Temferon, genetically modified Tie2-expressing monocytes (TEMs) targeting interferon a2 (IFNa2), showed the potential to activate the immune system and reprogram the tumor microenvironment in patients with newly diagnosed glioblastoma (GBM), according to preliminary findings from the phase 1/2a TEM-GBM study (NCT03866109)

“These results provide the initial evidence for on-target activity of Temferon in GBM,” said Bernhard Gentner, MD, study coauthor and the leader of the translational stem cell and leukemia research unit at San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, in a presentation of the findings at the 2022 AACR Annual Meeting.

Temferon is an investigational advanced therapy consisting of autologous CD34+ enriched hematopoietic stem and progenitor cells exposed to transduction with a lentiviral vector, driving myeloid-specific IFNa2 expression. Genetically modified TEMs target IFNa2 expression in the GBM tumor microenvironment.

“In order to guarantee stable delivery of genetically engineered TEMs into the tumor, we transduce hematopoietic stem and progenitor cells with a lentiviral vector carrying the IFNa2 transgene transcriptionally regulated by the Tie2 promoter and by post transcriptional elements that guarantee that the transgene is expressed only in myeloid cells that are recruited into the tumor,” Gentner said.

TEM-GBM is an open-label, dose-escalation study evaluating the safety and efficacy of Temferon in up to 21 newly diagnosed patients with GBM harboring an unmethylated MGMT promoter. Following surgical resection, up to 15 patients were assigned to 1 of 3 escalating doses of Temferon and 1 of 2 different conditioning regimens in part A of the trial. In Part B, 6 more patients will receive a single dose of Temferon at the recommended phase 2 dose.

Following completion of radiotherapy, patients received a conditioning regimen consisting of carmustine (BCNU) and thiotepa (Tepadina) in cohorts 1 to 4 or busulfan (Busulfex) and thiotepa in cohort 5 prior to administration of Temferon.

In-patient monitoring occurs until hematological recovery, then patients will undergo regular follow-up for up to 720 days. At that point, patients are invited to participate in a long term follow-up study for an additional 6 years.

Eligible adults aged 18 to 70 years must have an ECOG performance score of 0 to 1, a Karnofsky performance score greater than 70%, and adequate cardiac, renal, hepatic, and pulmonary function. Patients with active autoimmune disease or who have received any oral or parenteral chemotherapy or immunotherapy within 2 years of screening are excluded.

The primary end points of the study are Temferon engraftment over the first 90 days, proportion of patients achieving hematologic recovery 30 days after autologous stem cell transplantation, and short-term tolerability of Temferon as defined by stable blood counts, absence of cytopenias, absence of significant organ toxicities greater than grade 2, and absence of Replication Competent Lentivirus.

By the October 15, 2021, data cutoff, the median follow-up was 267 days (range: 60-749). Patients in cohorts 1 to 3 received a dose 0.5-2.0 x 106/kg Temferon with an average vector copy number of 0.70 and a transduction efficiency of 54%. Those in cohorts 4 and 5 received 2.0 x 106/kg Temferon with an average vector copy number of 0.77 and a transduction efficiency of 49%.

Investigators observed increasing proportions of Temferon-derived differentiated cells, as determined by the presence of vector genomes in the DNA of peripheral blood and bone marrow cells, reaching up to 30% at 1 month in the highest treatment cohort (2.0 x 106/kg). Those differentiated cells persisted at lower levels for up to 18 months.

 Temferon engraftment,” Gentner said. “Engraftment was highest at 1 month, and in many patients resembled pretty much the input fraction. …Engraftment then decreased, stabilizing at 3 to 6 months around 10%.

“Despite the significant proportion of engineered cells, only very low-medium concentrations of interferon alpha were detected in the plasma and in the cerebral spinal fluid, indicating a tight regulation of the vector expression.”

Gentner added that Temferon did not delay hemopoietic recovery, and neutrophil and platelet engraftment were similar to standard autologous stem cell procedure.

Investigators did not detect any dose limiting toxicities. Gentner said that, so far, adverse events have been related to progression or the transplant procedure, not to the IFNa2 itself.

Gentner B, Finocchiaro G, Farina F, et al. Genetically modified Tie-2 expressing monocytes target IFN-α2 to the glioblastoma tumor microenvironment (TME): Preliminary data from the TEM-GBM Phase 1/2a study. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract 5213.

Articles

Preliminary findings from the phase 1/2a TEM-GBM study highlight the potential utility of temferon, genetically modified Tie2-expressing monocytes targeting interferon a2 in treating patients with glioblastoma. 

Temferon Is a Viable Treatment Option in Newly Diagnosed Glioblastoma 

The addition of the innate cell engager AMF13 to preactivated and expanded natural killer (NK) cells may represent an effective treatment for pretreated patients with advanced lymphoma, according to findings from a phase 1/2 study (NCT04074746) that were presented during the 2022 AACR Annual Meeting. 

Results showed that patients experienced a median overall response rate (ORR) of 89.5% (n = 17/19). Overall, 10 patients experienced complete responses (CRs) and 7 experienced partial responses (PRs).

Lead author Yago Nieto, MD, PhD, a professor of medicine in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, in Houston, discussed the findings during a press conference during the meeting. He said the study team was pleasantly surprised by the quality of tumor responses in patients with resistant lymphomas.

“This is the first clinical trial using off the shelf cord blood-derived cytokine-induced memory-like 

 expanded NK cells precomplexed with the innate cell engager AMF13 construct to treat patients with CD30-positive relapsed/refractory Hodgkin lymphoma,” he said. “We saw very encouraging activity in this population of very heavily pretreated patients.”

