Transvaginal ultrasonography (TVUS) failed to identify nearly 5 times more endometrial cancer cases in Black women than in White women, says a simulated retrospective cohort finding published in 

 The screening tool, which serves to detect a need for diagnostic testing of endometrial cancer, may contribute to racial disparities of disease stage at diagnosis.

Data showed that the use of 4-mm TVUS endometrial tissue (ET) measurements to prompt biopsy led to a sensitive rate of 47.5% (95% CI, 46.0%-49.0%) among Black women vs 87.9% (95% CI, 87.6%-88.3%) among White women; the negative predictive values were 92% and 98%, respectively. Of the Black women who were referred for biopsy, 13.1% were endometrial cancer cases (95% CI, 12.5%-13.6%). The area under the curve (AUC) for the 4-mm or more threshold was 0.57 (95% CI, 0.56-0.57).

“The findings of this study suggest that adherence to current clinical guidelines results in systematic underdiagnosis in Black women with endometrial cancer owing to measurement thresholds that fail to account for uterine fibroids and nonendometrioid histologic type,” Kemi M. Doll, MD, MS, a gynecologic oncologist at University of Washington School of Medicine, and coinvestigators wrote in the publication.

In 2019, the estimated number of newly diagnosed endometrial cancer cases was 61,880 and 12,160 were deaths from endometrial cancer in the United States.2

TVUS, which is a noninvasive screening method, utilizes a test of endometrial thickness for further biopsies. Testing for this method was developed on large population-based studies from Scandinavia, Italy, and Hong Kong—none of which included Black women.

In the study, investigators sought to compare recommended TVUS ET thresholds with prompt endometrial biopsy by race as a screening method in a simulated cohort of symptomatic patients. Data were taken from the Surveillance, Epidemiology, and End Results (SEER) national cancer registry from 2012 to 2016 and the US Census; published estimates of ET distribution and fibroid prevalence, and diagnostic test characteristics of the 3- 4-, and 5-mm or more ET thresholds for biopsy to capture cancer diagnoses were calculated.

The simulated cohort was from February 2, 2020 to August 31, 2020, and the analysis occurred from September 30, 2020 to March 30, 2021. In total, 367,073 simulated Black and White females aged 45 years and older with postmenopausal bleeding were evaluated; 36,708 women had endometrial cancer. The distribution of disease histology was broken out by endometrioid (type 1; 2848 for Black women vs 27,926 for White women) and nonendometrioid (type 2; 1614 vs 4320, respectively).

The primary end point was accuracy of the TVUS ET threshold to correctly detect endometrial cancers, measured through sensitivity, negative predictive value, and AUC.

Further findings showed that, of the White women referred for biopsy, 14.6% had endometrial cancer (95% CI, 14.4%-14.7%), and the AUC was 0.73 (95% CI, 0.73-0.74).

Additionally, sensitivity, positive predictive value, and AUC were consistently lower for Black women than White women when evaluating the 3-mm or more and 5-mm or more ET thresholds.The 3-mm or more threshold led to a 51.1% (95% CI, 49.6%-52.6%) sensitivity rate at best for Black women vs 89.5% (95% CI, 89.1%-89.8%) at best in White women. For the 5-mm or more threshold, these rates were 92.2% (95% CI, 91.9%-92.5%) at best and 97.4% (95% CI, 97.3%-97.5%) at best among Black and White women, respectively.

“Based on the scenarios examined herein, there was none in which the TVUS ET strategy performed equally as well among Black women as it did among White women,” the investigators noted.

As the study was limited through the simulated cohort design, next steps following this research should include a real-world study, the investigators noted.

Doll KM, Romano SS, Marsh EE, Robinson WR. Estimated performance of transvaginal ultrasonography for evaluation of postmenopausal bleeding in a simulated cohort of Black and White women in the US. 

. Published online July 15, 2021. doi:10.1001/jamaoncol.2021.1700

Screening often misses endometrial cancer in Black women. News release. UW Medicine. July 15, 2021. Accessed August 16, 2021. 

This article was originally published on OncLive as“Transvaginal Ultrasound Misses Mark on Screening Endometrial Cancer in Black Women”

Articles

Adherence to current clinical guidelines may contribute to systematic underdiagnosis in Black women, says Kemi M. Doll, MD, MS.

Transvaginal Ultrasound Falls Short in Detecting Potential Endometrial Cancer in Black Women

Recent developments in bispecific antibodies, such as amivantamab-vmjw (Rybrevant), zenocutuzumab (MCLA-128), and tarlatamab (AMG-757), hold great therapeutic promise in the treatment of lung cancer, said Giorgio V. Scagliotti, MD, PhD, in a presentation during the 22nd Annual International Lung Cancer Congress, a program hosted by the Physicians’ Education Resource®, LLC.

“In thoracic malignancies, we have [these important] studies [highlighting these agents],” said Scagliotti, chief of the Medical Oncology Division, Department of Oncology at the University of Torino, in Italy. “[There is the role of amivantamab] in exon 20 insertion mutations, MCLA-128 in 

 fusion–positive tumors, and AMG 757 in small cell lung cancer.”

