Kevin Wright

Roughly 40% of patients with advanced, progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with pembrolizumab (Keytruda) in combination with lanreotide (Somulatine Depot) achieved stable disease, according to results from the phase 1b/2 PLANET clinical trial presented during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.

“Pembrolizumab has antitumor activity in a subset of GEP-NETs patients,” wrote the investigators. “We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEP-NETs," wrote the author led by Michael Morse, MD, of Duke Cancer Center.

In the PLANET study (NCT03043664), 22 patients with GEP-NETs who received a median of 2 prior systemic therapies (range 1-9) were treated with 90 mg of lanreotide and 200 mg of pembrolizumab every 3 weeks until disease progression or intolerable toxicity. A median of 6 doses of pembrolizumab (range, 2-15) and 7 doses of lanreotide (range, 2-15) were administered.

Median age at the time of enrollment was 60.9 years (range, 51.1-82.0). Twelve of the patients were male, and 10 were female. To be eligible for the study, participants were required to have 

A diagnosis of non-resectable, recurrent, or metastatic well- or moderately-differentiated GEP-NETs with disease progression in the last 12 months, received prior somatostatin analogue therapy, a minimum of 1 measurable lesion based on RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a tumor mitotic rate of ≤20/10 hpf and/or Ki67 index ≤20%.

Fourteen patients (63.6%) had tumors located within the gastrointestinal tract, of whom 8 patients (36.4%) had their primary tumor site located in the pancreas. The median time since diagnosis for all patients was 5.3 years, with 6 patients having received prior locoregional therapy and 3 patients receiving prior external beam therapy. Of the 12 tumors that were analyzed, 4 had detectable PD-L1 expression and 11 had tumor infiltrating lymphocytes.

The primary end point of the study was overall response rate (ORR), measured according to RECIST 1.1 criteria. Thirty-nine percent of patients showed stable disease (SD) and 52% of patients had progressive disease (PD). ORR, as measured by irRECIST to better assess the effect of immunotherapeutic agents, was 43% SD, 48% PD, with 9% of patients not evaluable.

Secondary end points were progression-free survival (PFS) and overall survival (OS). The median PFS was 5.4 months (95% CI, 1.7-8.3) and median OS at a median follow-up of 15 months was not reached.

Regarding safety, 6 of the 22 patients (27.3%) experienced treatment-related serious adverse events (AEs) including abdominal pain, pneumonitis, colitis, and hyperglycemia, which were all related to treatment with pembrolizumab. The most common treatment-related AE was hypothyroidism (23%), with other notable treatment-related AEs including colitis (9%), hyperglycemia (14%), and pneumonitis (5%). Three patients (13.6%) discontinued treatment due to AEs. No new safety signals were identified in the study.

Investigators noted that peripheral blood immune analyses were pending and would be reported subsequently.

“Further studies to identify other approaches to increase the immunogenicity of well/moderately differentiated GEP-NETs are required,” concluded the investigators.

Morse M, Halperin DM, Uronis HE, et al. Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET). Presented at: 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. January 15–17, 2021; virtual. Abstract 369.

Articles

Roughly 40% of patients with advanced, progressive gastroenteropancreatic neuroendocrine tumors treated with pembrolizumab in combination with lanreotide achieved stable disease, according to results from the phase 1b/2 PLANET clinical trial presented during the 2021 American Society of Clinical Oncology Gastrointestinal Cancer Symposium.

Pembrolizumab Plus Lanreotide Induces High Response Rates in GEP Neuroendocrine Tumors

Treatment with selinexor (Xpovio), bortezomib, and dexamethasone (SVd) demonstrated an increase in overall response rate (ORR) and progression-free survival (PFS) in patients with multiple myeloma and high cytogenetic risk despite a dosing schedule that utilized 40% less bortezomib and 25% less dexamethasone during the first 24 weeks of treatment, according to a presentation at the 2020 American Society of Hematology Annual Meeting.

“SVd is superior to Vd in patients with multiple myeloma, including high-risk disease, as supported by the progression-free survival in the different subgroups of patients with high-risk cytogenetics,” said Shambavi Richard, MD, of the Icahn School of Medicine at Mount Sinai. “Once weekly SVd is a highly active regimen, and may be an important treatment option for patients with high-risk multiple myeloma,” Richard added.

