Ivosidenib (Tibsovo) plus azacitidine received FDA approval for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) harboring 

 mutations who are aged 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

The expanded approval is supported by findings from the phase 3 AGILE trial, which showed that ivosidenib plus azacitidine significantly improved event-free survival (EFS) over azacitidine alone (HR, 0.35; 95% CI, 0.17-0.72; 2-sided 

 = .0038).2 The addition of ivosidenib also improved median overall survival (OS) compared with azacitidine alone, at 24.0 months (95% CI, 11.3-34.1) vs 7.9 months (95% CI, 4.1-11.3), respectively (HR, 0.44; 95% CI, 0.27-0.73; 

"Today's approval builds on the established body of evidence for [ivosidenib], which is now approved across multiple 

-mutated cancer types," David K. Lee, chief executive officer at Servier Pharmaceuticals, stated in a press release. "As a leader in oncology pioneering the science behind targeted IDH inhibition, we are proud to bring a new therapeutic option to the acute myeloid leukemia community and remain committed to pushing the boundaries of healthcare innovation in oncology and beyond."

The global, double-blind, placebo-controlled, phase 3 trial enrolled patients with a centrally confirmed diagnosis of previously untreated 

-mutated AML who were not eligible for intensive chemotherapy.

To participate, patients needed to be at least 18 years of age, had an ECOG performance status of 0 to 2, acceptable hepatic and renal function, and who did not receive prior treatment with an IDH1 inhibitor or hypomethylating agent for myelodysplastic syndrome.

Patients were not candidates to receive intensive chemotherapy if they were aged 75 years or older, and had 1 of the following conditions: an ECOG performance status of 2, a severe cardiac disorder, a severe pulmonary disorder, a creatinine clearance of less than 45 mL/min, or a bilirubin level greater than 1.5 times the upper limit of the normal range.

Study participants were administered ivosidenib at a once-daily dose of 500 mg (n = 72) or matched placebo (n = 74), in combination with azacitidine at 75 mg/m2 for 7 days as part of 28-day cycles. Stratification factors included geographic region and disease status (primary vs secondary disease).

Treatment was given for a minimum of 6 cycles unless relapse, progressive disease, intolerable toxicity, or death occurred.

The primary end point was EFS, and secondary end points included complete remission (CR), OS, CR or CR with partial hematologic recovery, objective response, safety, and health-related quality of life.

The demographic and clinical characteristics of the patients at baseline were comparable across the arms. Of those in the investigative arm, 75% had primary AML and 25% had secondary AML; these rates were 72% and 28%, respectively, in the control arm. Moreover, 22% of those who received ivosidenib in combination with azacitidine had poor-risk cytogenetic characteristics vs 27% of those who received azacitidine alone.

A total of 39 patients were receiving treatment at the data-cutoff date of March 18, 2021; 38% of these patients were in the investigative arm and 16% were in the control arm.

 showed that CR was achieved by 47% (95% CI, 35%-59%) of those in the ivosidenib arm and 15% (95% CI, 8%-25%) of those in the azacitidine-alone arm (

 < .001). The median duration of CR was not yet reached with ivosidenib vs 11.2 months in those who received azacitidine alone.

In those who achieved a CR, the estimated probability that a patient would remain in CR at 1 year was 88% vs 36% in the investigative and control arms, respectively. The median time to CR was 4.3 months (range, 1.7-9.2) in the ivosidenib/azacitidine arm and 3.8 months (range, 1.9-8.5) in the azacitidine-alone arm. CR or CR with partial hematologic recovery was observed in 53% (95% CI, 41%-65%) and 18% (95% CI, 10%-28%) of those in the investigative and control arms, respectively.

Moreover, 62% (95% CI, 50%-74%) of those who received ivosidenib/azacitidine experienced an objective response vs 19% (95% CI, 11%-30%) of those who received azacitidine alone (

 < .001). The median duration of response was 22.1 months (95% CI, 13.0–not estimable) and 9.2 months (95% CI, 6.6-14.1), respectively.

The safety profile of the combination proved to be consistent with previously published findings. The most common toxicities that were observed in patients with newly diagnosed AML who received the regimen included nausea, vomiting, electrocardiogram QT prolonged, insomnia, differentiation syndrome, leukocytosis, hematoma, hypertension, arthralgia, dyspnea, and headache.