Bispecific antibodies across human diseases hold great therapeutic promise through their ability to bridge cells on either effector cells or target cells, or on tumor cells through receptor inhibition. However, Scagliotti emphasized that translating the concept of bispecifics into practical treatments has been a challenge. In 2009, the first bispecific antibody catumaxomab was approved in the European Union as an intraperitoneal therapy of malignant ascites, but was found to be toxic for Fc-mediated off-target T-cell activation in the liver and was voluntarily withdrawn from market.

Emicuzumab (Hemlibra) is indicated for the treatment of patients with hemophilia A. In oncology, blinatumomab (Blincyto), a bispecific CD19-directed CD3 T-cell engager, is approved for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease greater than or equal to 0.1%, as well as those with relapsed/refractory B-cell precursor ALL.

“There was a lot of interest around the chronic inflammatory disorders, and only [recently there has been] a growing interest in the field of malignancies,” Scagliotti said.

The fully human EGFR-MET bispecific antibody amivantamab has immune-cell-directing activity that targets activating and resistance 

The agent has been evaluated in the phase 1 CHRYSALIS study (NCT02609776), where investigators enrolled patients with advanced non–small cell lung cancer (NSCLC) on a dose-escalation cohort from 140 mg to 1750 of amivantamab in an effort to determine the recommended phase 2 dose (RP2D).2 This was determined to be 1060 mg for those with a weight lower than 80 kg, or 1400 mg for those 80 kg or higher.

Cohort D of the single-arm trial was comprised of patients with 

 exon 20 insertion mutations who progressed on platinum-based chemotherapy. The safety population (n = 114) included this subset treated at the RP2D; the efficacy population (n = 81) featured those who had at least 3 disease assessments at clinical cutoff. By October 8, 2020, all responders in the efficacy population had at least 6 months of follow-up from their first disease assessment.

The primary end point was overall response rate (ORR) via RECIST v1.1 criteria; key secondary end points were clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The median age of the efficacy population was 62 years (range, 42-84), and 59% of patients were female. Nearly half (49%) were Asian, followed by White (37%), Black (3%), and not reported/multiple (11%). Fifty-three percent of patients were nonsmokers, and the median time from initial diagnosis was 17 months (range, 1-130). A total 22% of patients had a history of brain metastases, the median number of prior lines of therapy was 2 (range, 1-7), and prior systemic treatments (100%) included platinum-based doublet chemotherapy (100%), immunotherapy (46%), poziotinib (1%), or an EGFR TKI (25%) that was of first (9%), second (7%), or third generation (7%).

Through blinded independent central review (BICR) assessment and at a median follow-up of 9.7 months (range, 1.1-29.3), the ORR was 40% (95% CI, 29%-51%), which included 3 complete responses (CRs) and 29 partial responses (PRs); the stable disease (SD), progressive disease, and not evaluable rates were 48%, 10%, and 1%, respectively. The median duration of response (DOR) was 11.1 months (95% CI, 6.9–not reached [NR]) and the CBR was 74% (95% CI, 63%-83%).

Additionally, the best ORR and CBR by insertion region of exon 20, as detected by circulating tumor DNA (ctDNA; n = 80), was 100% and 100% in the helical region (n = 1); 41% and 70%, respectively, in the near loop (n = 54); 25% and 75% in the far loop (n = 8), and 39% and 83% in not detected by ctDNA (n = 18). Twenty-five distinct exon 20 insertion variants were identified through next-generation sequencing of ctDNA with Guardant360 from 63 evaluable patient samples.

“More relevantly, at the clinical level—at least for me—there is a significant proportion in the spider plot that is showing that […] you can obtain significant tumor shrinkage, but you can also have long-lasting responses,” Scagliotti pointed out.

At the time of data cutoff, 47% of patients remain on treatment, and 63% had responses lasting 6 months or longer. The median PFS and OS was 8.3 months (95% CI, 6.5-10.9) and 22.8 months (95% CI, 14.6–NR), respectively.

The safety profile of amivantamab was consistent with that of EGFR and MET inhibition, Scagliotti explained. In the safety population (n = 114), 2% of patients discontinued due to rash, and 12% had diarrhea (grade 1/2, 8.5%; grade 3, 3.5%)—10% of which was related to treatment. A total 94% of infusion-related reactions (IRRs) occurred with the first infusion, but this did not significantly impact patients’ ability to continue on subsequent treatments.

 as the first treatment for adult patients with NSCLC who harbor 

The regulatory agency also granted an approval to Guardant360 CDx for use as a companion diagnostic for the bispecific antibody.

 fusions are observed at low incidence across tumors that preserve the EGF-like domain and are potentially actionable; they are best detected through RNA-NFS. HER2-directed therapy has been found to be a suboptimal strategy but are currently under investigation.

Zenocutuzumab is being tested in the phase 1/2 eNRGy trial (NCT02912949), which is enrolling patients with 

 fusion–positive solid tumors. Investigators presented pooled data from eNRGy at the 2021 ASCO Annual Meeting.

The dataset comprised patients with pancreatic ductal adenocarcinoma (PDAC; n = 12), NSCLC (n = 25), and other malignancies (n = 10).

In the NSCLC cohort, the median age was 58 years (range, 32-84), 60% of patients were female, and 40% of patients had an ECOG performance status of 0. Twenty-one (84%) patients had adenocarcinoma histology, followed by 3 (12%) with invasive mucinous adenocarcinoma, and 1 (4%) with other histology.