The current standard of care for relapsed CD30-positive lymphomas is brentuximab vedotin (Adcetris), an antibody-drug conjugate that delivers a toxic cytoskeleton destabilizing agent to cells expressing CD30. However, not all these lymphomas respond to brentuximab vedotin. When that treatment fails, those tumors then become extremely resistant to killing and patients are left with very few effective therapeutic options.

To address the problem, investigators enrolled 22 patients with relapsed or refractory CD30+ lymphoma into this single-center phase 1/2 trial, 20 of whom were diagnosed with Hodgkin lymphoma (HL). All had active progressive disease at enrollment, and none received bridging therapy. Patients were heavily pretreated, with a median of 7 (range, 1-14) prior lines of therapy. Nine underwent autologous stem cell transplantation (SCT) and 5 received allogeneic SCT.

Eligible patients had relapsed/refractory CD30-positive classical HL, B-cell non-Hodgkin lymphoma, anaplastic large-cell lymphoma, or peripheral T-cell lymphoma that was refractory or intolerant to brentuximab vedotin. They needed to have an ECOG performance status of 2 or below, and adequate renal, hepatic, pulmonary, and cardiac function.

The median age was 40 years (range, 20-75). Most patients were white (68.2%) and male 68.1%).

Patients receive 2 cycles of fludarabine/cyclophosphamide, followed by AFM13-CB NK cells at 3 dose levels—DL1 (106 NK/gg), DL2 (107 NK/kg), and DL3 (108 NK/kg)—on day 0 plus 3 weekly intravenous infusions of 200 mg AFM13, a CD30/CD16A bispecific antibody. Nineteen patients completed both planned cycles of treatment.

Nieto and colleagues isolated NK cells from cord blood, then used a mixture of cytokines to activate the cells into a memory-like state, making them more persistent and effective. They then expanded the cells in culture and complexed them with AFM13.

At a median follow-up of 11 months, progression-free survival (PFS) and overall survival (OS) rates across all 3 dose levels were 52% and 81%, respectively. Across all dose levels, 53% of patients experienced CR and 37% had PR. Eleven percent had progressive disease.

Expansion of NK cells occurred immediately after infusion and persisted for 3 weeks.

Investigators established DL3 as the recommend phase 2 dose (RP2D). All 13 (100%) patients treated at this dose level responded to therapy, including eight CRs (62%).“Five of those patients were in CR after cycle 1, and 3 additional patients converted from PR to CR after cycle 2,” Nieto added.

The median PFS was 67% and the median OS was 93% in the RP2D population.

Investigators did not record any cytokine release syndrome or graft vs host disease (GVHD), or neurotoxicity. “Our preliminary results show an excellent tolerability profile,” Nieto said.

There was no instance of infusion-related reactions (IRRs) associated with AFM13-NK cells across 40 infusions. There was 1 instance of grade 3 IRR and 4 grade 2 IRRs in 108 infusions of AFM13 alone. Investigators observed no dose limiting toxicities.

“Never before in mankind have we seen this approach, really leading to pretty staggering results,” Timothy Yap, MBBS, PhD, FRCP, a medical oncologist and associate director of translational research in the Institute for Personalized Cancer Therapy at the University of Texas MD Anderson Cancer Center, said. “Everyone can see for themselves how impressive these results are. In addition to that, the actual tolerability profile is truly excellent with no instances of cytokine release syndrome, no neurotoxicity, no GVHD. Truly, truly impressive.”

Nieto Y, Banerjee P, Kaur I, et al. Innate cell engager (ICE) AFM13 combined with preactivated and expanded cord blood (CB)-derived NK cells for patients with refractory/relapsed CD30+ lymphoma. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CTPL01.

Natural killer cells complexed with a bispecific antibody may provide new treatment option for patients with advanced lymphoma. News release. AACR. Published April 10, 2022. Accessed April 10, 2022.

Patients with heavily pretreated lymphoma experienced promising clinical responses following treatment with the innate cell engager AMF13 plus preactivated and expanded natural killers (NK) cells.

Adding Bispecific Antibody to Natural Killer Cells May Be Effective in Heavily Pretreated Lymphoma

Radiotherapeutic treatment options for patients with prostate cancer have continue to evolve to become more patient-friendly, according to Walter J. Curran Jr, MD, FACR, FASCO.

Furthermore, although radiotherapy has existed as a prostate cancer treatment option for more than a century, in the past 100 years, this treatment strategy has evolved from a crude method to a potentially curative therapy that can be administered within 2 weeks, he noted.

Curran, professor emeritus with the Department of Radiation Oncology at Emory University School of Medicine and the 2021 Giants of Cancer Care® award winner for radiation oncology, recently delivered the Giants of Cancer Care® keynote address during the 

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, during which he provided a quick glance of the treatment landscape for this specialty and future directions for the field.

Brachytherapy (BT) was the first type of therapeutic radiation and was developed, largely, by efforts led by Marie Sklodowska-Curie. BT has been an accepted radiotherapy strategy since the 1920s. However, in 2022, health care providers have a wide array of radiotherapeutics with which they can treat patients. With multiple potentially effective treatments, disease stage and determine risk are the driving factors behind treatment selection, said Curran.

Today, intensity-modulated radiation therapy (IMRT), 3D-confromal radiation, and proton beam therapy are all available radiotherapeutics. However, external beam radiation (EBRT) is considered the primary radiotherapy method for men with prostate cancer.