The select laboratory abnormalities that were experienced include decreased leukocytes, platelets, hemoglobin, neutrophils, phosphate, and magnesium, as well as increased lymphocytes, aspartate aminotransferase, alkaline phosphatase, and potassium.

Servier announces FDA approval of Tibsovo (ivosidenib tablets) in combination with azacitidine for patients with newly diagnosed IDH1-mutated acute myeloid leukemia. News release. Servier Pharmaceuticals. May 25, 2022. Accessed May 25, 2022. https://prn.to/3sX1OOw

Montesinos P, Recher C, Vives S, et al. Ivosidenib and azacitidine in 

. 2022;386(16):1519-1531. doi:10.1056/NEJMoa2117344

Articles

Ivosidenib plus azacitidine received FDA approval for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) harboring IDH1 mutations.

FDA Grants Ivosidenib Plus Azacitidine Approval for Newly Diagnosed AML With IDH1 Mutations

The FDA has approved azacitidine (Vidaza) to treat pediatric patients with newly diagnosed juvenile myelomonocytic leukemia (JMML).

The regulatory decision is supported by data from the international, multicenter, open-label AZA-JMML-001 (NCT02447666), in which investigators examined the safety and efficacy of azacitidine vs historical controls in pediatric patients with newly diagnosed myelodysplastic syndrome or JMML before hematopoietic stem cell transplantation (HSCT).

A total of 18 study participants were administered intravenous azacitidine at a daily dose of 75 mg/m2 on days 1 through 7 of a 28-day treatment cycle for a minimum of 3 cycles and a maximum of 6 cycles. The primary end point of the trial was response rate, which was comprised of complete remission (cCR) or clinical partial remission (cPR) per International JMML response criteria, at 3 months.

Results showed that 50% of patients (95% CI, 26%-74%) experienced confirmed clinical responses with the drug. Of these patients, 3 achieved a cCR and 6 experienced a cPR.

Moreover, the median time to response was 1.2 months (range, 0.95-1.87). Ninety-four percent of patients went on to receive HSCT, and the median time to transplant was 4.6 months (range, 2.8-19).

Prior data indicated that 38% of those who required platelet transfusion were free of transfusion following the third cycle of therapy. Of the 17 patients who went on to undergo HSCT, 82% were leukemia free at a median follow-up of 23.8 months (range, 7.0-39.3).

Regarding safety, the most common effects included pyrexia, rash, upper respiratory tract infection, and anemia.

FDA approves azacitidine for newly diagnosed juvenile myelomonocytic leukemia. News release. FDA. May 20, 2022. Accessed May 23, 2022. https://bit.ly/3Lt1VrL

Niemeyer CM, Flotho C, Lipka DB, et al. Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial. 

. 2021;5(14):2901-2908. doi:10.1182/bloodadvances.2020004144

Azacitidine (Vidaza) is now FDA approved for pediatric patients with newly diagnosed myelomonocytic leukemia.

FDA Grants Azacitidine Approval For Pediatric Patients With Myelomonocytic Leukemia

Relugolix (Orgovyx), an oral gonadotropin-releasing hormone receptor (GnRH) antagonist, demonstrated a manageable toxicity profile with acceptable tolerability in patients being treated for advanced prostate cancer, according to results from a detailed safety analysis of the pivotal phase 3 HERO trial (NCT03085095) presented during the 2022 American Urological Association (AUA) Annual Meeting.

A lower percentage of patients who received relugolix experienced major adverse cardiovascular events (MACE) compared with those who were given leuprolide (Lupron), at 2.9% and 6.2%, respectively. Specifically, Kaplan-Meier estimates of incidence rate revealed a risk reduction of 54% with relugolix (HR, 0.46; 95% CI, 0.24-0.88).

Notably, in a subset of men who had a reported medical history of cardiovascular events, MACE rates on study drug treatment in the investigative and control arms were 3.6% and 17.8%, respectively; this translated to 5.8-fold higher odds of experiencing MACE with leuprolide vs relugolix.

“Relugolix, an oral nonpeptide GnRH receptor antagonist, was generally well tolerated in the phase 3 HERO study,” lead study author Bryan Mehlhaff, MD, of the Oregon Urology Institute, and colleagues, wrote in a poster on the data. “Adverse effects [AEs] occur with varying time of onset and duration depending on the type of event.”

HERO enrolled patients with histologically or cytologically confirmed adenocarcinoma of the prostate that needed at least 1 year of continuous androgen deprivation therapy.