In 24 evaluable patients with NSCLC, the confirmed ORR was 25%; 1 additional PR was confirmed after the cutoff date, bringing the ORR in this subset to 29% (7/24).

The bispecific antibody also showed promise in other solid tumors. The ORRs for the 12 patients with PDAC and 9 patients with other 

 fusion–positive cancers were 42% and 22%, respectively. Additionally, tumor reduction was reported for 34 patients (76%) overall.

Regarding safety, the majority of adverse events (AEs) with zenocutuzumab were grade 1/2, with a notable absence of severe gastrointestinal toxicity, skin toxicities, and clinical cardiotoxicities. All-grade and grade 3/4 treatment-related AEs (TRAEs) occurred in 59% and 3% of patients, respectively, including diarrhea (all-grade, 20%; grade 3/4, 0%), asthenia/fatigue (all-grade, 13%; grade 3/4 <1%), nausea (all-grade, 10%; grade 3/4, 0%), and infusion-related reaction (all-grade, 7%; grade 3/4, 1%). No grade 4 treatment-related AEs were reported, with 1 grade 5 AE hypersensitivity occurring in 1 patient with preexisting severe aortic stenosis that was previously reported.

Tarlatamab, a half-life extended bispecific T-cell engager against DLL3, is being explored in small cell lung cancer (SCLC). Updated results from a multicenter, open-label, phase 1 trial (NCT03319940) with the novel agent in this patient population were also presented at the 2021 ASCO Annual Meeting.

Patients with SCLC had to have received at least 1 line of systemic therapy and either progressed or recurred following at least 1 platinum-based chemotherapy, as well as an ECOG performance status of 0 to 2, at least 1 measurable lesion, and adequate organ function.

In the study of 66 patients, the median age was 64 years (range, 32-80), 74% of patients were former smokers, and 98% of patients had an ECOG performance status of 0 to 1. Patients had either 1 to 2 (73%) or more than 3 (27%) prior lines of therapy; the median number of prior treatments was 2 (range, 1-6). Forty-four percent of patients had received prior anti–PD-1/PD-L1 therapy. Most patients (95%) had extensive-stage disease at initial diagnosis; 24% had brain metastases and 47% had liver metastases.

Data showed that tumor shrinkage was observed across tarlatamab doses, which ranged from 0.3-mg to 100-mg target doses. At a median follow-up of 11.2 months, the confirmed PR rate of 64 evaluable patients was 20%; the unconfirmed PR rate was 2%. The SD and disease control rates were 27% and 47%, respectively. For patients with a confirmed PR (n = 13), the median DOR was 8.7 months, the median time to response was 1.8 months.

Fifteen percent of patients completed at least 6 months of treatment, and 7 of 13 patients with confirmed PR are still on treatment and have an ongoing response.

Five percent of patients discontinued treatment due to TRAEs; dose-limiting toxicities included grade 5 pneumonitis at the 0.3-mg dose in 1 patient and grade 3 encephalopathy at the 100-mg dose in 1 patient.

Grade 3 or higher TRAEs occurred in 27% of patients. Additionally, 44% of patients experienced all-grade cytokine release syndrome; 1 patient had this as a grade 3 or higher TRAE.

“The main problem is related to cytokine release syndrome that is manageable and reversible in the vast majority of the cases, but we need to keep an eye on it,” Scagliotti added.

Select bispecific antibody constructs are currently being investigated in other solid malignancies, including the HER2-targeted ISB 1302 in breast cancer (NCT03983395), the PD-1/CTLA-4–directed AK104 in gastric cancer/gastroesophageal junction adenocarcinoma (NCT03852251), the EGFR-directed variant III AMG 596 in glioblastoma (NCT03296696), the PSMA-targeted AMG 160 in metastatic castration-resistant prostate cancer (mCRPC; NCT03792841) and pasotuxizumab (NCT01723475), the GD2-directed GD2Bi-aATC in OS/NB (NCT02173093), the MUC16-directed REGN4018 in ovarian cancer (NCT03564340), and the GD2-targeted Hu3F8-BsAb GD2 in solid tumors (NCT03860207).

Scagliotti, GV. Bispecific antibodies in lung cancer. Presented at: the 22nd Annual International Lung Cancer Congress; July 30-August 1, 2021; Huntington Beach, CA.

RYBREVANT - CHRYSALIS Study. JanssenMD. Updated June 17, 2021. Accessed July 30, 2021. 

FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed May 21, 2021. 

Schram AM, O’Reilly EM, O’Kane GM, et al. Efficacy and safety of zenocutuzumab in advanced pancreas cancer and other solid tumors harboring NRG1 fusions. 

. 2021;39(suppl 15):3003. doi:10.1200/JCO.2021.39.15_suppl.3003

Owonikoko TK, Champiat S, Johnson ML, et al. Updated results from a phase 1 study of AMG 757, a half-life extended bispecific T-cell engager (BiTE) immuno-oncology therapy against delta-like ligand 3 (DLL3), in small cell lung cancer (SCLC). 

. 2021;39(suppl; abstr 8510). doi:10.1200/JCO.2021.39.15_suppl.8510

This article was originally published on OncLive as 

“Bispecifics Prove to Have Intriguing Role in Lung Cancer”

Bispecific antibodies like amivantamab-vmjw, zenocutuzumab, and tarlatamab, are novel in the landscape of lung cancer treatment due to their ability to bridge cells and inhibit tumor growth. 