In 2016, Curtis Bryant, MD, MPH, and colleagues published results from a review of the medical records of 1327 men with localized prostate cancer who received proton beam therapy treated at the University of Florida from 2006 to 2010. Ninety-eight percent of patients received 78 Gy or higher and 18% received androgen deprivation therapy (ADT).

At a median follow-up time of 5.5 years, the freedom from biochemical progression (FFBP) rate was 99% for men with low-risk disease. FFBP was 94% for intermediate-risk and 74% for high-risk patients. Furthermore, investigators concluded that incidence of high-grade toxicity was low.

“The bottom line is [proton beam] is an effective means of providing long progression-free survival for men with early-stage prostate cancer,” Curran said. “What remains to be determined is if it superior to IMRT. There are ongoing trials that are exploring that at this point.”

Curran said that data produced in the 1980s and 1990s showed that escalation in total radiation dose was associated with better tumor control. “The problem with that is these now, significantly higher doses in standard fractionation would require 8 to 9 weeks of daily visits to execute, which is a significant time commitment of both centers, as well as patients,” he said. “As the ability to target improved, what we really clearly saw was the idea that perhaps a treatment course could be shortened significantly, and that the term hypofractionation became commonly applied to men with prostate cancer.”

The concept behind hypofractionation, Curran said, is that a short course of highly targeted, high-dose radiation could provide similar results as a longer course of small-dose fractions. Hypofractionated treatment must be as carefully planned as the standard fractionation course.

“What it really requires is a high level of quality of planning technology as well as delivering technology, a tighter margin has to be made around the target area, and that there needs to be that onboard imaging…with a cone-beam CT,” said Curran. “There’s also GPS devices which can be implanted into the prostate, so there's really a full level of certainty as to the location and the delivery of the beam. Because prostate cancer can be slow growing and therefore less radiosensitive than faster-growing malignancies, there are some biologic advantages of large dose per fraction if it can be delivered safely.”

In 8-year follow-up data from the phase 3 CHHiP trial (NCT00392535) published in 2020 (N = 3216), investigators found that a shorter course of radiotherapy administered as 20 treatments over 4 weeks is just as effective and safe as the previous, more conventional 7.5-week treatment.

Between October 2002 and June 2011, patients were randomized to receive either standard therapy with 74 Gy in 37 fractions or experimental therapy with either 60 Gy in 20 fractions or 5

In findings first published in 2016, the proportion of patients who were biochemical or clinical failure free at 5 years was 88.3% (95% CI 86.0%-90.2%) in the 74 Gy group, 90.6% (88.5%-92.3%) in the 60 Gy group, and 85.9% (83.4%-88.0%) in the 57 Gy group.

The follow-up data confirm the 60 Gy schedule is noninferior to the 74 Gy schedule. Eight-year event-free rates were 80.6% among the control group compared with 83.7% in the 60 Gy group, and 78.5% in the 57 Gy group.

Although standard fractionation is administered across 35 to 40 treatments and close to 9 weeks, hypofractionation can be delivered in as few as 4 to 5 treatments in about 2 weeks, Curran noted. Furthermore, physicians can also offer patients single-implant, low dose BT; high-dose BT, robotic radiation—which can be delivered in merely 3 to 6 fractions, or significant hypofractionation—which is typically administered as stereotactic body radiation (SBRT) in 4 to 5 fractions.

While SBRT was originally developed to treat lung cancer, it is now a common treatment strategy for patients with prostate cancer. This therapy involves a highly precise, high dose radiation for 1 to 5 fractions, requiring a sharp drop in dose gradient to reduce risk to nearby tissues.

In one of the largest trials assessing SBRT, 515 patients with organ-confined prostate cancer received a regimen of 5-fraction SBRT at a dose of 35 Gy to 36.25 Gy from 2006 to 2010. According to NCCN criteria, 324 patients were low risk, 153 were intermediate risk, and 38 were high risk.

At a median follow-up of 84 months, the 8-year biochemical disease-free survival (bDFS) rate was 93.6% for low-risk patients, 84.3% for intermediate risk, and 65.0% for and high-risk patients. Overall, 106 favorable intermediate-risk patients had excellent outcomes with no significant difference compared with low-risk patients (7-year bDFS, 95.2% vs 93.2%).

In an analysis of the same patient population, the actuarial 7-year FFBF was 95.8%, 89.3%, and 68.5% for low-, intermediate-, and high-risk groups, respectively (

 <.001). No patients experienced acute grade 3/4 acute complications and fewer than 5% of patients had any acute grade 2 urinary or rectal toxicity.

Investigators in the ongoing phase 3 NRG GU-005 trial (NCT03367702) are assessing 5 fractions of 7.25 Gy SBRT for superiority vs 28 fractions of 2.5 Gy IMRT in patients with stage IIA to B prostate cancer (N = 622).8 The estimated primary completion date is December 2025.

According to Curran, radioligand therapy (RLT) is continuing to emerge as one of the most promising new treatments currently under development. RLT functions by targeting the prostate-specific membrane antigen (PSMA); this mechanism of action enables tumor-specific treatment against prostate cancer cells over-expressing PSMA.

Investigators have developed several PSMA ligands such as PSMA-617 or PSMA-I&T that can be labeled with β‑radiating lutetium-177. These ligands are being employed in compassionate use programs to treat metastatic castration-resistant prostate cancer (mCRPC) and is currently being offered in several nuclear medicine departments throughout Germany.