 To be eligible for enrollment, patients needed to be at least 18 years of age, and have 1 of the following 3 clinical presentations: evidence of biochemical or clinical relapse after local primary intervention with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease that is not likely to be cured by local primary intervention with curative intent.

If patients experienced MACE within 6 months of study start, they were excluded.

Study participants were randomized 2:1 to receive oral relugolix at a once-daily dose of 120 mg following a single loading dose of 360 mg, or leuprolide injections given every 12 weeks for 48 weeks. Stratification factors included geographic region, presence or absence of metastatic disease, and age.

The primary end point of the trial was sustained castration rate, and key secondary end points included noninferiority of relugolix to leuprolide regarding sustained castration rate with a noninferiority margin of -10 percentage points.

Other end points included cumulative probability of testosterone suppression to less than 50 ng per deciliter on day 4 and 15, the percentage of patients with a prostate-specific antigen (PSA) response at day 15 with confirmation at day 29, the profound castration rate on day 15, and the FSH level at the end of week 24.

FDA approved relugolix for use in patients with advanced prostate cancer

 based on earlier findings from HERO.3 Data showed that 96.7% (95% CI, 94.9-97.9) of those who received relugolix (n = 622) maintained castration through 48 weeks vs 88.8% (95% CI, 84.6%-91.8%) of those who were given leuprolide (n = 308); the difference of 7.9 percentage points (95% CI, 4.1-11.8) was indicative of noninferiority and superiority of relugolix.

Notably, all secondary end points showed superiority with relugolix over leuprolide (

< .001). The cumulative probability of castration on day 4 with relugolix was 56.0% vs 0% with leuprolide; on day 15, these rates were 98.7% and 12.0%, respectively. Moreover, the cumulative probability of testosterone suppression to profound castrate levels on day 15 was 78.4% with relugolix and 1.0% with leuprolide. More patients in the investigative arm had a confirmed PSA response at day 15 vs those in the control arm, at 79.4% and 19.8%, respectively (

Updated data from the HERO trial shared at the 2021 AUA Annual Meeting showed that 

relugolix did not significantly delay onset of castration resistance vs leuoprolide

 At 48 weeks, the castration resistance–free survival (CRFS) rate was 74.3% (95% CI, 68.6%-79.2%) with relugolix vs 75.3% (95% CI, 66.7%-81.9%) with leuprolide in the metastatic disease cohort (n = 434; HR, 1.03; 95% CI, 0.68-1.57; 

= .84). Similar CRFS rates were reported in the modified intention-to-treat population (n = 1074).

At this year’s meeting, investigators shared a review of the safety findings from the trial, including an analysis of toxicity onset and duration. The safety population was comprised of 622 patients who received relugolix and 308 patients who were given leuprolide.

Data indicated that 92.9% of those in the investigative arm and 93.5% of those in the control arm experienced AEs. The AEs that occurred in more than 10% of patients in the relugolix and leuprolide arms, respectively, included hot flash (54.3% vs 51.6%), fatigue (21.5% vs 18.5%), constipation (12.2% vs 9.7%), diarrhea (12.2% vs 6.8%), and arthralgia (12.1% vs 9.1%).

Grade 3 or higher toxicities were experienced by 18.0% of those in the relugolix arm vs 20.5% of those in the leuprolide arm. Grade 3 or higher AEs reported in 1% or more of patients in the investigative and control arms, respectively, comprised hypertension (1.6% vs 0.6%), diabetes (1.0% vs 0.6%), and syncope (1.0% vs 1.0%). All other grade 3 or higher toxicities were reported with comparable incidence in both arms.

For the toxicities that were experienced by more than 10% of patients, the median time to onset ranged from 19.0 days to 142.0 days in the investigative arm and 41.0 days to 189 days in the control arm. The duration of these effects varied.

Notably, diarrhea was noted to have a short median duration compared with other toxicities; this AE had a median duration of 9 days (range, 1-370) in the relugolix arm vs 3 days (range, 1-224) in the leuprolide arm. Fatigue and hot flash were found to be more persistent. The median duration of fatigue in those who received relugolix was 289 days (range, 2-429) vs 274 days (range, 3-426) in those who were given leuprolide. Moreover, hot flash lasted for a median of 342 days (range, 15-477) with relugolix vs 331 days (range, 1-428) with leuprolide.