Bispecific Antibodies May Change Lung Cancer Paradigm 

The evolution of checkpoint blockade and VEGF TKIs, as well as the regulatory approval of combination therapies involving these inhibitors, have led to a significant improvement in the 5-year survival rates of patients with renal cell carcinoma (RCC).

“[We see that] there is a definitive role in having dual therapy,” said Laura S. Wood, RN, MSN, OCN, Renal Cancer Research Coordinator at Cleveland Clinic Taussig Cancer Center, in a presentation during the 

 School of Nursing Oncology meeting. “We’re seeing a number of new combinations with PD-1/PD-L1 inhibitors plus 1 of our TKIs, so the story continues as far as the evolution of our therapies. And, this is what will account for improvements in response rate, progression-free survival, and overall survival.”

The shifted balance of treatment toward anticancer immunity with combination strategies involving PD-1/PD-L1 and VEGF inhibitors has been reported through several pivotal clinical trials that have led to improved outcomes in RCC: CheckMate-214 (NCT02231749), KEYNOTE-426 (NCT02853331), CheckMate-9ER (NCT03141177), and CLEAR (NCT02811861).

Such clinical findings led to the approvals of nivolumab (Opdivo) plus ipilimumab (Yervoy), pembrolizumab (Keytruda) plus axitinib (Inlyta), avelumab (Bavencio) plus axitinib, and cabozantinib (Cabometyx) plus nivolumab. While nivolumab/ipilimumab is approved in intermediate- and poor-risk patients only, the other dual strategies are approved for all-comers with RCC.

“It’s very difficult and challenging to do cross-trial comparisons,” said Wood. “It’s definitely not highly recommended, but it is what we use in clinical practice to help us in patients use shared decision-making to make treatment decisions.”

The phase 3 CheckMate-214 trial was the basis for the April 2018 FDA approval of nivolumab/ipilimumab as first-line treatment for intermediate- and poor-risk patients with RCC.

In the trial, patients with metastatic clear cell RCC were randomized to receive 3 mg of nivolumab plus 1 mg of ipilimumab or sunitinib as first-line therapy. Four-year follow-up data showed that, at a median follow-up of 55 months, the combination led to a 31% reduction in the risk of death when compared with sunitinib (Sutent) in the intent-to-treat population.

 Specifically, the median overall survival (OS) was not reached with nivolumab/ipilimumab and 38.4 months with sunitinib (HR, 0.69; 95% CI, 0.59-0.81).

The median progression-free survival (PFS), however, was 12.2 months and 12.3 months, respectively; the ORR rates were 39% and 32%, respectively. The complete response (CR) rates were 11% vs 3%, respectively.

In intermediate- and poor-risk patients, nivolumab/ipilimumab was also favored over sunitinib for OS (HR, 0.65; 95% CI, 0.54-0.78).

Pembrolizumab and axitinib was tested up front in the phase 3, open-label KEYNOTE-426 trial, in which treatment-naïve patients with advanced clear cell RCC were randomized to receive the PD-1/VEGF TKI combination or sunitinib.

Extended follow-up results showed that the median OS was not reached compared with 35.7 months with sunitinib (HR, 0.68; 95% CI, 0.55-0.85; 

 = .0003) at a 30.6-month median follow-up.3 Additionally, the median PFS was 15.4 months and 11.1 months, respectively (HR, 0.71; 95% CI, 0.60-0.84; 

 <.0001). The combination elicited a 60% ORR while sunitinib’s ORR was 40% (

 <.0001); the CR rates were 9% and 3%, respectively.

Based on earlier data from KEYNOTE-426, the FDA approved pembrolizumab and axitinib in the up-front setting for patients with RCC in April 2019.

Avelumab/axitinib is also available as a frontline combination regimen in patients with advanced RCC as of May 2019. The decision was based on the phase 3 JAVELIN Renal 101 trial, which showed that the combination led to a 31% reduction in the risk of disease progression or death vs sunitinib in the overall group of patients with treatment-naïve advanced RCC, regardless of PD-L1 expression.

In the international, phase 3 CheckMate-9ER trial, investigators evaluated nivolumab plus cabozantinib compared with sunitinib in the frontline setting for patients with advanced clear cell RCC.

At a median follow-up of 23.5 months, the median OS with the combination was not reached vs 29.5 months with sunitinib (HR, 0.66; 95% CI, 0.50-0.87; 

 = .0034), and the median PFS was doubled at 17.0 months vs 8.3 months with sunitinib (HR, 0.52; 95% CI, 0.43-0.64; 

 <.0001).5 The ORRs were 55% and 27% with nivolumab/cabozantinib and sunitinib, respectively; the CR rates were 9% vs 4%, respectively.

The FDA approved nivolumab plus cabozantinib in this setting in January 2021, based on the earlier phase 3 CheckMate-9ER data. The recommended dose is 240 mg of nivolumab every 2 weeks via a 30-minute intravenous (IV) infusion, or at 480 mg every 4 weeks via 30-minute IV infusion, in combination with oral, once-daily cabozantinib at 40 mg once daily without food until either progressive disease or intolerable toxicity.