Findings from several retrospective case series show that RLT is associated with PSA decrease greater than 50% in 30% to 60% of patients with mCRPC.

Investigators in the phase 3 VISION trial (NCT03511664) evaluated the targeted RLT 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC. From June 2018 to October 2019, a total of 831 of 1179 screened patients were randomly assigned to 7.4 GBq 177Lu-PSMA-617 every 6 weeks for 4 to 6 cycles plus protocol-permitted standard care (n = 551) or standard care alone (n = 280).

At a median follow-up of 20.9 months, both imaging-based median progression-free survival (8.7 vs 3.4 months; HR, 0.40; 99.2% CI, 0.29-0.57; 

 <.001) and median overall survival (15.3 vs 11.3 months; HR, 0.62; 95% CI, 0.52-0.74; 

 < .001) were superior in the experimental group. Furthermore, all the key secondary end points—objective response, disease control, and time to first symptomatic skeletal event or death—significantly favored 177Lu-PSMA-617.

In September 2021, the FDA granted a priority review to 177Lu-PSMA-617 for the treatment of mCRPC in the post-androgen receptor pathway inhibition, post–taxane-based chemotherapy setting based on results from VISION. The agency is expected to make a ruling in the first half of 2022.

Further exploration of 177Lu-PSMA-617’s ability to improve outcomes in patients with prostate cancer is currently underway in 2 investigational trials, in which the drug is brought into earlier lines of therapy (NCT04689828; NCT04720157). These studies respectively evaluate 177Lu-PSMA-617 in the pre-taxane setting and the metastatic hormone-sensitive setting.

Curran W. The contributions of radiation oncology to advances in urologic malignancies. Presented at: 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 11-12, 2022; New York, NY.

Kułakowski A. The contribution of Marie Skłodowska-Curie to the development of modern oncology. 

. 2011;400(6):1583-1586. doi:10.1007/s00216-011-4712-1.

Bryant C, Smith TL, Henderson RH, et al. Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer. 

. 2016;95(1):422-434. doi: 10.1016/j.ijrobp.2016.02.038.

Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. 

. 2016;17(8):1047-1060. doi:10.1016/S1470-2045(16)30102-4.

Dearnaley DP, Griffin C, Syndikus I, et al. Eight-year outcomes of a phase III randomized trial of conventional versus hypofractionated high-dose intensity modulated radiotherapy for prostate cancer (CRUK/06/016): update from the CHHiP trial. 

. 2020,38(suppl 6; abstr 325). doi:DOI: 10.1200/JCO.2020.38.6_suppl.325.

Katz A, Formenti SC, Kang J. Predicting biochemical disease-free survival after prostate stereotactic body radiotherapy: risk-stratification and patterns of failure. 

. 2016;6:168. doi:10.3389/fonc.2016.00168.

Katz AJ, Kang J. Quality of life and toxicity after SBRT for organ-confined prostate cancer, a 7-year study. 

. 2014 Oct 28;4:301. doi:10.3389/fonc.2014.00301.

Stereotactic body radiation therapy or intensity-modulated radiation therapy in treating patients with stage IIA-B prostate cancer. Last updated January 21, 2022. Accessed March 16, 2022. 

https://clinicaltrials.gov/ct2/show/NCT03367702

Heck MM, Retz M, Tauber R, et al. Radionuklidtherapie des Prostatakarzinoms mittels PSMA-Lutetium [PSMA-targeted radioligand therapy in prostate cancer]. 

. 2017;56(1):32-39. doi:10.1007/s00120-016-0274-3.

Sartor O, de Bono J, Chi KM, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. 

. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322.

This article was originally published on OncLive as “Radiotherapy Treatments Are Getting Shorter and Faster in Prostate Cancer”

Radiotherapy treatment has continued to evolve to become both shorter and faster in potentially curing prostate cancer. 

Radiotherapy Treatments Continue With Patient-Friendly Focus in Prostate Cancer

Patients with advanced prostate cancer achieved deep PSA responses with apalutamide (Erleada), an androgen receptor inhibitor, according to findings from a post-hoc analysis of data from the phase 3 TITAN (NCT02489318) and SPARTAN (NCT01946204) trials.

Moreover, participants in the studies also maintained their health-related quality of life and physical wellbeing, Eric Jay Small, MD, explained during a poster presentation of the findings at the 2022 Genitourinary Cancers Symposium.

“Not only does a deep PSA response identify patients who will have improved survival and progression-free outcomes, but also it is also associated with maintenance of health-related quality of life, improved patient reported physical wellbeing, and a reduced risk of worsening pain and fatigue intensity,” said Small, coleader of the UCSF Prostate Cancer Program and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center.

Small said that previous results from TITAN and SPARTAN showed that apalutamide plus androgen depravation therapy (ADT) was associated with improved overall survival (OS), preserved health-related quality of life (HRQoL), and rapid and deep reductions in PSA. In this analysis, he and his colleagues set out to determine the relationship between PSA decline and HRQoL following apalutamide.

Investigators assessed HRQoL in the 2 trials separately because each had “distinct” patient populations with different disease burdens and different prior therapies. Small said that at 3 and 6 months, patients whose PSA was at or below 0.2 ng/mL had prolonged time to deterioration in their Functional Assessment of Cancer Therapy-Prostate total (FACT-P) and FACT-P Physical Wellbeing scores on both studies. In TITAN, patients had better scores on the Brief Pain Inventory-Short Form (BPI-SF) worst pain intensity progression and Brief Fatigue Inventory (BFI) worst fatigue intensity progression (TABLE).