Regarding MACE, the median time to onset with relugolix was 177 days (range, 38-343) vs 132 days (range, 8-352) with leuprolide.

“MACE appeared to occur earlier and with a higher percentage in leuprolide vs relugolix groups, possibly supporting a different risk/mechanism between GnRH agonists and antagonists,” the authors concluded.

Mehlhaff B, Shore ND, George DJ, et al. Oral relugolix for androgen deprivation therapy in advanced prostate cancer: detailed safety analysis from the randomized phase 3 HERO study. Presented at: 2022 American Urology Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP27-16.

Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. 

. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

FDA approves first oral hormone therapy for treating advanced prostate cancer. News release. FDA. December 18, 2020. Accessed May 14, 2022. http://bit.ly/2Ws5nvz

Saad F, George DJ, Cookson MS, et al. Relugolix vs leuprolide effects on castration resistance-free survival from the phase 3 HERO study in men with advanced prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-07.

Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, demonstrated a manageable toxicity profile for patients with advanced prostate cancer. 

Patients With Advanced Prostate Cancer on Relugolix Experience Manageable Toxicity Levels 

The FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) as a treatment option for adults with unresectable or metastatic HER2-positive breast cancer and have already received anti–HER2-based treatments in the metastatic, neoadjuvant or adjuvant settings, and have experienced disease recurrence during or within 6 months of therapy completion.

Previously, in December 2019, the antibody-drug conjugate was granted an accelerated approval from the regulatory agency for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.

The multicenter, open-label, DESTINY-Breast03 trial (NCT03529110) served as the confirmatory trial for the approval.

 To be eligible for enrollment, patients needed to have HER2-positive, unresectable or metastatic breast cancer that had progressed during or following treatment with trastuzumab (Herceptin) and a taxane in the context of advanced or metastatic disease or that had progressed within 6 months following neoadjuvant or adjuvant treatment involving trastuzumab or a taxane. Those with clinically stable, previously treated brain metastases were permitted.

If patients had brain metastases that were symptomatic or required treatment; if they previously received a HER2-targeted ADC, including trastuzumab emtansine (Kadcyla; T-DM1), for metastatic disease; or if they had a history of noninfectious ILD for which they had been given glucocorticoids, they were excluded.

A total of 524 study participants were randomized 1:1 to receive intravenous (IV) trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) vs IV T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). Treatment was administered until disease progression or intolerable toxicity.

Stratification factors included hormone receptor status (positive vs negative), previous treatment with pertuzumab (Perjeta; yes vs no), and history of visceral disease (yes vs no).

The primary end point of the trial was progression-free survival (PFS) per blinded independent central review (BICR), and overall survival (OS) served as a key secondary end point. Other end points included overall response per BICR and investigator assessment, investigator-assessed PFS, and safety.

Demographic and baseline disease characteristics were found to be comparable between the 2 treatment arms, and were also determined to be largely representative of the overall population of patients with HER2-positive breast cancer.

Of note, 49.8% of those in the investigative arm and 46.8% of those in the control arm had received 1 prior line of therapy, not including endocrine therapy, for metastatic disease. Moreover, 62.1% of those in the trastuzumab deruxtecan arm vs 60.1% of those in the T-DM1 arm previously received pertuzumab. Stable brain metatases were noted in 23.8% and 19.8% of patients, respectively.

The median follow-up in the investigative arm was 16.2 months (range, 0-32.7) vs 15.3 months (range, 0-31.3) in the control arm. Trastuzumab deruxtecan significantly improved PFS vs T-DM1. Specifically, the median PFS was not yet reached (95% CI, 18.5–not estimable [NE]) in the investigative arm vs 6.8 months (95% CI, 5.6-8.2) in the control arm (HR, 0.28; 95% CI, 0.22-0.37; 

Moreover, at 12 months, 75.8% (95% CI, 69.8%-80.7%) of patients who received trastuzumab deruxtecan were still alive and free of disease progression vs 34.1% (95% CI, 27.7%-40.5%) of those who were given T-DM1.

Per investigator assessment, the median PFS in the investigative arm was 25.1 months (95% CI, 22.1-NE) vs 7.2 months (95% CI, 6.8-8.3) in the control arm (HR, 0.26; 95% CI, 0.20-0.35; 

Notably, the PFS benefit achieved with trastuzumab deruxtecan over T-DM1 was noted across all subsets of patients examined, irrespective of prior lines of therapy received.

