 37.8%, respectively.

“This was a phase 2 study and needs further study to determine if there is a role of CDK4/6 and hormonal therapy,” Pothuri added.

Patients with CN-high endometrial cancer form a group that is classically comprised of 

 positive-tumors, Pothuri explained, adding that homologous recombination deficiency is frequent in this subset and may be actionable.

For example, in a phase 2 trial (NCT01367002), patients with HER2-neu uterine serous carcinoma were randomized to receive carboplatin/paclitaxel for 6 cycles with or without IV trastuzumab (Herceptin) until progression or unacceptable toxicity. Data showed that in all patients, the median PFS was 12.6 months with the addition of trastuzumab vs 8.0 months for carboplatin/paclitaxel alone (HR, 0.44; 90% CI, 0.26-0.76; 

 In those with primary stage III to IV disease, the median PFS was 17.9 months and 9.3 months, respectively (HR, 0.40; 90% CI, 0.20-0.80; one-sided 

 = .013). In recurrent disease, the median PFS was 9.2 months and 6.0 months, respectively (HR, 0.14; 90% CI, 0.04-0.53; 

An updated analysis showed an OS benefit in the stage III to IV subgroup, in which the median OS was not reached in the trastuzumab arm vs 25.4 months with chemotherapy alone (HR, 0.49; 90% CI, 0.25-0.97; 

“[There is] lots of great interest and it is really an exciting time to be in the endometrial cancer space,” Pothuri said. “The role of trastuzumab and other HER2/neu-directed therapies for CN-high biomarker-positive tumors also needs further investigation in phase 3 trials.”

Pothuri B. Biomarker driven management of endometrial cancer. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY.

Levine DA,The Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma. 

 2013;497(7447):67-73. doi:10.1038/nature12113

FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Accessed November 4, 2021. https://bit.ly/3k62CMS

O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab (pembro) in patients (pts) with microsatellite instability-high (MSI-H) advanced endometrial cancer (EC): Updated results from KEYNOTE-158. 

. 2021;32(suppl_5):S725-S772. doi:10.1016/annonc/annonc703

Oaknin A, Tinker AV, Gilbert L, et al. Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer: a nonrandomized phase 1 clinical trial. 

. 2020;6(11):1766-1772. doi:10.1001/jamaoncol.2020.4515

6. Oaknin A, Gilbert L, Tinker AV, et al. Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study. 

. 2021;162(suppl 1):S12-S13. doi:10.1016/S0090-8258(21)00672-7

7. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. 

. 2021;162(suppl 1):S4. doi:10.1016/S0090-8258(21)00657-0

Mirza MR, BjørgeL, Marmé F, et al. A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel versus carboplatin-paclitaxel-trastuzumab in uterine serous carcinomas that overexpress human epidermal growth factor receptor 2/neu. 

. 2018;36(20):2044-2051. doi:10.1200/JCO.2017.76.5966

Fader AN, Roque DM, Siegel E, et al. Randomized phase II trial of carboplatin-paclitaxel compared with carboplatin-paclitaxel-trastuzumab in advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress her2/neu (NCT01367002): updated overall survival analysis. 

 2020;26(15):3928-3935. doi:10.1158/1078-0432.CCR-20-0953

This article was originally published on OncLive as “Checkpoint Blockade Moves Needle in Molecularly Driven Endometrial Cancer Paradigm”

An expert from NYU Langone outlines how checkpoint blockade approvals have helped advance endometrial cancer management. 

Checkpoint Blockade Drives Progress in Endometrial Cancer Treatment

Although currently minimal residual disease (MRD) offers little that can be utilized in clinical practice, it still demonstrates prognostic potential, explained Naval Daver, MD, in a presentation during the 39th Annual CFS®: Innovative Cancer Therapy for Tomorrow, a program by Physicians’ Education Resource (PER®), LLC. Moreover, newer modalities are seeking to pinpoint the extent to which MRD negativity in acute myeloid leukemia (AML) can inform prognoses and help shape treatment decisions.

