High tumor mutational burden (TMB-H) was associated with high response rates to the single-agent dostarlimab-gxly (Jemperli) among patients with endometrial cancer. This response was consistent across mismatch repair (MMR) and microsatellite stability (MSI) status, suggest findings from a post-hoc analysis of the phase 1 GARNET trial (NCT02715284) presented during the 2021 ESMO Congress.

Dostarlimab elicited an overall response rate (ORR) of 44.9% (95% CI, 34.8%-55.3%) in patients with TMB-H status (n = 44/98) vs 13.0% (95% CI, 8.1%-19.3%) in those with TMB-low (TMB-L) status (n = 20/154).

In those with TMB-H and mismatch repair deficient (dMMR)/microsatellite instability­–high (MSI-H) status (n = 39/87), the ORR with the agent was 44.8% (95% CI, 34.1%-55.9%) vs 23.1% (95% CI, 5.0%-53.8%) in those with dMMR/MSI-H and TMB-low status (n = 3/13). In those with TMB-H status and mismatch repair proficient (MMRp)/microsatellite stable (MSS) disease, the ORR with the agent was 45.5% (95% CI, 16.7%-76.6%) vs just 12.1% (95% CI, 7.2%-18.6%) in those with TMB-L status and MMRp/MSS disease (n = 17/141).

“Notably, the ORR [experienced by] patients with MMRp and TMB-H endometrial cancer was comparable to the ORR of those with TMB-H and dMMR/MSI-H [disease],” lead study author Ana Oaknin MD, principal investigator of Vall d'Hebron Institute of Oncology’s Gynecological Malignancies Group, noted in a poster presentation on the data. “TMB-H status in patients with MMRp endometrial cancer was not due to MSI-H or POLe-mutated status.”

Dostarlimab is a humanized PD-1 monoclonal antibody that blocks interaction with the PD-1 ligands, PD-L1, and PD-L2. In April 2021, the FDA granted an accelerated approval to the agent for use as a monotherapy in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after a platinum-containing regimen.

 in the European Union to be used as a single agent in patients with dMMR/MSI-H endometrial cancer that has progressed on or following a platinum-containing regimen.

Both of the regulatory decisions were based on data from the single-arm phase 1 GARNET trial, which evaluated dostarlimab monotherapy in multiple tumor types, including 2 cohorts of patients with endometrial cancer.

TMB has been previously studied as a predictor of response to anti–PD-1 therapy, but data in endometrial cancer are limited. As such, in the analysis, investigators sought to examine the antitumor activity of dostarlimab in patients with dMMR/MSI-H or MMRp/MSS endometrial cancer by TMB status.

The GARNET study was conducted in multiple parts, with part 1 serving as the dose-finding portion, and part 2A comprised of a fixed-dose safety run-in. Part 2B of the study included expansion cohorts of patients with dMMR/MSI-H (cohort A1; n = 129) and MMRp/MSS endometrial cancer (cohort A2; n = 161).

To be eligible for enrollment on cohorts A1 and A2, patients must have progressed on or after platinum doublet therapy, have received 2 or fewer prior lines of treatment for recurrent or advanced disease, and had measurable disease at baseline. Patients also needed to be naïve to anti–PD-L1 agents.

Patients could be screened based on local MMR/MSI testing results through the use of immunohistochemistry (IHC), polymerase chain reaction, or next-generation sequencing (NGS) performed in a certified local laboratory. However, patient cohort assignment was based on MMR IHC results.

Study participants received 500 mg of intravenous (IV) dostarlimab every 3 weeks for 4 cycles, and then 1000 mg every 6 weeks thereafter, until disease progression.

The primary end points of the study were ORR and duration of response per RECIST v1.1 criteria and blinded independent central review (BICR).

In the post-hoc analysis, and TMB status was an exploratory biomarker determined using the Foundation One test. TMB-H status was defined as having 10 or more mutations/megabase, and TMB-L status was defined as having less than 10 mutations/megabase.

As of a data cutoff date of March 1, 2020, a total of 129 patients with dMMR/MSI-H endometrial cancer and 161 patients with MMRp/MSS disease were enrolled and received treatment with dostarlimab. These populations comprise the safety populations of cohorts A1 and A2, respectively.

The primary efficacy population included those with 24 weeks or more of follow-up time in the study, and who had at least 1 measurable lesion at baseline, per BICR. Overall, 105 patients with dMMR/MSI-H disease and 156 patients with MMRp/MSS disease were evaluable for the analysis.