At the data cutoff of May 21, 2021 for the interim analysis, 94.1% (95% CI, 90.3%-96.4%) of patients in the investigative arm will still alive at 12 months vs 85.9% (95% CI, 80.9%-89.7%) of those in the control arm (HR, 0.55; 95% CI, 0.36-0.86; 

=.007). The difference between the treatment arms was not found to be statistically significant, although the data are immature.

Moreover, the objective response rate based on the patients with measurable disease assessed by BICR at baseline was 82.7% (95% CI, 77.4%-87.2%) with trastuzumab deruxtecan vs 36.1% (95% CI, 30.0%-42.5%) with T-DM1.

Regarding safety, the most frequent toxicities experienced by patients who received trastuzumab deruxtecan were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain.

Serious effects that were reported in more than 1% of patients who received the ADC included vomiting, ILD, pneumonia, pyrexia, and urinary tract infection.

The FDA stated that prescribing information for trastuzumab deruxtecan includes a Boxed Warning to advise of the risk of ILD and embryo-fetal toxicity.

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed May 4, 2022. https://bit.ly/3ybhZLL

Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. 

. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022

Fam-trastuzumab deruxtecan-nxki is now an FDA-approved regimen for the treatment of patients with unresectable or metastatic HER2-positive breast cancer.

FDA Approves Trastuzumab Deruxtecan for Unresectable or Metastatic HER2+ Breast Cancer

Following the submission of new drug application (sNDA), the FDA will conduct a priority review of darolutamide (Nubeqa) plus docetaxel for patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The application is supported by findings from the phase 3 ARASENS trial (NCT02799602), in which the combination of darolutamide, docetaxel, and androgen deprivation therapy (ADT) resulted in a 32.5% reduction in the risk of death compared with docetaxel/ADT (HR, 0.68; 95% CI, 0.57-0.80; 

 The 4-year overall survival (OS) rate in the darolutamide arm was 62.7% (95% CI, 58.7%-66.7%) vs 50.4% (95% CI, 46.3%-54.6%) in the control arm.

“Bayer remains dedicated to addressing unmet needs in prostate cancer treatment for various stages of the disease,” Christine Roth, member of the executive committee of the Pharmaceutical Division and head of the Oncology SBU at Bayer, stated in a press release. “Today’s sNDA acceptance, confirmation of priority review and participation in Project Orbis, bring us closer to adding a new indication for [darolutamide] in combination with docetaxel to benefit men with mHSPC.”

Patients with histologically or cytologically confirmed prostate cancer were enrolled to the international, double-blind, placebo-controlled, phase 3 ARASENS trial. To be eligible for participation, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 1, and be candidates to receive ADT and docetaxel per investigator judgment.

Patients who had regional lymph-node involvement only or who received ADT more than 12 weeks before randomization were excluded. Patients also could not have received androgen-receptor pathway inhibitors, chemotherapy, or immunotherapy for their disease before randomization, nor could they have received radiotherapy within 2 weeks before randomization.

Within 12 weeks before randomization, all study participants received ADT or underwent orchiectomy. They were also administered docetaxel at a dose of 75 mg/m2 on day 1 of every 21-day cycle for 6 cycles, and prednisone or prednisolone, which was given per investigator discretion and started within 6 weeks prior to randomization.

Patients (n = 1306) were randomized 1:1 to receive either darolutamide at 600 mg twice daily (n = 651) or matched placebo (n = 655). They received treatment until progressive disease, a change in antineoplastic therapy, unacceptable toxicity, patient of physician decision, death, or nonadherence.

Participants were stratified based on stage of metastasis (nonregional lymph-node metastases only vs bone metastases with or without lymph-node metastases vs visceral metastases with or without lymph-node or bone metastases) and alkaline phosphatase level (below the upper limit of normal [ULN] vs able the ULN).

OS served as the primary end point for the research, and key secondary end points comprised time to castration-resistant disease, time to pain progression, symptomatic skeletal event-free survival, time to a first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, time to initiation of opioid treatment for 7 or more consecutive days, and safety.

The full analysis set was comprised of 1305 patients, 651 of whom were on the darolutamide arm and 654 of whom were on the control arm.