“At this time, there is really no clear way to direct or eradicate MRD in patients with AML,” said Daver, who is director of the Leukemia Research Alliance Program, and an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center.
“Although MRD is prognostic, it really is not definitive. If you have a patient who becomes MRD negative and you still believe they have high-risk baseline features, [we still] use baseline molecular cytogenetic features to decide [whether to go to] transplant—because we know that even in those who become MRD negative, there can be a 30% relapse risk and vice versa.”


Two methods of detecting MRD involve multiparametric flow cytometry, which has been most used, and real-time quantitative polymerase chain reaction (PCR) in the form of next-generation sequencing (NGS) and digital droplet sequencing, among others. Although the PCR approach is becoming a more preferred method, it has proven to be both expensive and time consuming, Daver noted, who was also awarded PER®’s 2021 Educator of the Year during this year’s conference.


Utilizing MRD as a Prognostic Tool in AML Outcomes


MRD assessed by flow cytometry also has been shown to be highly prognostic in young patients with AML. For example, a study of 280 younger patients with AML were treated with intermediate-dose cytarabine and idarubicin-based induction chemotherapy and achieved remission; 186 patients were assessed for MRD via an 8-color multiparameter flow cytometry panel with a sensitivity rate of at least 0.1%.


In the 166 patients with available samples 1 to 2 months after induction at the time of complete remission (CR), 79% were MRD negative; MRD-negative status was linked with an improvement in relapse-free survival (RFS; P = .0002), as well as overall survival (OS; P = .0002). During consolidation, 116 patients were evaluated for MRD status, and in turn, 86% were MRD negative; MRD negativity was also associated with a significant improvement in RFS (P < .0001) and OS (P < .0001).


Upon treatment completion, 69 patients were evaluated for their MRD status, and 84% were MRD negative with negative status associated with an RFS improvement (P < .0001) and OS improvement (P < .0001). A multivariate analysis, which included age, cytogenetics, response, and MRD showed that MRD-negative status was the most significant independent predictor of RFS and OS at response (P = .008 and P = .0008, respectively), during consolidation (P < .0001 for both), and at therapy completion (P < .0001 and P = .002, respectively).


“The key is to achieve MRD negativity, and more and more, we’re starting to realize…that MRD is really a marker of sensitivity of the cancer to the chemotherapy being used,” Daver said. “Basically, for those who achieve MRD negativity, whether it is early or late, the cancer is sensitive to that particular therapy and that is being shown here with the achievement of MRD negativity.”


Daver added that in most cases in clinical practice, transplant is considered if patients do not achieve MRD negativity following 3 or 4 treatment cycles of intensive chemotherapy.


MRD can also be utilized as a tool to predict relapse in patients with AML following receipt of hypomethylating agents (HMAs). In a 9-color flow cytometry–based study of older patients with AML who were treated HMAs, MRD negativity was not found to have a significant impact on OS (median 12.9 months for MRD-negative patients vs 11.6 months for MRD-positive patients at 3-months post remission; P = .81).

 However, MRD negativity was strongly linked with RFS (10.94 months for MRD-negative patients vs 4.74 months for MRD-positive patients, both 3 months post remission; P = 0.21).


The use of PCR is likely to have an uptick in AML practice in the next 5 to 10 years, according to Daver, which will “hopefully” allow researchers to have more consistent large-scale randomized clinical trial data sets to establish it as a clinical and regulatory marker.


Researchers in a European study conducted NGS in patients with newly diagnosed AML at diagnosis and following CR with induction therapy. A total 89.2% of patients had at least 1 detected mutation; of these patients, 51.4% had mutations that persisted during CR and were present at various allele frequencies.


Once persistent DTA mutations were excluded, detection of molecular MRD was linked with a significantly higher relapse rate vs no detection, at 55.4% vs 31.9%, respectively (HR, 2.14; P <.001). The RFS rates were 36.6% and 58.1%, respectively (HR, 1.92; P <.001) and OS rates were 41.9% and 66.1%, respectively (HR, 2.06; P <.001).