The efficacy behind the combination of lenvatinib (Lenvima) and pembrolizumab, also compared with sunitinib, in the frontline setting of RCC was recently presented at the 2021 Genitourinary Cancers Symposium.

Additionally, investigators tested the efficacy and safety of lenvatinib plus everolimus (Afinitor) vs sunitinib in this setting as a separate cohort.

At a median follow-up of 27 months in the phase 3 CLEAR trial, pembrolizumab/lenvatinib had a 34% reduction in the risk of death when compared with sunitinib; the median OS was not reached in either arm at a median 27-month follow-up (HR, 0.66; 95% CI, 0.49-0.88; 

 = .005). The median PFS was 23.9 months and 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49; 

 <.001); the ORRs were 71% vs 36% and the CR rates were 16% vs 4%, respectively.

Regarding the arm of lenvatinib plus everolimus vs sunitinib, the data showed statistically significant improvements in PFS and ORR, but not in OS (HR, 1.15; 95% CI, 0.88-1.5; 

Based on the CLEAR findings, the FDA granted a priority review designation in May 2021 to a supplemental biologics license application to the combination of lenvatinib and pembrolizumab as a frontline treatment for patients with advanced RCC. The agency is expected to make a decision on the approval by August 25, 2021.

“What’s important to note is that even though [lenvatinib and pembrolizumab] has one of the shorter overall duration of evaluation for the date, [it has a] 71% overall response rate and 16% complete response rate in just 27 months of follow-up for patients on active treatment,” Wood explained. “So, we are continuing to see improvements in our combinations and improvements in outcomes for these regimens.”

Utilizing Guidelines, Prognostic Factors and More for the Best RCC Treatment

The regulatory decisions and encouraging clinical data have also made an impact on the National Comprehensive Cancer Network (NCCN) guidelines for frontline therapy in advanced kidney cancer, and combination therapies are now defined by favorable, intermediate-, and poor-risk status.

Preferred regimens (category 1) for favorable-risk patients include axitinib/pembrolizumab, nivolumab/cabozantinib, and lenvatinib/pembrolizumab; poor-/intermediate-risk patients are recommended to receive axitinib/pembrolizumab, nivolumab/cabozantinib, nivolumab/ipilimumab, lenvatinib/pembrolizumab (all category 1), or cabozantinib.

Preferred agents, listed as category 1 recommendations, for subsequent lines of treatment in clear cell RCC include cabozantinib, lenvatinib/everolimus (Afinitor), and nivolumab.

Updates to NCCN guidelines have also occurred in the advanced non–clear cell RCC setting, Wood noted; preferred regimens include cabozantinib, sunitinib, and a clinical trial.

Overall, evidence-based decision-making, International Metastatic RCC Database Consortium (IMDC) risk stratification, histology, biomarkers, and comorbidities are all factors to consider when choosing treatment for a patient with RCC, Wood emphasized.

Regarding biomarkers, she added that based on data with pembrolizumab/axitinib, avelumab/axitinib, and nivolumab/ipilimumab, PD-L1 expression does not predict benefit or response in RCC compared with other malignancies.

“Patients irrespective of biomarker status will benefit from these combination therapies, so we’re continuing to try to identify biomarkers which will contribute to the knowledge of treatment decision-making,” Wood said.

Other disease characteristics are being identified as poor prognostic features, including sarcomatoid histology. However, in the KEYNOTE-426 study, patients with advanced RCC who had sarcomatoid features had an improved response to pembrolizumab/axitinib (58.8%) vs sunitinib (31.5%), providing clinicians with an option to recommend to their patients with this poor prognostic indicator, Wood added.

Cytoreductive nephrectomy has been evaluated as an immediate or deferred approach in patients with metastatic RCC. However, Wood explained that it’s been demonstrated that deferred surgery may have improved outcomes compared with immediate cytoreductive nephrectomy.

“A delayed cytoreductive nephrectomy allows for the identification of patients with aggressive or inherently resistant disease to our VEGF-targeted therapies, and those are individuals who may not benefit from a nephrectomy up front” she said, adding that initial systemic therapy is preferred in those with Memorial Sloan Kettering Cancer Center/IMDC poor-risk disease, poor [Karnofsky performance score] and/or large-volume metastatic burden.

However, select patients are likely to benefit from an up-front surgery, including those with single-site metastatic disease and those with good performance status, Wood mentioned.

Sixty-five percent of patients with RCC present with localized disease, suggesting a need for adjuvant treatment in this malignancy. At the 2021 ASCO Annual Meeting, data from the phase 3 KEYNOTE-564 trial (NCT03142334) were presented and demonstrated the benefit of adjuvant pembrolizumab vs placebo in the post-nephrectomy setting for patients with RCC.

In the double-blind, multicenter study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Eligibility criteria included categorizing patients as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.

Patients had to have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, had to have an ECOG performance status of 0 or 1, and obtainable tissue sample for PD-L1 assessment.

All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

Data showed that, at a median follow-up of approximately 2 years, the median investigator-assessed disease-free survival (DFS) was not reached with either pembrolizumab or placebo (HR, 0.68, 95% CI, 0.53-0.87; 

 = .0010).8 The estimated 1-year DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively. The 2-year rates were 77.3% and 68.1%, respectively.