Both demographic and baseline characteristics were well balanced between the arms. The median age of patients was 67 years, and most patients had an ECOG performance status of 0 (71%), a Gleason score of 8 or higher (78.2%), and metastatic disease (approximately 86%) at the time of their diagnosis. All patients had metastatic disease at baseline; 79.5% had bone metastases and 17.5% had visceral metastases.

 showed that the addition of darolutamide to docetaxel/ADT resulted in improved time to development of castration-resistant disease vs docetaxel/ADT alone (HR, 0.36; 95% CI, 0.30-0.42; 

Time to pain progression (HR, 0.79; 95% CI, 0.66-0.95; 

= .01), symptomatic skeletal event-free survival (HR, 0.61; 95% CI, 0.52-0.72; 

< .001), time to first symptomatic skeletal event (HR, 0.71; 95% CI, 0.54-0.94; 

= .02), and time to the initiation of subsequent systemic antineoplastic therapy (HR, 0.39; 95% CI, 0.33-0.46; 

< .001) was also improved with the addition of darolutamide.

Regarding safety, any-grade toxicities were experienced by 99.5% of the 652 patients in the investigative arm included in the safety analysis set, vs 98.9% of the 650 patients in the control arm; effects were grade 3 or higher in 70.2% and 67.5% of patients, respectively. Serious adverse effects (AEs) were experienced by 44.8% of those in the darolutamide arm vs 42.3% of those in the control arm.

Select grade 3 or 4 AEs of interest that were noted in the investigative arm included neutropenia (33.7%), febrile neutropenia (7.8%), hypertension (6.4%), anemia (4.8%), pneumonia (3.2%), hyperglycemia (2.8%), alanine aminotransferase increase (2.8%), aspartate aminotransferase increase (2.6%), and weight increase (2.1%).

Moreover, 13.5% of those who received darolutamide experienced toxicities that resulted in permanent treatment discontinuation vs 10.6% of those who received placebo. Docetaxel was permanently discontinued in 8.0% of those in the investigative arm and 10.3% of those in the control arm.

In March 2022, a Variation Type II application was also submitted to the European Medicines Agency seeking the approval of darolutamide plus docetaxel in patients with mHSPC.

That application is also supported by findings from ARASENS. Additional global submissions in mHSPC are underway, according to Bayer.

US FDA accepts supplemental new drug application (sNDA) and grants priority review for NUBEQA (darolutamide) in combination with docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC). News release. Bayer; May 3, 2022. Accessed May 3, 2022. 

Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. 

. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115

Bayer submits applications in the US and EU for additional indication of NUBEQA (darolutamide). News release. Bayer; March 9, 2022. Accessed May 3, 2022. 

The FDA has granted a priority review designation to darolutamide plus docetaxel for patients with metastatic hormone-sensitive prostate cancer. 

FDA Launches Priority Review of Darolutamide for Metastatic Hormone-Sensitive Prostate Cancer

Patients with recurrent or metastatic nasopharyngeal cancer experienced superior progression-free survival (PFS) following frontline treatment with the PD-1 inhibitor tislelizumab (BGB-A317) and chemotherapy compared with chemotherapy alone, hitting the primary end point of the phase 3 RATIONALE 309 trial (NCT03924986).

An independent review committee (IRC) assessment confirmed the improvement in the intent-to-treat population. In addition, tislelizumab was not tied to any new safety signals when administered alongside chemotherapy; its toxicity profile was consistent with previous reports.

At an upcoming medical meeting, BeiGene, Ltd., the developer of tislelizumab, plans to present these data and will also share the full results with regulatory authorities.

“We are excited to see a clinically meaningful improvement in PFS in our phase 3 trial for tislelizumab plus chemotherapy in patients with nasopharyngeal cancer. This is our fifth positive phase 3 readout for tislelizumab, which we are developing broadly as a potentially differentiated anti–PD-1 antibody,” Yong (Ben) Ben, MD, chief medical officer of Immuno-Oncology at BeiGene, stated in a press release. “We are grateful for the patients and clinicians who participated in this trial and hopeful that they may have a new treatment option in the future.”

In the double-blind, placebo-controlled, phase 3 trial, investigators sought to examine the safety and efficacy of tislelizumab plus gemcitabine and cisplatin compared with placebo plus gemcitabine/cisplatin in the frontline treatment of patients with recurrent or metastatic nasopharyngeal cancer.