The median age of patients was 64 years (range, 30-86). Most patients with dMMR/MSI-H status had FIGO stage I or II disease at primary diagnosis (54.3%); the majority of those in the MMRp/MSS cohort had FIGO stage III or IV disease (62.8%). In terms of histology, most patients in cohort A1 presented with endometrioid carcinoma grade 1/2 (67.6%), and most patients in cohort A2 presented with serous disease (37.8%). In both cohorts A1 and A2, the majority of patients had a least 1 prior line of therapy (62.9% and 46.2%, respectively) and had received prior radiation (70.5% and 60.9%, respectively).

Among those with dMMR/MSI-H endometrial cancer (n = 105), 82.9% (n = 87) had TMB-H status, 12.4% (n = 13) had TMB-L status, and 4.8% (n = 5) had TMB status that could not be determined. For those with MMRp/MSS disease (n = 156), 90.4% (n = 141) had TMB-L status, 7.0% (n = 11) had TMB-H status, and 2.6% (n = 4) had TMB status that could not be determined.

The median number of mutations/megabase in patients with dMMR/MSI-H endometrial cancer (n = 100) was 20.17 (range, 2.52-428.69), compared with 3.78 (range, 0-83.22) in those with MMRp/MSS disease (n = 152).

The data cutoff date for the prespecified interim analysis was March 1, 2020, and additional data showed that TMB-high status and dMMR/MSI-H status had substantial overlap in the patient populations, and TMB-H endometrial cancers and dMMR/MSI-H endometrial cancers experienced similar response rates with dostarlimab, at 44.9% and 44.8% (n = 47/105; 95% CI, 35.0%-54.8%), respectively.

Moreover, the ORR achieved with the agent in patients with MMRp disease and TMB-H status was notably comparable to that ORR experienced by those with dMMR/MSI-H and TMB-H status, at 45.5% and 44.8%, respectively.

“Of the 11 patients with MMRp/TMB-H endometrial cancer, all had MSI and POLe test results available,” Oaknin said. “One patient was MSI-H, according to Foundation Medicine NGS testing, and 1 patient had an intermediate MSI score; 9 were MSS. None of the 11 patients had a POLe exonuclease domain mutation identified.”

The study was not powered to assess antitumor activity by TMB status, and interpretation is limited by the small number of patients in each subgroup, Oaknin concluded.

Oaknin A, Gilbert L, Tinker AV, et al. Analysis of antitumor activity of dostarlimab by tumor mutational burden (TMB) in patients (pts) with endometrial cancer (EC) in the GARNET trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 76P.

FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. April 22, 2021. Accessed September 16, 2021. 

European Commission approves GSK’s Jemperli (dostarlimab), the first anti-PD-1 therapy approved for recurrent or advanced endometrial cancer. News release. GlaxoSmithKline, April 23, 2021. Accessed September 16, 2021. 

Articles

Patients with endometrial cancer and high tumor mutational burden experienced superior overall response rates to the agent dostarlimab than patients with low mutational burden. 

Dostarlimab Elicits Superior Responses in Patients with High Mutational Burden in Endometrial Cancer

For this episode of “The Vitals,” we spoke with Chastity Washington, MPH, CHES, Center for Cancer Health Equity, Ohio State University, about how the COVID-19 pandemic has exacerbated preexisting disparities in cancer care. Chastity spoke to our team about the direct and indirect impacts of COVID 19 on disadvantaged communities, vaccine hesitancy amongst those communities, and more.

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“We’ve had periods of time where things were shut down. We do have telemedicine, that was expanded, but telemedicine doesn’t work for everyone. If you don’t have internet access, if you don’t have the ability to understand the technology….”


COVID-19 Pandemic Emphasizes Disparities in Cancer Care

Lindsay Fischer is the Associate Editor at ONN. She joined MJH life sciences in 2021 after graduating from Rutgers University with majors in both English and Spanish and a minor in creative writing. When she is not writing, or researching the latest oncology nursing news, Lindsay is an amateur backpacker and rollerblader. Email Lindsay at lfischer@mjhlifesciences.com

Darolutamide (Nubeqa) demonstrated a similar safety profile as placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) continuing androgen-deprivation therapy (ADT), with comparable adverse event (AE) onset and occurrence rates, according to results from the ARAMIS trial presented during a poster presentation at the virtual 2021 ESMO Congress.

In the ARAMIS trial (NCT02200614), there was only a ≤2% difference in AE incidence of interest between the experimental and placebo group, and severity was low for both arms across 24 months. Fatigue was the only exception, with 12.6% of the darolutamide group who experienced the AE.