However, it was noted in a multivariate analysis that detection of non-DTA persistent mutations often linked with clonal hematopoiesis in CR had independent predictive value. This was shown in rates of relapse (HR, 1.89; P <.001), RFS (HR, 1.64; P = .001), and OS (HR, 1.64; P = .003).


“NGS-based MRD tracking of AML mutations could be used for long-term survival,” Daver said. Combining NGS and flow cytometry could increase the strength of predicting relapse in patients with AML, he added; this showed a concordance rate 69.1%.


A large-cohort meta-analysis of 81 studies comprising 11,151 patients with AML also showcased the impact that MRD negativity has on OS (HR, 0.36; 95% CI, 0.33-0.39) and disease-free survival (DFS; HR, 0.37; 95% CI, 0.34-0.40).

 The 5-year OS and DFS rates for MRD-negative patients were 68% and 64%, respectively, compared with 34% and 25%, respectively, for MRD-positive patients.


“If I see MRD negativity, I feel more confident to tell my patients, especially with this very large data set, that the chance of long-term survival is much better, and getting to the 65% to 75% range,” Daver noted. “If they are MRD positive, of course, we are thinking of transplant and interventions, but even with those transplant and interventions, we are still going to expect a lower long-term survival at this time. Maybe with posttransplant maintenance approaches, this could improve over time.”


Defining the Role of Transplant in an MRD-Filled Era


Even upon remission, patients with AML continue to be at risk for disease relapse following allogeneic hematopoietic stem cell transplantation (HSCT). However, in an analysis of a phase 3 trial, researchers set out to determine whether modulating the intensity of transplant conditioning regimens in MRD-positive patients with AML could prevent relapse and improve OS.

 Patients who were in morphologic CR had been randomized to receive myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC). Ultra-deep error-corrected sequencing was performed for 13 commonly mutated genes.


Data showed that in patients with a detectable mutation—deemed NGS-positive— the 3-year cumulative incidence of relapse was 19% vs 67% for those who received MAC vs RIC, respectively (P <.001). The 3-year OS rates were 61% vs 43%, respectively (P = .02). Furthermore, when adjusting for disease risk and donor group in multivariable analysis of these patients, increased relapse (HR, 6.38; 95% CI, 3.37-4.69; P <.001), decreased RFS (HR, 2.94; 95% CI, 1.84-4.69; P <.001), and decreased OS (HR, 1.97; 95% CI, 1.17-3.30; P = .01) were all observed with RIC compared with those on MAC.


“One of the key messages from this paper, that we use in clinical practice, is that if there is an MRD-positive [result], whether it’s by NGS and I would say by flow cytometry, one would lean more toward using a myeloablative conditioning in this population [rather] than a RIC-based approach,” Daver said.


In a second analysis, the impact of transplant was also evaluated in both MRD-negative and -positive patients with AML who were in first CR.

 The primary end point was 1-year relapse incidence following transplant. Data showed that patients with MRD-positive disease had a higher incidence of relapse at 32.6% vs 14.4% for those with MRD-negative disease (P = .002), and inferior rates of leukemia-free survival, at 43.6% vs 64.0% (P = .007), respectively, and OS at 48.8% vs 66.9% (P = .008), respectively.


“Our approach at MD Anderson has been to take patients to transplant who we would have taken to transplant based on the baseline [European Leukemia Net] risk factor. [As such,] the patients who have high-risk molecular cytogenetic abnormalities, FLT3 positivity, RUNX1, TP53, we will take to transplant even if they are MRD positive,” Daver explained. “Our opinion is that transplant can still help mitigate the risk [in MRD-positive patients], and they will do less poorly than they would have without a stem cell transplant.”


For example, in an analysis of patients with AML who were in morphological CR and underwent a first stem cell transplant, a subset with MRD-positive disease who were stratified into an intermediate-risk group were found to have “reasonably well” outcomes to stem cell transplant, with a 1-year relapse incidence rate of 29% and a 1-year OS rate of 61%.


Next Steps: Examining Posttransplant Settings and Novel Drugs With Potential


There have been many approaches of interest to modulate MRD, including maintenance strategies, modulating donor lymphocyte infusions, incorporating oral CC-486 and FLT3 inhibitors in different settings, and exploring the use of early intervention with HMAs based on the loss of donor chimerism.