Is Associated with Positive Patient-Reported Outcomes at 3 months

A total of 1052 patients with metastatic castration-sensitive prostate cancer enrolled in TITAN and were randomly assigned to apalutamide 240 mg daily plus or placebo. Both groups received standard ADT.

In findings published in 2021, the median OS for patients treated with apalutamide was not reached (NR) compared with 52.2 months for patients assigned to apalutamide (HR, 0.65; 95% CI, 0.53-0.79; 

 < .0001). At 48 months, the OS rate was 65.1% vs 51.8% in favor of apalutamide.

Patients with nonmetastatic castration-resistant prostate cancer in SPARTAN were assigned to apalutamide (n = 806) or placebo (n = 401). At a median follow-up of 52 months, the median OS was 73.9 months (95% CI, 61.2-NR) in the apalutamide group compared with 59.9 months (95% CI, 52.8-NR) with placebo (HR, 0.78; 95% CI, 0.64-0.96; 

The FDA approved apalutamide for this indication in February 2018 based on results from SPARTAN.

Is Associated with Positive Patient-Reported Outcomes at 6 months

Small EJ, Chi KN, Chowdhury S, et al. Association between patient-reported outcomes (PROs) and changes in prostate-specific antigen (PSA) in patients (pts) with advanced prostate cancer treated with apalutamide (APA) in the SPARTAN and TITAN studies. 

. 2022;40(suppl 6; abstr 73). doi: 10.1200/JCO.2022.40.6_suppl.073

Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. 

. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488

Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. 

. 2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. News release. Updated May 3, 2018. Accessed February 17, 2022. https://bit.ly/33sXJrU

Lowentritt B, Brown G, Kernen K, et al. Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistance prostate cancer patients. J Urol. 2021;206(suppl 1):e58. doi:10.1097/JU.0000000000001969.08

A post-hoc analysis of 2 studies revealed that patients with advanced prostate cancer receiving apalutamide reported positive wellbeing scores during treatment. 

Patients With Advanced Prostate Cancer Report Positive Wellbeing Scores With Apalutamide 

Patients with previously untreated advanced renal cell carcinoma (RCC) experienced superior quality of life (QoL) with nivolumab (Opdivo) and cabozantinib (Cabometyx) compared with sunitinib, according to findings from a patient-reported outcome (PRO) data from the phase 3 CheckMate-9ER trial (NCT03141177) published in 

Specifically, patients who received sunitinib experienced a deterioration in their health status while patients who received nivolumab/cabozantinib either maintained or achieved improved symptoms. These findings follow the earlier overall data in 2021, which demonstrated that the combination doubled survival rate in this population vs sunitinib, which was evaluated as the standard of care.

“Historically in cancer, most new treatments that extend survival come at a cost,” study investigator David Cella, PhD, chair of the Department of Medical Social Sciences at Northwestern University Feinberg School of Medicine, said in a press release. “In this study, we found that the combination is actually easier on patients, so it has the double benefit.”

The open-label, randomized, international phase 3 trial enrolled patients with previously untreated advanced renal cell carcinoma and a clear-cell component. Eligible patients needed to be at least 18 years of age, have measurable disease per RECIST v1.1 criteria, a Karnofsky performance status score of 70% or more, and available tumor tissue. Patients could have any International Metastatic RCC Database Consortium (IMDC) risk score.

Those with active central nervous system metastases, active autoimmune disease, conditions requiring systemic treatment with corticosteroids or immunosuppressive medications within 14 days of randomization, malignancy within the prior 3 years, tumors invading the superior vena cava, or select predefined gastrointestinal and vascular disorders, were excluded.

A total of 651 study participants with advanced RCC were randomized 1:1 to receive either nivolumab/cabozantinib (n = 323) or sunitinib (n = 328). Those in the investigative arm received intravenous nivolumab at 240 mg every 2 weeks plus oral cabozantinib at 40 mg daily. Those in the control arm were given oral sunitinib at a daily dose of 50 mg on a 4-weeks-on/2-weeks-off schedule. Treatment was continued until disease progression or unacceptable toxicity.

The primary end point of the trial was progression-free survival (PFS) via blinded independent central review (BICR) in the intention-to-treat population. Key secondary end points comprised overall survival (OS) and objective response rate (ORR) per BICR in the ITT population, and safety in those who received at least 1 dose of treatment on the study. PROs served as an exploratory end point for the research.

Investigators analyzed PROs in the ITT population at baseline and every 6 weeks until week 115. Disease symptoms were evaluated using the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and global health status was assessed with the 3-level EQ-5D (EQ-5D-3L) visual analogue scale (VAS) and UK utility index. Change from baseline was evaluated using mixed-model repeated measures. A time-to-deterioration analysis was done for first and confirmed deterioration events.

The proportion of patients who completed PRO assessments proved to be comparable across the treatment arms. Those who completed the FKSI-19 and EQ-5D-3L instruments at baseline was high, at 93%, for both groups. The completion rate for both instruments remained at 75% or higher at most time points for the investigative group until week 103; then, the completion rate dropped to less than 65%. In the control group, the completion rate was 75% or higher at most time points until week 79, and then was noted to decrease thereafter.

Patients in both treatment groups had relatively low symptom burden at baseline; the population was also noted to have a baseline health status that was slightly lower than population norms, but higher than previously reported patient scores.