Notably, the incidence of rash was very low and nearly all cases of fatigue were reported early on in treatment. Most events were grade 1 or 2. The investigators noted that 

darolutamide poses a particular significance

 to the overall wellbeing of men with nmCRPC, given their potentially prolonged treatment time.

“Men with nonmetastatic castration-resistant prostate cancer are generally asymptomatic and may receive prolonged treatment with androgen receptor inhibitors (ARIs),” Christian Gratzke, MD, professor and chair in the Department of Urology at the Albert-Ludwigs-University in Freiburg, Germany, explained in a corresponding abstract presented alongside the poster. “Understanding the burden and time course of adverse events commonly associated with ARIs that may impact patients’ daily life will help inform optimal treatment selection for men with nmCRPC.”

Researchers analyzed the AEs most associated with antigen receptor inhibitors to provide patients with optimal treatment selection information. Kaplan-Meier estimates were utilized to analyze the incidence of AEs across the first 24 months. Time interval-specific analysis determined new event rates per each scheduled study visit.

Participants were randomized 2:1 to either receive darolutamide or placebo while continuing treatment with androgen deprivation therapy. The darolutamide group included 995 men, while the placebo group included 554.

Observed AEs across the darolutamide and placebo arms, respectively, included falls (0.2% vs 0.7%), fractures (0.4% vs 0.5%), mental impairment (0% vs 0.4%), hypertension (1.7% vs 1.1%), and rash (0.7% vs 0.2%).

Fatigue was reported by 12.6% of the men who received darolutamide, and by 8.3% of the placebo arm. Nearly half of all men who reported fatigue experienced it during the first month (5.9% vs 4.0%, respectively). The total rash incidences was 2.9% by 24 months. Half of all reported cases of rash appeared in the first 4 months, and almost all were grade 1 or 2. Serious AE incidence and initial onset were similar between the 2 groups.

Fatigue was shown to increase in cumulative incidence over time. In comparison, falls and fractures were mostly reported in the first month of treatment.

Hypertension onset was not specific to time interval. The number of cumulative incidences reported were similar across treatments. Although mental impairment was rare (<1% per treatment group), incidence occurrence was consistent across both groups.

While most cases of rash were grade 1 or 2, there were 2 patients who reported a grade 3 rash from the darolutamide group, and 1 patient who reported a grade 3 rash from the placebo group.

“The findings from this analysis confirm the safety profile of darolutamide showing a low incidence in a similar onset and cumulative incidence versus placebo,” Gratzke concluded.

Gratzke CJ, Fizazi K, Shore ND, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial. Presented at: 2021 European Society Medical Oncology Congress; September 16-21, 2021’ Virtual. Abstract 630P.

Patients with nonmetastatic castration-resistant prostate cancer often undergo prolonged treatment periods, making the safety profile of therapies like darolutamide an important factor in optimum treatment selection. 

Addition of Darolutamide to ADT Shows Comparable Safety Profile Among Patients With nmCRPC

Yoga can promote an improved quality of life among patients with prostate cancer, show phase 2 trial findings presented at the 2021 AUA Annual Meeting. In addition, the meditative activity may result in antitumor immune responses and reduced inflammation in patients undergoing prostatectomy.

Yoga has a direct effect on the vagus nerve, which can shape how a person thinks, remembers, and feels. And patients with prostate cancer have a 20% to 30% incidence and prevalence of depression and anxiety.

In previous studies, yoga has demonstrated an improved quality of life for patients with cancer, as well as lower inflammation. Additionally, newer, emerging data has demonstrated that mindfulness exercises, such as yoga, can cause the frontal and limbic parts of the brain to structurally change.

“However, if you look at hierarchy of evidence, most data on immune benefits of yoga is from small series and case reports, no such data exists for prostate cancer. Given these findings of improvement in quality of life with yoga, we started looking at [the] role of yoga in prostate cancer,” said Dharam Kaushik, MD, associate professor in the department of urology at the University of Texas Health, San Antonio, during the presentation of the data.

The primary outcomes of this clinical trial [NCT02620033] was self-reported outcomes of quality of life at baseline, and 6 weeks. Secondary outcomes included immune cell status and cytokine levels, also at baseline and 6 weeks.

“We wanted to evaluate the quality of life from multiple vantage points, therefore we utilized 4 different quality of life questionaries,” Kaushik mentioned. Self-reported outcomes were assessed by the Expanded Prostate Index Composite (EPIC), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Five Facets of Mindfulness Questionnaire (FFMQ).