The Emphasis on Multidisciplinary Care in RCC

In conclusion, the spectrum of GU malignancies embodies the multidisciplinary care approach, with Wood expressing the importance of urologic surgeons, medical oncologists, radiation oncologists, and palliative care in a patient’s course of treatment.

“Palliative care is huge for us. At least for renal cell carcinoma, there are many patients who see palliative care for assistance with symptom management before we even get started on systemic therapy,” she concluded. “If we don’t get palliative care’s input to help us manage the underlying disease and the symptoms associated with it, patients are never going to tolerate an aggressive regimen, which is necessary to control the disease and improve their overall survival.”

Wood LS. Renal cell carcinoma and supportive care in GU cancers. Presented at: 

School of Nursing Oncology; August 6-7, 2021; virtual.

Albiges L, Tanniir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. 

. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079

Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. 

. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8

FDA approves Bavencio (avelumab) plus Inlyta (axitinib) combination for patients with advanced renal cell carcinoma. Pfizer Oncology. May 14, 2019. Accessed August 9, 2021. https://on.pfizer.com/2HtdCzF.

Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. 

. 2021;39(suppl 6):308. doi:10.1200/JCO.2021.39.6_suppl.308

Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). 

. 2021; 39(suppl_6):269. doi:10.1200/JCO.2021.39.6_suppl.269

Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. 

. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab vs placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase 3 KEYNOTE-564 study. 

. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5

This article was originally published on OncLive as

 “Checkpoint Inhibitor/TKI Combos Jump RCC Treatment to Next Level”

Recently approved combination therapies have contributed to significantly improved survival rates in renal cell carcinoma. 

Checkpoint Inhibitor/TKI Combos Increase Survival in Renal Cell Carcinoma

Preliminary results from the phase 4 MITO-BCG study (EUDRACT) showed that consecutive treatments with Bacillus Calmette-Guérin (BCG) and the chemotherapy mytomicin resulted in a safety profile comparable to BCG alone in patients with high-risk non-muscle-invasive bladder cancer (NMIBC).

No significant differences in safety were reported between the 2 arms. Results showed that 6 patients experienced posttreatment adverse effects (AEs) overall, with 3 reported in the combination therapy–arm. Five of the 6 AEs, which were Common Terminology Criteria for Adverse Events grade 1, comprised urethral sub-stenosis, fever, asthenia, fainting, and cystitis and did not require further treatment.

One grade 3 AE, which was acute epididymo-orchitis with abscess, was reported in the BCG-monotherapy arm and required orchiectomy. No grade 3 or higher AEs occurred in the combination arm.

“Preliminary results of our experience [in the MTIO-BCG study] support that sequential combination therapy with mytomicin and BCG is a [safe] treatment in high-risk NMIBC,” said study author Antonio Nacchia, MD, medical director of urology, Sapienza University of Rome, in a virtual presentation of the data during the meeting.

In the ongoing, open-label, phase 4 MITO-BCG study (NCT03790384), investigators are evaluating the efficacy and safety of sequential treatment with mitomycin and BCG combination therapy versus BCG alone in patients with high-risk NMIBC. The protocol had been approved by the Italian Medicines Agency in August 2018 and then by the Ethical Committee in Italy in December 2018; the protocol started in March 2019.

To be eligible for enrollment, patients must have high-risk NMIBC that was either: T1, grade 3, carcinoma in situ, multiple and recurrent large Ta, G1G2, or were in the last EAU recurrence category of EAU/EORTC recurrence score ≥10. Patients need to be between 40 and 75 years of age.

Those with low-risk NMIBC, muscle-invasive bladder cancer, concomitant urothelial bladder cancer in the upper-urinary tract, had prior bladder or prostate surgery, prior prostate or bladder radiotherapy, urinary tract infection, chronic urinary retention or indwelling catheters, have neurologic issues, had prior BCG infections, prior or current chemotherapy for other malignancies, or residual tumor on re-transurethral resection of the bladder were excluded from enrollment.

 Additionally, patients could have a World Health Organization performance status between 3 and 4.

Thirty-six patients were randomized to receive standard BCG induction therapy as an instillation once weekly for 6 weeks with an 81-mg Connaught strain of BCG (n = 21) or the BCG protocol with 40 mg of mitomycin instillation given the day before BCG starts at once weekly for 6 weeks (n = 15). Cystoscopy and urine cytology were both conducted every 3 months along with annual CT scans. The median age of patients was 67 years.

The primary end point of the trial is recurrence rate, with overall toxicity being a secondary end point. Assessments of health-related quality of life serves as an exploratory end point.

Trial enrollment will continue until 200 patients are included on the study, Nacchia concluded.

(UGN-101; Jelmyto) as the first therapy to treat patients with low-grade upper tract urothelial cancer. Mitomycin gel uses the RTGel™ technology platform and is designed to permit longer exposure of mitomycin to urinary tract tissue, which allows for the nonsurgical treatment of these tumors. The therapy is administered to patients using standard ureteral catheters.

De Nunzio C, Nacchia A, Lombardo R, et al. Safety evaluation of sequential Mitomycin and Bacillus Calmette-Guérin treatment versus Bacillus Calmette-Guérin monotherapy in patients with high risk non-muscle invasive bladder cancer: MITOBCG study (EUDRACT Number 2017-004540-37) preliminary results.Presented at: 36th Annual European Association of Urology Congress; July 8-12, 2021; virtual. Abstract P0447.