Data from a mixed-model repeated measures (MMRM) analysis showed that following an initial decline in most scores across the groups, nivolumab/cabozantinib was linked with scores that were either stable (FKSI-19 total score, FSKI-19 functional wellbeing, and EQ-5D-3L UK utility index) or improved (FKSI-19 disease-related symptoms version 1, FKSI-19 disease-related symptoms physical scale, and EQ-5D-3L VAS) over time 

. Those in the sunitinib arm were noted to experience a decline from baseline in scores across all instruments.

However, none of the changes from baseline were found to have exceeded the predefined clinically meaningful threshold in any group except for deterioration of EQ-5D-3L UK utility index values in the control group; this was clinically meaningful at many time points following week 55.

For FKSI-19 total score, FKSI-19 disease-related symptoms version 1, and EQ-5D-3L UK utility index, the overall difference in mean score change from baseline until week 115 was found to be nominally significant in favor of the combination vs the monotherapy. Data from a pattern-mixture model sensitivity analysis favored the combination, generally aligning with what had been reported in the MMRM analysis.

Those in the combination group experienced a longer median time to first deterioration in FKSI-19 total score than those in the monotherapy group, at 6.24 months (95% CI, 4.34-8.34) vs 3.48 (95% CI, 2.86-4.21), respectively (HR, 0.70; 95% CI, 0.56-0.86; 

= .0007). The median time to confirmed deterioration was 19.38 months (95% CI, 12.48–not estimable) vs 6.97 months (95% CI, 4.50-10.09), respectively (HR, 0.63; 95% CI, 0.50-0.80; 

= .0001). The combination also resulted in a significant reduction in the risk of first and confirmed deterioration in all other FKSI-19 scores compared with sunitinib.

FDA approved nivolumab plus cabozantinib for the frontline treatment of patients with advanced RCC

 based on data from CheckMate-9ER, which indicated that the doublet resulted in a 49% reduction in the risk of disease progression or death, significantly improved OS, and doubled the ORR compared with sunitinib in this population.5

At a median follow-up of 18.1 months, the median PFS was 16.6 months with nivolumab plus cabozantinib vs 8.3 months with sunitinib (HR, 0.51; 95% CI, 0.41-0.64; 

 showed that the doublet induced activity across several subgroups evaluated, spanning age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.3

The median OS had not yet been reached in either treatment arm, translating to a 40% reduction in the risk of death with the investigational doublet (HR, 0.60; 95% CI, 0.40-0.89; 

 = .0010). The ORRs in the investigative and control arms were 55.7% and 27.1%, respectively (

The doublet also demonstrated a favorable safety profile. Any-grade and high-grade treatment-related adverse effects (TRAEs) were comparable between the arms. More than half of the participants who received the doublet required dose reductions of cabozantinib due to AEs.

Moreover, 15.3% of patients who were given cabozantinib/nivolumab reported TRAEs that resulted in treatment discontinuation vs 8.8% of those who were administered sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib because of toxicities, 5.6% discontinued nivolumab only, and 6.6% discontinued cabozantinib only.

The rate of serious AEs was also similar between the arms, although liver toxicity was found to be more commonly experienced by those who received the combination. Nineteen percent of participants in the investigative arm required corticosteroids because of immune-associated toxicities; 4% of these patients needed to receive corticosteroids for at least 30 days.

“Immune therapy is revolutionizing the treatment of advanced kidney cancer,” Cella, who is the associate director for cancer prevention and control research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, added in the release. “For the first time in decades, we are seeing benefits to both survival and quality of life with these new treatments. People with kidney cancer have more effective treatment options than ever before. Not only are they living longer, [but] they are living better.”

Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. 

. Published online January 12, 2022. doi:10.1016/S1470-2045(21)00693-8.

FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA; January 22, 2021. Accessed January 20, 2022. 

Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. 

. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

In cancer treatment, quality of life matters more and more: study found fewer side effects from new, more effective chemotherapy. News release. Northwestern University; January 13, 2022. Accessed January 25, 2022. 

FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. FDA; January 22, 2021. Accessed January 25, 2022. 

This article was originally published on OncLive as “Nivolumab/Cabozantinib Combo Improves Patient-Reported Outcomes Over Sunitinib in RCC”

Patient-reported outcomes demonstrated that nivolumab plus cabozantinib was associated with improved quality of life, while sunitinib was associated with health-related deterioration, in treatment-naïve renal cell carcinoma.

Patients With Treatment-Naïve RCC Achieve Superior QoL With Nivolumab/Cabozantinib 

Telotristat ethyl (Xermol) was found to improve symptoms and patient satisfaction in individuals with carcinoid syndromes, according to findings presented in a poster during the 2021 NANETS Annual Meeting.

In findings from a survey of 215 patients treated in the RELAX study (NCT03223428), investigators found that 78% of 107 patients with baseline and month 6 responses were satisfied or very satisfied with control of their carcinoma syndrome and diarrhea (CSD) symptoms following 6 months of treatment with telotristat ethyl. At 6 months, 76% of patients reported stable or increased weight.

“Results of this long-term follow-up from the RELAX patient registry continues to show very encouraging sustained benefit with [telotristat ethyl] in helping neuroendocrine tumor patients control the symptoms of carcinoid syndrome, maintain weight, and reduce impairments to work productivity and activity,” lead author Daneng Li, MD, said in a news release.

 Li is an assistant professor in the Department of Medical Oncology and Therapeutics Research, and is co-director of the Neuroendocrine Tumor Program at City of Hope.