The study consisted of 30 men who were newly diagnosed with localized prostate cancer and scheduled for a radical prostatectomy. Patients were randomized to either yoga (n = 15) or standard of care (n = 15). And patients in the yoga group, performed the activity for 60 minutes twice a week for 6 weeks before their prostatectomy and 3 to 6 weeks after.

Yoga “meaningfully” improved EPIC-sexual scores, FACIT-F, FACT general and FACT-P. In substratification, there were improvements in sexual, physical, and social well-being in the yoga group.

Additionally, participants in the yoga group demonstrated increased numbers of CD4+ (

There was also an increase in the natural killer cells IFNNK (

 = .041), “indicating a robust immune response,” Kaushik added.

Yoga also had an enhanced effect on antitumor activity, decreasing the numbers of regulator T-cells and myeloid-derived suppressor cells: CD11b+CD33+ (

There was also a decrease in cytokine cells including, G-CSF (

 = .032), which had shown to activate production endothelial cell and cytokines. Additionally, there was a decrease in MCP-1 (

 = .044), which are associated with proception against dementia, and FLt-3L (

 = .053) which has been linked to reducing chronic inflation, Kaushik mentioned.

The benefits demonstrated in this study require further investigation, the authors concluded in the abstract.

Kaushik D, Shah P, Mukherjee N, et al. A phase 2 randomized clinical trial of yoga in men with prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-03.

Yoga has a positive impact on the vagus nerve, which influences how people think, remember, and feel, and therefore can improve the mental well-being of patients with prostate cancer. 

Yoga Encourages Antitumor Response, Boosts Quality of Life in Patients with Prostate Cancer 

The FDA has approved mobocertinib (Exkivity) for the 

indication of adult patients with locally advanced or metastatic non-small cell lung cancer

 (NSCLC) whose disease harbors an epidermal growth factor receptor (EGFR) exon 20 insertion mutation as detected by an FDA-approved test, either following or beyond platinum-based chemotherapy.

This first-in-class, oral tyrosine kinase inhibitor (TKI) is the first approved oral therapy engineered to target EGFR exon 20 insertion mutations, according to Takeda Pharmaceutical Company Limited, the manufacturer of the small-molecule TKI.

“EGFR Exon20 insertion+ NSCLC is an underserved cancer that we have been unable to target effectively with traditional EGFR TKIs,” said Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute, in a press release. “The approval of EXKIVITY (mobocertinib) marks another important step forward that provides physicians and their patients with a new targeted oral therapy specifically designed for this patient population that has shown clinically meaningful and sustained responses.”

The regulatory decision is based on findings from the phase 1/2 trial of Exkivity. In the trial, 114 patients with EGFR Exon20 insertions who had been previously treated with platinum-based therapy received mobocertinib at a 160-mg dosage. Findings revealed an overall response rate (ORR) of 28% through an independent review committee (IRC) and 35% through investigator analysis. The median duration of response (DOR) was 17.5 months. The median overall survival (OS) was 24 months, and the median progression-free survival (PFS) was 7.3 months. DOR, OS, and PFS were all determined by IRC.

Notable adverse events from the study drug included diarrhea, rash, nausea, stomatitis, vomiting, decreased appetite, paronychia, fatigue, dry skin, and musculoskeletal pain. Patients and providers should be aware that there is a risk of interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea associated with the drug.

“Patients with EGFR Exon20 insertion+ NSCLC have historically faced a unique set of challenges living with a very rare lung cancer that is not only underdiagnosed, but also lacking targeted treatment options that can improve response rates,” added Marcia Horn, executive director, Exon 20 Group at ICAN, International Cancer Advocacy Network. “As a patient advocate working with EGFR Exon20 insertion+ NSCLC patients and their families every day for nearly five years, I am thrilled to witness continued progress in the fight against this devastating disease and am grateful for the patients, families, healthcare professionals and scientists across the globe who contributed to the approval of this promising targeted therapy.”

A confirmatory trial will determine continued approval for the indication.

Takeda’s Exkivity (mobocertinib) approved by US FDA as the first oral therapy specifically designed for patients with EGFR Exon20 insertion _NSCLC. Takeda. News release. Accessed September 15, 2021. https://www.businesswire.com/news/home/20210915006101/en/Takeda%E2%80%99s-EXKIVITY%E2%84%A2-mobocertinib-Approved-by-U.S.-FDA-as-the-First-Oral-Therapy-Specifically-Designed-for-Patients-with-EGFR-Exon20-Insertion-NSCLC

The FDA has green lit mobocertinib for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with an EGFR exon 20 insertion mutation. 