Sequential combination therapy in bladder cancer (MITOBCG). ClinicalTrials.gov. Updated December 31, 2018. Accessed July 10, 2020. 

https://clinicaltrials.gov/ct2/show/NCT03790384

“Sequential Mitomycin/BCG Combo Shows Preliminary Safety in High-Risk NMIBC”

Preliminary study results recently presented at the 2021 European Association of Urology Congress demonstrate that the safety profile of the combination of Bacillus Calmette-Guérin (BCG) and mitomycin is comparable to BCG alone. 

 Preliminary Results Show Novel Combo Appears Safe in High-Risk Non-Muscle-Invasive Bladder Cancer

New FDA approval means that pediatric and adult patients with acute lymphoblastic leukemia (ALL) and lympoblastic lymphoma who are allergic to the E. coli-derived asparaginase products, are now able to be treated with asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) as part of a chemotherapy regiment.

The approval of Rylaze is supported by a study of 102 patients who either had a hypersensitivity to E. coli-derived asparaginases or experienced silent inactivation, results of which showed that the recommended dose of Rylaze provided the target level of asparaginase activity in 94% of patients.

"It is extremely disconcerting to patients, families and providers when there is a lack of access to critical drugs for treatment of a life-threatening, but often curable cancer, due to supply issues," said Gregory Reaman, MD, associate director for pediatric oncology in the FDA's Oncology Center of Excellence. "Today's approval may provide a consistently sourced alternative to a pivotal component of potentially curative therapy for children and adults with this type of leukemia."

The review of Rylaze was conducted under Project Orbis, which is conducted through the FDA's Oncology Center of Excellence, which allows for concurrent submission and review of oncology agents across global regulatory agencies. In this review, the FDA collaborated with Health Canada. The application review for Rylaze in Canada is currently pending.

Previously, the only other FDA-approved drug for patients who have these allergic reactions has been in a global shortage since 2016, the agency stated. Each year, ALL occurs in approximately 5700 patients; about half of these are children, in which ALL is the most common type of pediatric malignancy.

Asparaginase, which is 1 component of the chemotherapy regimen, kills cancer cells by depriving them of substances that are necessary for survival. Approximately 20% of patients are allergic to the standard E. coli-derived asparaginase, and therefore require need an alternative treatment.

Regarding safety, the most common adverse effects associated with Rylaze include hypersensitivity reactions, pancreatic toxicity, blood clots, hemorrhage, and liver toxicity.

FDA Approves Component of Treatment Regimen for Most Common Childhood Cancer. News release. FDA. June 30, 2021. Accessed June 30, 2021. https://prn.to/3xe7rbi

“FDA Approves Rylaze for Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma”

The FDA has approved asparaginase erwinia chrysanthemi (recombinant)-rywn (Rylaze) as a complement of treatment for the most common childhood cancer. 

FDA Approves Rylaze as Alternative for Patients with ALL and Lymphoblastic Lymphoma 

In addition to the ongoing trials’ population of patients with minimal residual disease (MRD)- positive disease, a phase 1 study (NCT04310592) of CYNK-001 will now include patients with relapsed/refractory acute myeloid leukemia (AML) following a case of conversion to MRD negativity at its highest dose level, according to Celularity, a clinical-stage biotechnology company.

The study will continue to evaluate the effects of the off-the-shelf cell therapy. 

-negative AML who had received 5.4 billion CYNK-001 cells, did not experience a dose-limiting toxicity (DLT), and converted from MRD-positive disease to MRD-negative disease upon assessment. The patient also had good-risk cytogenetics.

After primary induction treatment with 7+3 chemotherapy failed, the patient received second induction treatment followed by high-dose cytarabine consolidation. The patient experienced a complete clinical response (CR); however, the MRD was persistent and did not clear after 4 months of azacitidine; MRD was confirmed on a marrow biopsy.

The patient then entered on the phase 1 trial and received lymphodepletion before receiving 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, totaling to 5.4 billion CYNK-001 cells. On day 28, the patient not only had confirmed conversion from MRD-positive to MRD-negative disease, but CYNK-001 cells were present in both the peripheral blood and bone marrow.

“The absence of DLT to date in the phase 1 trial enables us to continue with our scheduled dose escalation and to expand the trial to include patients with [relapsed/refractory] AML,” said Robert J. Hariri, MD, PhD, founder, chairman, and CEO of Celularity. “In addition, the demonstrated ability to deliver a total [natural killer] cell dose of 5.4 billion cells in the outpatient setting without DLT and the observation of achieving a conversion from an MRD-positive to MRD-negative state on bone marrow examination with CYNK-001 cells persisting in bone marrow and blood at 28 days after day 0 infusion, is compelling and supports our trial dose escalation and indication expansion.”

To date, no DLTs have been observed at any of the dose levels, including the total dose levels of 1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cells on days 0, 7, and 14, respectively, the company noted.

Celularity is developing off-the-shelf allogeneic therapies that are derived from postpartum human placenta. CYNK-001 is an allogeneic unmodified natural killer (NK) cell being investigated in solid and hematologic malignancies, as well as infectious diseases. The cryopreserved allogeneic off-the-shelf cell therapy is enriched for CD56+/CD3– NK cells that are expanded from human placental CD34+ cells.