The latter approach was tested in the phase 2 RELAZA2 trial (NCT01462578), which included patients aged 18 years or older with advanced myelodysplastic syndrome or AML who had achieved CR following conventional chemotherapy or allogeneic HSCT.

 At a median follow-up of 13 months (IQR 8.5-22.8) following the start of MRD-guided therapy, the 1-year RFS rate was 46% (95% CI, 32%-59%) in MRD-positive patients who were treated with azacitidine compared with 88% (95% CI, 82%-94%) in MRD-negative patients (HR, 6.6; 95% CI, 3.7-11.8; P <.0001).


“Using preemptive therapy with azacitidine based on the donor chimerism could be a good way to use early intervention without waiting for a full MRD-based relapse,” Daver said. “[Researchers] were able to show that using this approach of early HMA intervention based on loss of chimerism, even before true detectable flow [cytometry] or molecular MRD, was useful.”


Additionally, the use of FLT3 inhibitors is being investigated in the posttransplant setting, most recently in the ongoing BMT-CTN 1506/Morpho trial (NCT02997202), which is randomizing 346 posttransplant patients with FLT3-ITD–mutated AML 1:1 to receive either gilteritinib (Xospata) or placebo.10 Investigators are seeking to answer whether there is a benefit to FLT3 inhibition posttransplant; whether the detection of a FLT3-ITD mutation by a validated, sensitive MRD assay predicts relapse; and whether a potent FLT3 inhibitor prevents relapse when a MRD assay detects a FLT3-ITD mutation.


Ongoing research is focused on uncovering MRD-converting drugs, and with current investigations on bispecific antibodies, cellular therapies with both natural killer and CAR T cells and potentially CD47, “then we will have a really important path forward to use these MRD erasers in the future,” Daver concluded.


References
1.	Daver N. Using measurable residual disease to guide decision-making for AML. Presented at: 39th Annual CFS®: Innovative Cancer Therapy for Tomorrow; November 3-5, 2021; New York, NY.
2.	Ravandi F, Jorgensen J, Borthakur G, et al. Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia. Cancer. 2017;123(3):426-435. doi:10.1002/cncr.30361
3.	Boddu P, Jorgensen J, Kantarjian H, et al. Achievement of a negative minimal residual disease state after hypomethylating agent therapy in older patients with AML reduces the risk of relapse. Leukemia. 2018;32(1):241-244. doi:10.1038/leu.2017.285
4.	Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular minimal residual disease in acute myeloid leukemia. N Engl J Med. 2018.378(13):1189-1199. doi:10.1056/NEJMoa1716863
5.	Short NJ, Zhou S, Fu C, et al. Association of measurable residual disease with survival outcomes in patients with acute myeloid leukemia: a systematic review and meta-analysis. JAMA Oncol. 2020;6(12):1890-1899. doi:10.1001/jamaoncol.2020.4600
6.	Hourigan CS, Dillon LW, Gui G, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38(12):1273-1283. doi:10.1200/JCO.19.03011
7.	Oran B, Jorgensen JL, Marin D, et al. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia. Haematologica. 2017;102(1):110-117. doi:10.3324/haematol.2016.144253
8.	Shah MV, Jorgensen JL, Saliba RM, et al. Early post-transplant minimal residual disease assessment improves risk stratification in acute myeloid leukemia. Biol Blood Marrow Transplant. 2018;24(7):1514-1520. doi:10.1016/j.bbmt.2018.02.003
9.	Platzbecker U, Middeke JM, Sockel K, et al. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial. Lancet Oncol. 2018;19(12):1668-1679. doi:10.1016/S1470-2045(18)30580-1
10.	A trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor gilteritinib administered as maintenance therapy following allogeneic transplant for patients with FLT3/internal tandem duplication (ITD) acute myeloid leukemia (AML). ClinicalTrials.gov. Updated October 8, 2021. Accessed November 3, 2021. https://www.clinicaltrials.gov/ct2/show/NCT02997202

This article was originally published on OncLive as “MRD Continues to Show Prognostic Potential in AML and Shape Treatment Decisions”


Newer modalities seek to use MRD to provide more definitive prognoses. 