FDA Approves Mobocertinib for NSCLC with EGFR Exon 20 Insertion Mutations

Patients with progressed multiple myeloma experienced deep and durble responses through CAR T-cell therapy ciltacabtagene autoleucel therapy. 


Cilta-cel CAR T-Cell Therapy May Satisfy Need For Deeper Treatment Responses in Multiple Myeloma 

Patients with chronic lymphocytic leukemia (CLL) are at an increased risk for infection. 

Infection Control a Necessity in Treating CLL

Zanubrutinib received an accelerated approval for the indication of adults with marginal zone lymphoma with at least 1 prior treatment with an anti-CD20-based therapy. 



FDA Approves Zanubrutinib To Treat Patient With Marginal Zone Lymphoma

Treating patients with myeloproliferative neoplasms in accelerated phase (MPN-AP) remains an ongoing challenge as there are still no standard therapeutic approaches, says an expert.

Myeloproliferative Neoplasms in Accelerated Phase Continue to Present as Treatment Challenge

Updates from the ongoing S1619 trial suggest that a triplet combination regimen of neoadjuvant cisplatin, pemetrexed, and atezolizumab is effective and tolerable in the treatment of patients with resectable pleural mesothelioma. 

Neoadjuvant Triplet Regimen Safe, Effective in Patients With Resectable Mesothelioma

Due to the favorable efficacy and safety profiles of daratumumab plus lenalidomide and dexamethasone, researchers speculate that the combination may become the new standard of care in multiple myeloma treatment. 

Daratumumab-Lenalidomide-Dexamethasone Combination May Become Preferred Treatment for Newly Diagnosed Multiple Myeloma 

Researchers identified a slower rate of health-related quality of life deterioration, as well as an ability to postpone locally invasive procedures, in patients with nonmetastatic castration-resistant prostate cancer who received darolutamide. 

Darolutamide Postpones Need For Procedure, Slows Down Quality of Life Deterioration in Patients with nmCRPC

Patients with myeloma and a negative MRD may be at a reduced risk of mortality and other progression-free survival events. 

Minimal Residual Disease May Anticipate Outcomes in Myeloma Following Stem Cell Transplant

Patients with both COVID-19 and malignant pleural mesothelioma showed high rates of hospitalization and mortality. 

Study Identifies High Mortality Rates in Patients with COVID-19 and Malignant Pleural Mesothelioma 

While survival rates in T-cell acute lymphoblastic leukemia remain around 90%, researchers are optimistic that the use of targeted therapies and immunotherapies will continue to improve treatment options.  

Targeted Therapies Continue to Improve OS in T-Cell Acute Lymphoblastic Leukemia

International lung cancer clinical trial sites reported that flexibilities in time and place were effective strategies to mitigate COVID–19-related patient concerns and to increase participation. 

Modified Monitoring Requirements, Telehealth Increase Lung Cancer Clinical Trial Enrollment in COVID-19 Era

Selectively targeting the EGFR exon insertion mutations was associated with improved outcomes in patients with previously treated non-small cell lung cancer. 



Patients Report Improved Outcomes Following Mobocertinib Treatment for NSCLC Subtype

Chronic graft-versus-host disease management has continued to advance in recent years, with new and anticipated treatment options for its treatment landscape. 



Advancements in cGVHD Yield New and Anticipated Treatment Options

After the 3-arm, JAVELIN Ovarian 100 trial terminated at the interim analysis, researchers concluded that avelumab is not yet a suitable first-line treatment option for patients with advanced epithelial cancer. 

Study Results Advise Against Avelumab Maintenance Therapy in Endometrial Cancer Treatment

Stephanie Jackson, DNP, MSN, RN, AOCNS, BMTCN, discusses her recent School of Nursing Oncology presentation. 

Top Medical News

Dostarlimab Elicits Superior Responses in Patients with High Mutational Burden in Endometrial Cancer

COVID-19 Pandemic Emphasizes Disparities in Cancer Care

Addition of Darolutamide to ADT Shows Comparable Safety Profile Among Patients With nmCRPC

Yoga Encourages Antitumor Response, Boosts Quality of Life in Patients with Prostate Cancer

FDA Approves Mobocertinib for NSCLC with EGFR Exon 20 Insertion Mutations

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