Of the 402 patients enrolled in the BOSTON study, 192 (48%) had high-risk (SVd, n = 97; Vd, n = 95) and 210 (52%) had standard-risk (SVd, n = 98; Vd, n = 112) cytogenetics. The SVd regimen demonstrated improved PFS relative to Vd in the high-risk (12.9 vs 8.1 months; HR, 0.67; 95% CI, 0.45-0.98; 

 = .0192) and standard-risk (16.6 vs 9.7 months; HR, 0.63; 95% CI, 0.42-0.95; 

 = .0131) groups. Moreover, ORR was significantly improved in the high-risk group (77.3% vs. 55.8%, respectively; 

For this post-hoc analyses, patients were deemed to be of high cytogenetic risk if they were found have at least of the following abnormalities in at least 10% of screened plasma cells:

The SVd regimen improved PFS in all high-risk subgroups except t(14;16), which was the smallest subgroup. Patients with a 17p deletion saw the greatest benefit, with a PFS of 12.22 months for those receiving the SVd regimen, vs 5.91 months for those treated with Vd. Patients with a 17p deletion also saw the greatest benefit in terms of ORR (76.2% vs 37.5%; 

The safety profiles of SVd and Vd in the high-risk and standard-risk groups were consistent with the overall study population. Of note, the rate of grade 2 or lower peripheral neuropathy was lower with SVd compared with Vd in both the high-risk (25.7% vs 35.7%, respectively; 

 = .100) and standard-risk groups (18.4% vs. 33.6%, respectively; 

“Despite recent advances in myeloma, high-risk anomalies such as deletion 17p, translocation 4;14 and translocation 4;16 are still associated with shorter progression-free survival and overall survival relative to those with standard-risk cytogenetic features,” noted Richard, adding “There’s an unmet need for novel therapies to improve outcomes of high-risk cytogenetics in myeloma patients. Selinexor’s novel mechanism [of] reactivating tumor suppressor proteins and reducing levels of oncoproteins may be particularly suited for high-risk disease.”

Richard, S. Once Weekly Selinexor, Bortezomib, and Dexamethasone (SVd) Versus Twice Weekly Bortezomib and Dexamethasone (Vd) in Relapsed or Refractory Multiple Myeloma: High Risk Cytogenetic Planned Subgroup Analyses from the Phase 3 BOSTON Study. Presented at: 62nd American Society for Hematology (ASH) Annual Meeting and Exposition; December 5-8, 2020. Abstract 1385.

Treatment with selinexor, bortezomib, and dexamethasone demonstrated an increase in overall response rate and progression-free survival in patients with multiple myeloma and high cytogenetic risk despite a dosing schedule that utilized 40% less bortezomib and 25% less dexamethasone during the first 24 weeks of treatment.

Selinexor Demonstrates Significant Benefit in Pretreated Multiple Myeloma as Once Weekly Regimen

A significantly longer overall survival (OS) was observed with olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) who had tumors with at least 1 alteration in 

, compared with those who received enzalutamide (Xtandi) or abiraterone (Zytiga) plus prednisone, according to research presented at the 21st Annual Meeting of the Society of Urologic Oncology.

The PROfound study enrolled 387 patients with mCRPC who had disease progression on prior new hormonal agents and an alteration in 1 or more qualifying gene with a direct or indirect role in HRR.

Cohort A was comprised of patients with mutations in 

 and were considered the primary population for the analysis. Cohort B was comprised of patients with all other HRR mutations.

Overall results of the trial were positive, with patients in cohort A demonstrating higher radiographic progression-free survival (PFS; 7.4 mo vs 3.6 mo, respectively; HR 0.34 0.25-0.47, P<0.001), median time to pain progression (HR 0.44 0.22-0.91, P <0.02), and overall survival (19.1 months vs 14.7 mo, HR 0.69 9.50-0.97 P =0.02) than patients in cohort B.

Additionally, 81% of patients who progressed after receiving the control treatment crossed over to the olaparib arm.

“Olaparib is the first targeted therapy to demonstrate a radiographic PFS and OS benefit in phase 3 trials in metastatic castration-resistant prostate cancer patients with HRR mutations, thus really ushering in the era of precision medicine in prostate cancer,” said PROfound investigator Maha Hussain, MD, deputy director, Robert H. Lurie Comprehensive Cancer Center.

Results of the PROfound study, previously published in the 

An exploratory gene by gene analysis showed that the benefit of olaparib varied significantly between patients based on their underlying mutation. Patients with 

 appeared to derive the most benefit, with a median overall survival of 24.8 months (95% CI; 17.4-NC) vs 15.2 months (95% CI; 10.7-19.8) for the control group. Survival benefits were also indicated for patients with 

 mutations (11.7 months vs. 9.4 months, respectively), ATM mutations (18.0 months vs. 15.6 months, respectively), CDK12 mutations (14.1 months vs. 11.5 months, respectively) and RAD54L (19.3 months vs. 5.7 months, respectively).

As a caveat, Hussain noted that gene-level analysis is complex, and results may be confounded by multiple factors.

The gene-level breakdown was the subject of a counterpoint presentation from Daniel Spratt, MD, chair of Genitourinary Clinical Research at the University of Michigan Rogel Cancer Center, who noted that the signal of benefit outside of 

 mutations was not as strong, and that the FDA approval of olaparib may have been too broad.