Carcinoid syndrome is a rare condition that occurs in patients with metastatic neuroendocrine tumors. It is characterized by frequent and debilitating diarrhea, as well as by facial flushing, abdominal pain, fatigue and, over time, heart valve damage.

RELAX is an ongoing, real-world, noninterventional prospective registry of US patients with carcinoid syndrome. Study participants completed online surveys at baseline and every 6 months for up to 3 years. At each time interval, patients reported on changes in their clinical symptoms, use of rescue medication, weight, and work productivity and activity impairment (WPAI). Investigators also assessed patient satisfaction with telotristat ethyl treatment at each 6-month interval.

The primary objective of the study is to estimate the proportion of patients with carcinoid syndrome who are satisfied with their overall symptom control 6 months after initiating treatment with telotristat ethyl. Key secondary end points include the proportion of patients reporting satisfaction with their CS-related diarrhea and flushing control, effect of telotristat ethyl on work productivity and activity impairment, and the effect of telotristat ethyl on weight gain or maintenance.

At 6 months, investigators found that patient satisfaction with control of CSD improved from 47% at baseline to 78% in those with baseline and month 6 responses. Most patients reported improvement in number of daily bowel movements (84%) and control of CS symptoms (80%).

Most patients reported reduced or stable use of rescue medication after 6 (75%), 12 (76%), and 18 (83%) months of treatment. Furthermore, 76% of patients reported stable or increased weight after 6 months; 80% after 12 months of treatment and 74% did so after 18 months of treatment.

Of 69 participants who were employed at baseline, the mean number of work hours missed due to carcinoid syndrome over the previous 7 days declined from 3.7 hours at baseline to 1.5 hours at 6 months. Similarly, presenteeism (–14.1%), impaired work productivity (–13.2%), and impaired activity (–9.4%) all declined from baseline to 6 months. However, there was a slight increase in absenteeism (5.2%). Although there were numerical improvements in work productivity and activity impairment, investigators cautioned that these results came from small sample sizes.

Li D, Darden C, Sayeed S, et al. Patient-reported clinical and productivity outcomes from the longitudinal telotristat ethyl treatment registry. Presented at: 2021 NANETS Annual Meeting; November 3-6, 2021; virtual. Abstract 98.

TerSera presents patient-reported clinical and productivity outcomes associated with Xermelo® (telotristat ethyl): long-term registry trial of patients with carcinoid syndrome diarrhea. News release. TerSera Therapeutics. November 9, 2021. Accessed November 9, 2021. https://prn.to/3bYBU42

This article was originally published on OncLive as “Telotristat Ethyl Improves Symptoms and Patient Satisfaction in Carcinoid Syndrome

The majority of patients who received telotristat ethyl to treat their carcinoid syndrome reported stable or increased weight at a 6-month follow-up. 

Telotristat Ethyl Linked to Patient Satisfaction in Carcinoid Syndrome

Patients receiving immune checkpoint inhibitors (ICIs) for renal cell carcinoma (RCC) or melanoma were able to safely tolerate the COVID-19 vaccine, according to findings from a retrospective chart review presented during the 2021 SITC Annual Meeting.

COVID-19 poses a significant threat to patients with cancer or receiving anticancer treatment, commented study co-author Hannah Dzimitrowicz, MD, highlighting the importance of being able to safely vaccinate this population.

“In a solid tumor population at high risk for severe COVID-19 infections, vaccination is important to mitigate this risk,” said Dzimitrowicz, a medical instructor in the department of medicine at the Duke University School of Medicine in Durham, North Carolina. “In a heterogeneous population of patients with RCC and melanoma receiving immune checkpoint inhibitor therapy, COVID-19 vaccination appears to be well tolerated and safe.”

Vaccines appeared to be effective in this patient population. Two patients in the ICI group (n = 74) developed COVID-19 infection after 1 vaccine dose and no patients developed COVID-19 infection after 2 doses.

Although patients receiving active cancer treatment were excluded from COVID-19 vaccine trials, major oncologic organizations including the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend vaccination.

To evaluate the safety and tolerability of COVID-19 vaccines in this population, Dzimitrowicz and her colleagues used electronic medical records to identify all patients who received at least 1 dose of an FDA-authorized COVID-19 vaccine from December 1, 2020, to April 1, 2021, had received ICI at the time of vaccination, and had at least 3 months of documented follow up at Duke Cancer Center.

They then compared safety results for those who received ICIs (n = 74) vs those who did not (n = 74). Safety outcomes measured included adverse events (AEs) attributed to vaccination, immune-related AEs (irAEs) following vaccination, and incidence of subsequent COVID-19 infections.

The proportion of patients with RCC (49%) and melanoma (51%) was the same in both cohorts.

The median age was 70 years (range, 33 to > 90) in the ICI cohort compared with 73 years (range, 35-88) in the control group. The experimental group was primarily male (70%) while the control group was more balanced (51%).

Most patients in the ICI group received the Pfizer vaccine (62%), followed by Moderna (35%) and Johnson & Johnson (3%). In the control group, those numbers were 83%, 16%, and 1%, respectively.

Half of patients received nivolumab (Opdivo), 16% received pembrolizumab (Keytruda), 15% received nivolumab plus cabozantinib (Cabometyx), 10% received nivolumab plus ipilimumab (Yervoy), 7% received pembrolizumab plus axitinib (Inlyta), and 1% received ipilimumab.