In the open-label, multi-dose, phase 1 trial, investigators are evaluating the maximum-tolerated dose (MTD) or maximum-planned dose of CYNK-001 in an estimated 22 patients with AML.2 The estimated completion date of the trial is January 3, 2022.

To be eligible for enrollment, patients must have primary or secondary AML who are in first of second morphological CR, morphological CR with incomplete hematologic recovery, or morphologic leukemia-free state as defined by the European LeukemiaNet recommendations for AML Response Criteria. Additional eligibility criteria include MRD positivity, between the ages of 18 and 80 years old, an ECOG performance status of 2 or lower, and the ability to be off immunosuppressive therapy for at least 3 days prior to CYNK-001 infusion.

Prior central nervous system involvement is permitted if it was treated, and cerebral spinal fluid is clear for at least 2 weeks prior to start of lymphodepletion.

Those who have any significant medical conditions that would prevent them from participating on the trial, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, inadequate organ function, autoimmune disease, and uncontrolled graft-vs-host disease or GVHD requiring corticosteroids, among other factors, were excluded from enrollment.

Patients are administered cyclophosphamide and fludarabine followed by CYNK-001 at 3 varying dose levels on days 0, 7, and 14. The primary end points of the trial are the number of patients who experience a DLT, MTD, and frequency and severity of adverse effects. Secondary outcome measures include the number of patients who convert from MRD positivity to negativity, time to and duration of MRD response, progression-free survival, time to progression, duration of morphologic complete remission, and overall survival.

In their announcement, Celularity noted that it intends to continue dose escalation in the MRD indication to a total 9.0 billion CYNK-001 cells in addition to expanding the study to include those with relapsed/refractory AML.

To enhance the persistence of CYNK-001 therapy, the trial’s expansion arms of MRD and relapsed/refractory AML will comprise an augmented lymphodepletion protocol of 3600 mg of cyclophosphamide and 120 mg of fludarabine given over the course of 4 days compared with 900 mg of cyclophosphamide and 75 mg of fludarabine over 3 days. The dosing schedule analysis is used as a method to increase post-lymphodepletion interleukin (IL)-15 levels and to also add subcutaneous IL-2.

Celularity announces expansion of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) phase 1 trial in patients with acute myeloid leukemia. News release. Celularity. June 29, 2021. Accessed June 29, 2021.

Natural killer cell (CYNK-001) infusions in adults with AML (CYNK001AML01). ClinicalTrials.gov. Updated March 2, 2021. Accessed June 29, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04310592

This article was originally published on OncLive as “

Phase 1 CYNK-001 Trial Expands to Include Relapsed/Refractory AML Population

The efficacy of CYNK-001 will now be studied with patients with relapsed/refractory AML.

 Patients With Relapsed/Refractory AML to Be Included in Phase 1 CYNK-001 Trial 

on the phase 2 CodeBreaK100 trial (NCT03600883) reported continued durable clinical benefit with Sotorasib (Lumakras) in the treatment of KRAS p.G12C-mutated non-small cell lung cancer (NSCLC).

At a median follow-up of 15.3 months, sotorasib was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]), a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2), and an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%), which included 4 complete responses (CRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9–NE).

“This makes sotorasib the first KRAS G12C inhibitor to demonstrate an OS benefit in a registrational phase 2 clinical trial,” Ferdinandos Skoulidis, MD, PhD, lead study author and assistant professor in the Department of Thoracic and Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a presentation during the meeting. “The efficacy of sotorasib was observed across various patient subgroups prespecified by baseline patient characteristics.”

Additionally, sotorasib had activity in molecularly-defined subgroups from exploratory analyses within the study, including in those with 

-mutant tumors remain poor, and novel therapies are needed for those who progress on frontline therapy with checkpoint inhibition alone or with platinum-doublet chemotherapy, Skoulidis said.

Sotorasib is a first-in-class, irreversible, and selective KRAS G12C inhibitor that has demonstrated durable clinical benefit in previously treated patients with 

 p.G12C-mutant NSCLC. Based on earlier findings of CodeBreaK, the FDA approved sotorasib in May 2021 as the first treatment for adult patients with non–small cell lung cancer whose tumors harbor 

 G12C mutations and who have received at least 1 prior systemic therapy.3

With the longer follow-up of the phase 2 CodeBreaK100 trial, investigators presented updated efficacy and safety data, including mature OS, with a data cutoff date of March 15, 2021. The findings also incorporated data from biomarker subgroups and baseline characteristics.

In the phase 2 CodeBreaK100 trial, investigators enrolled 126 patients with locally advanced or metastatic NSCLC with a 

 p.G12C mutation as assessed by central testing of tumor biopsies to receive sotorasib orally at 960 mg once daily until disease progression. Patients with stable brain metastases were permitted.

Sotorasib produced continued durable clinical benefit in patients with pretreated KRAS p.G12C+ NSCLC.  

Gina Mauro

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FDA Approves Rylaze as Alternative for Patients with ALL and Lymphoblastic Lymphoma

Patients With Relapsed/Refractory AML to Be Included in Phase 1 CYNK-001 Trial

Sotorasib Produces Durable Clinical Benefit in Treatment of KRAS p.G12C + NSCLC

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