Despite the practice-changing results of the PROfound trial, Hussain concluded by noting that questions and answers still remained.

“Certainly, there is plenty of work to be done,” Hussain said. “Clearly we have to optimize the timing of therapy in relationship to other life prolonging treatments for castration-resistant disease, develop PARP inhibitor-based combination treatments, evaluate the role of PARP inhibitors in an earlier disease setting, and continue to invest in research to conquer prostate cancer.”

1. Hussain M. New Second Line Therapy for mCRPS:PARPi: Results from PROfound. Presented at 2020 SUO Annual Meeting; December 2-5.

2. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in Metastatic Castration-Resistant Prostate Cancer [published online ahead of print, 2020 Sep 20]. 

. 2020;10.1056/NEJMoa2022485. doi:10.1056/NEJMoa2022485

A significantly longer overall survival was observed with olaparib in patients with metastatic castration-resistant prostate cancer who had tumors with at least 1 alteration in BRCA1, BRCA2, or ATM, compared with those who received enzalutamide or abiraterone plus prednisone, according to research presented at the 21st Annual Meeting of the Society of Urologic Oncology.

Olaparib Treatment Leads to Significant Survival Improvement  in Patients with mCRPC

Enfortumab vedotin (Padcev) monotherapy demonstrated significant long-term results in updated findings from the EV-201 trial (NCT03219333) presented at the 2020 ESMO Virtual Congress.

 At 1 year, half of patients with locally advanced or metastatic urothelial carcinoma treated with enfortumab vedotin were still alive and about one-third were still alive at 18 months. 

Data from cohort 1 of EV-201, a single-arm phase 2 pivotal trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer previously treated with platinum-based chemotherapy and immune checkpoint inhibitors, demonstrated overall survival (OS) rates of 50.4% at 12 months and 34.2% at 18 months, respectively.

The study enrolled 125 patients, with a median age of 69 years and a median of 3 prior systemic treatments. The median follow-up for all patients was 22.3 months (range, 0.5-27.3+), and median OS was 12.4 months (95% CI; 9.46-15.57). Patients received 1.25 mg/kg of enfortumab vedotin intravenously on days 1, 8, and 15 of a 28-day cycle. The median duration of treatment was 4.6 months, with a maximum duration of treatment of 27.3 months (ongoing as of data cutoff).

Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.

FDA previously granted accelerated approval to enfortumab vedotin 

based on data that demonstrated an overall response rate of 44%, which was the primary endpoint of EV-201. That data indicated that 12% of patients experienced complete response, and the median progression-free survival for patients receiving enfortumab vedotin was 5.8 months (95% CI, 4.9-7.5), with a median duration of response of 7.6 months (range, 0.95-11.30).

The most common treatment-related adverse events (AEs) included alopecia (49.6%), fatigue (49.6%), and decreased appetite (44%). The most common treatment-related AEs that were grade 3 or higher included neutropenia (8.0%), anemia (7.2%), and fatigue (6.4%). Twelve percent of patients discontinued treatment due to AEs, with peripheral sensory neuropathy (6%) being the most common. The investigators did report 1 treatment-related death from interstitial lung disease, confounded by high-dose corticosteroid use and suspected 

A confirmatory phase 3 trial, EV-301 (NCT03474107), has completed enrollment. That study will compare OS for patients with locally advanced or metastatic urothelial carcinoma treated with enfortumab vedotin with patients treated with chemotherapy.

1. O’Donnell MD, Galsky JE, Petrylak DP, et al. EV-201: Long-term results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial caner previously treated with platinum and PD-1/PD-L1 inhibitors. Poster presented at: ESMO Virtual Congress 2020; September 19-21, 2020. Abstract 746P.

2. Rosenberg J, Sridhar SS, Zhang J, et al. EV-101: A Phase I Study of Single-Agent Enfortumab Vedotin in Patients With Nectin-4-Positive Solid Tumors, Including Metastatic Urothelial Carcinoma. 

. 2020;38(10):1041-1049. doi:10.1200/JCO.19.02044

Enfortumab vedotin monotherapy demonstrated significant long-term results in updated findings from the EV-201 trial presented at the 2020 ESMO Virtual Congress.

Kevin Wright | Authors

Articles

Pembrolizumab Plus Lanreotide Induces High Response Rates in GEP Neuroendocrine Tumors

Selinexor Demonstrates Significant Benefit in Pretreated Multiple Myeloma as Once Weekly Regimen

Olaparib Treatment Leads to Significant Survival Improvement in Patients with mCRPC

Long-Term Enfortumab Vedotin Results Show OS Benefit in Advanced Urothelial Cancer