One patient in the control group reported fatigue and arm pain. Twenty percent of patients in the ICI group reported at least 1 AE including fevers (7%), chills (7%), myalgias (7%), arm pain (5%), headache (5%), fatigue (5%), diarrhea (3%), erythema at the injection site (3%), and nausea and vomiting (1%).

“It is important to note that all of these symptoms reported by patients were mild and none resulted in hospitalizations or treatment interruption,” Dzimitrowicz said.

Investigators also recorded AEs that patients or clinicians thought could be attributed to vaccination. One patient in the ICI group developed porokeratoses following the second vaccine dose. One patient in the control group developed a stye and 1 developed premature ventricular contractions.

Nine (12%) patients in the ICI cohort developed a new or worsening irAE that required a treatment hold, systemic steroids, and/or hospital admission. The most common irAE was colitis (n = 4). Two patients developed hepatitis and 1 patient each developed pancreatitis, gastritis, dermatitis, and adrenal insufficiently.

Dzimitrowicz pointed out that these data reflect the experience at a single institution, and physicians saw patients undergoing active therapy more frequently, so those patients had more opportunities to report AEs. She also pointed out that the study did not include to patients receiving concurrent cytotoxic chemotherapy, thus limiting applicability to that group

“It’s important to note that larger cohort studies of patients receiving immune checkpoint inhibitors are needed to fully assess the safety and efficacy of COVID-19 vaccination in this population,” she said. “Despite these limitations, this study provides valuable information regarding the safety of COVID-19 vaccination in patients receiving immune checkpoint inhibitors in real world practice.”

Hwang JK, Dzimitrowicz H, Riddhishkumar S, et al. COVID-19 vaccination in patients with renal cancer or melanoma receiving immune checkpoint inhibitors. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 625. https://jitc.bmj.com/content/9/Suppl_2/A655

This article was originally published on OncLive as “Patients with RCC, Melanoma Taking ICIs Can Safely Receive COVID-19 Vaccination”

Patients receiving immune checkpoint inhibitors for renal cell carcinoma or melanoma responded well to the COVID-19 vaccine. 

COVID-19 Vaccine Appears Well Tolerated in Patients with RCC, Melanoma Receiving Immune Checkpoint Inhibitors 

Superior outcomes were observed in men with intermediate-risk prostate cancer who received magnetic resonance (MR)-guided focused ultrasound (MRgFUS) focal therapy than patients in the same population were treated with radical prostatectomy or radiation therapy, demonstrate findings from a phase 2b study (NCT01657942) presented at the 2021 American Urological Association Annual Meeting.

“ExAblate MR-guided focal therapy using real-time MR thermometry preserves urinary incontinence and sexual function and it’s an effective for grade group 2 and 3 prostate cancer cancers are based on 2-year biopsy outcomes,” said lead author Behfar Ehdaie, MD, MS, a urologic surgeon at Memorial Sloan Kettering Cancer Center. “ExAblate MR-guided focus ultrasound may enable men to consider a tissue preserving approach and defer or avoid radical therapy.”

At 24 months, 88% of men had no evidence of grade group 2 or 3 prostate cancer in the treatment area according to targeted prostate biopsy. Additionally, 60% of men had no evidence of grade group 2 or 3 disease anywhere in the prostate gland, including outside of the treatment area. Serum PSA levels decreased by almost 50% after treatment and stabilized after 6 months.

Ehdaie said that men who undergo prostatectomy or radiation therapy often experience significant declines in erectile function and urinary incontinence. Data from a study of 3262 men published in 2020 showed that, at 12 months, about 60% experienced erectile dysfunction following nerve-sparing radical prostatectomy and approximately 50% experienced the same following external beam radiation therapy.

 Men who have intermediate-risk prostate cancer, grade group 2 or 3, are often ineligible for active surveillance or experience early disease progression, up to 40% in findings from the ProtecT trial (NCT02044172), leading to surgery or radiation therapy.

Ehdaie and colleagues explored MRgFUS as an alternative therapy that reduces side effects while maintaining cancer control by targeting areas of no cancer within the prostate gland. He said the ExAblate MR-guided focus ultrasound device delivers targeted high intensity focused ultrasound therapy through the rectum. Ehdaie added that multicenter retrospective studies have shown focal therapy for prostate cancer is safe, and approximately 80% of men require no further prostate cancer-directed treatment.

Investigators evaluated MRgFUS in a single arm, multicenter trial. Men (N = 101) were treated at 7 academic centers and 1 private practice. MRgFUS was delivered focally to the lesion with a margin of normal tissue of greater than or equal to 5 mm based on planning. Treatment was monitored with real-time MR thermometry. Concurrent grade group 1 prostate cancer foci were not treated.

Men with untreated unilateral and more visible, grade group 2 or 3 prostate cancer were eligible. Patients were excluded if they were unable to undergo MRI or had large calcification between the rectum and the planned targeted treatment zone that could interfere with treatment.

Patients underwent targeted and systematic biopsies at 6 and 24 months after treatment, and examinations with quality of life measurements every 3 months.

The primary end points were efficacy and safety. Secondary end points included change in baseline patient-reported quality of life at 24 months.

The average patient age was 63 years and 86% of the cohort was White. The median PSA was 5.7 ng/mL. Eighty-four patients had at least clinical stage T1c disease. Seventy-eight percent of patients were in grade group 2 and 22% were in grade group 3.

Patients with prostate cancer fared better following treatment with magnetic resonance-guided focused ultrasound focal therapy than with radical prostatectomy or radiation therapy, shows study presented at 2021 AUA Annual Meeting.


Jason Harris