MRD’s Role in AML Continues to Develop

Patients with treatment-naïve triple-negative breast cancer (TNBC) responded well to carboplatin plus neoadjuvant paclitaxel followed by doxorubicin and cyclophosphamide, according to findings from the phase 3 BrighTNess trial (NCT02032277).

The 4-year follow-up, presented during the 2021 ESMO Congress, revealed significantly improved pathological complete response (pCR) rates and event-free survival (EFS) among participants.

Notably, the addition of veliparib to carboplatin had no impact on the primary endpoints.

At a median follow-up of 4.5 years, the addition of the PARP inhibitor veliparib to carboplatin and paclitaxel resulted in a 37% reduction in the risk of events or death compared with paclitaxel alone (HR, 0.63; 95% CI, 0.43-0.92; 

 = .02). However, when the veliparib regimen was compared with carboplatin/paclitaxel, no event-free survival (EFS) benefit was observed (HR, 1.12; 95% CI, 0.72-1.72; 

 = .62). Post-hoc analyses showed that EFS was most improved with carboplatin/paclitaxel compared with paclitaxel (HR, 0.57; 95% CI, 0.36-0.91; 

“Adding carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pathologic complete response significantly, and this translated into an improved EFS by an absolute 11% after a median follow-up of 4.5 years,” Sibylle Loibl, MD, lead study author and chair of the German Breast Group in Germany, said in a virtual presentation on the findings. “The addition of veliparib did not impact pCR, EFS, or [overall survival]. These findings, overall, support the inclusion of carboplatin into neoadjuvant chemotherapy for stage II to III TNBC, regardless of germline 

TNBC is known to have the highest risk of recurrence and a worse overall prognosis for survival compared with other breast cancers. Standard treatment is comprised of neoadjuvant chemotherapy followed by surgery.

In the double-blind, placebo-controlled, phase 3 BrighTNess trial, 634 patients with treatment-naïve stage II/III TNBC were randomized 2:1:1 to receive paclitaxel at 80 mg/m2 weekly for 12 doses in up to 16 weeks plus carboplatin at area under the curve (AUC) 6 mg/mL every 3 weeks for 4 cycles plus veliparib at 50 mg orally twice daily (arm A; n = 316); carboplatin plus paclitaxel plus placebo (arm B; n = 160); or paclitaxel plus placebo (arm C; n = 158).

Doxorubicin was then given at a 60-mg/m2 dose with cyclophosphamide at 600 mg/m2 every 2 or 3 weeks for 4 cycles. Patients underwent surgery 2 to 8 weeks following the last dose of chemotherapy. A postsurgical assessment was done every 3 months until 1 year after surgery, followed by every 6 months until 2 years after surgery, and then annually until 4 years after surgery or until an EFS event.

To be eligible for enrollment, patients had to be at least 18 years old, have histologically or cytologically confirmed invasive stage II/III TNBC, have an ECOG performance status of 0 or 1, and be eligible for potentially curative surgery with documented germline 

Those who received prior anticancer therapy, had prior or concurrent cancer, or were on ovarian hormonal replacement therapy were excluded from study enrollment.

Patients were stratified based on germline 

 status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration.

The primary end point of the trial was pCR; secondary end points were EFS and OS using a fixed testing procedure that ordered arm A vs arm C; and then arm A vs arm B. Both coprimary end points had to be statistically significant to continue formally testing secondary end points, Loibl noted.

Efficacy evaluations were done in all randomized patients; safety was analyzed in those who received at least 1 dose. In the primary pCR analyses, arm A was found to be superior to arm C, but not to arm B.

Baseline characteristics were similar across all 3 arms. The median age was 50 years (range, 22-79), and 46.6% of patients were from North America compared with 38.6% from Europe and 15% from Asia-Pacific. Moreover, 14.6% of patients had deleterious germline 

 mutations; most patients (71.3%) had T2 stage tumors and 58% had N0 stage disease. Additionally, 55.3% of patients received doxorubicin/cyclophosphamide every 2 weeks. When breaking down patients by histological primary tumor grade, 59.6% had high grade, 20.3% had intermediate, 5.3% had low grade, and 14.3% of patients’ data were unknown/not reported.

Previously reported findings from the double-blind, placebo-controlled, phase 3 trial showed that the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the pCR rates in this patient population, but there was no benefit to adding veliparib to carboplatin and paclitaxel alone.

At that time point, the pCR rates were higher in the paclitaxel, carboplatin, and veliparib group, at 53% compared with 31% in patients who received paclitaxel alone (

 <.0001) but was not superior vs the patients who received carboplatin/paclitaxel at 58% (

However, the impact of neoadjuvant carboplatin on long-term outcomes remained uncertain, explained Loibl, who added that based on the primary analyses, the subsequent secondary analyses are descriptive with nominal 

At the 4.5-year median follow-up, additional results from a statistical analysis of OS showed that there were 38 deaths in arm A (12%), 16 in arm B (10%), and 22 deaths in arm C (14%). OS was not statistically significant different with the addition of veliparib to carboplatin/paclitaxel vs paclitaxel alone (HR, 0.82; 95% CI, 0.48-1.38; 

 = .45), but there was a trend for the carboplatin/paclitaxel (HR, 1.25; 95% CI, 0.70-2.24; 

 = .46). Carboplatin plus paclitaxel also showed a trend toward improved OS vs paclitaxel (HR, 0.63; 95% CI, 0.33-1.21; 

Additionally, the 4-year EFS rates were 78.2% (95% CI, 73.5%-83.2%) in arm A, 79.3% (95% CI, 72.9%-86.2%) in arm B, and 68.5% (95% CI, 61.3%-76.6%) in arm C.

In the patients who experienced events in arm A (n = 65), arm B (n = 30), and arm C (n = 47), few patients experienced progressive disease prior to surgery; this occurred in 1, 1, and 4 patients, respectively. Sixteen percent of patients in both arms A and B experienced any recurrence compared with 22% of patients in arm C. Secondary non-breast cancer malignancies occurred in 4% of patients on arm A, 2% on arm B, and 3% on arm C.

Investigators also studied the impact of pCR on EFS in all patients and subgroups by germline 

 status. pCR had a positive correlation with EFS in all patients (HR, 0.26; 95% CI, 0.18-0.38; 

 = .0004), and those whose tumors were germline 

 wild-type (HR, 0.29; 95% CI, 0.19-0.44; 

Death as the first event occurred in 13 patients on arm A, 3 on arm B, and 6 on arm C.

Regarding safety, the rates of treatment-emergent and posttreatment-emergent myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and secondary malignancies were similar between all treatment arms. Pancytopenia occurred in 4, 3, and 0 patients on arms A, B, and C, respectively, and MDS occurred in 1, 0, and 1 patient(s), respectively.

In arm A with veliparib, secondary malignancies included acute leukemia (n = 1), AML (n = 2), chronic myeloid leukemia (n = 1), lung neoplasm (n = 1), and malignant melanoma (n = 1). In arm B with carboplatin/paclitaxel, these included AML (n = 3), basal cell carcinoma (n = 1), and colon cancer (n = 1). In the paclitaxel-alone arm, these were MDS (n = 1) and pancreatic carcinoma (n = 2).

Loibl S, Sikov W, Huober J, et al. Event-free survival (EFS), overall survival (OS), and safety of adding veliparib (V) plus carboplatin (Cb) or carboplatin alone to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) after 4 years of follow-up: BrighTNess, a randomized phase 3 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 119O.

Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. 

. 2018;19(4):497-509. doi:10.1016/S1470-2045(18)30111-6

A 4-year follow-up of patients with treatment-naïve triple-negative breast cancer who received carboplatin plus neoadjuvant paclitaxel, followed by doxorubicin and cyclophosphamide, suggests that the regime induces superior pathological complete response and event-free survival.  

Gina Mauro

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