Evaluable participants were between the age of 18 and 75 years, had histologically or cytologically confirmed, recurrent, or metastatic nasopharyngeal cancer, had an ECOG performance status of 0 to 1, at least 1 measurable lesion per RECIST v1.1 criteria, and were treatment naïve for recurrent or metastatic disease.2 The ability to provide fresh or archival tumor tissues was also required.

Anyone with a local recurrence eligible for curative surgery or radiotherapy, who received an approved systemic anticancer therapy, any immunotherapy or previous therapies targeting PD-1 or PD-L1, who had active leptomeningeal disease or uncontrolled, untreated brain metastases, were excluded from the study.

A total of 263 Asian participants were randomized 1:1 to the tislelizumab/chemotherapy arm or the placebo/chemotherapy arm. Those in the experimental arm received 200 mg of intravenous (IV) tislelizumab once every 3 weeks plus IV gemcitabine at 1 g/m2 on days 1 and 8 of each 3-week cycle for 4 to 6 cycles, and IV cisplatin at 80 mg/m2 on day 1 of each 3-week cycle for 4 to 6 cycles. In the control arm, patients received the same dose and schedule of chemotherapy, without tislelizumab.

The primary end point of the trial was PFS per IRC assessment, while secondary end points comprised overall survival, IRC-assessed objective response rate and duration of response, as well as investigator-assessed PFS.

The China National Medical Products Administration has given tislelizumab market authorization in the following indications:

Full approval for use in combination with chemotherapy in the frontline treatment of patients with advanced squamous non–small cell lung cancer (NSCLC)

Conditional approval for use in patients with classical Hodgkin lymphoma who had previously received at least 1 therapy

Conditional approval for use in patients with locally advanced or metastatic urothelial carcinoma with a high PD-L1 expression who experienced progression during or after a platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy

Moreover, 3 supplemental biologics license application for the drug have been accepted by the Center for Drug Evaluation and are under review in China for the following indications:

In combination with chemotherapy in the frontline treatment of patients with advanced nonsquamous NSCLC

Second- or third-line treatment of patients with locally advanced or metastatic NSCLC who experienced progression on previous platinum-based chemotherapy

Patients with previously treated unresectable hepatocellular carcinoma

BeiGene announces positive topline results from phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal cancer. News release. BeiGene, Ltd. May 21, 2021. Accessed May 21, 2021. https://bit.ly/3oEAxgl

Tislelizumab combined with chemotherapy versus chemotherapy alone in recurrent or metastatic nasopharyngeal cancer. ClinicalTrials.gov. Updated June 11, 2020. Accessed May 21, 2021. https://clinicaltrials.gov/ct2/show/NCT03924986

This article was originally published on OncLive as “Frontline Tislelizumab Plus Chemo Improves PFS in Recurrent or Metastatic Nasopharyngeal Cancer”

The phase 3 RATIONALE 309 trial highlighted the combined efficacy of tislelizumab and chemotherapy in the frontline treatment of patients with recurrent or metastatic nasopharyngeal cancer.

Tislelizumab/Chemo Combo Extends Progression-Free Survival in Recurrent or Metastatic Nasopharyngeal Cancer

Frontline treatment with carboplatin/etoposide and atezolizumab (Tecentriq) plus the anti-TIGIT immunotherapy tiragolumab did not significantly improve progression-free survival in patients with extensive-stage small cell lung cancer (ES-SCLC), according to updated findings form the phase 3 SKYSCRAPER-02 trial (NCT04256421).

The treatment regimen, therefore, did not reach its co-primary endpoint.

In addition, the other co-primary endpoint of the study was also not met at the interim analysis and is not anticipated to reach statistical significance by the planned final analysis. Although overall survival (OS) and PFS data were not positive, the combination was associated with acceptable tolerability and no new safety signals.

A more extensive analysis of the interim findings will be presented at an upcoming medical conference, according to Roche.

“Today’s outcome is disappointing as we had hoped to continue building on the advances of [atezolizumab] in ES-SCLC, which remains difficult to treat,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release.

An immune checkpoint inhibitor with an intact Fc region, tiragolumab was designed to selectively bind to TIGIT, which is known to suppress the response of the immune system to cancer. Preclinical data have indicated that the agent can serve as an immune amplifier when paired with other immunotherapeutic agents.

Although the TIGIT pathway is distinct to the PD-L1/PD-1 pathway, it is also complementary. Investigators have hypothesized that the combination of tiragolumab and an immunotherapy like atezolizumab could serve to overcome immune suppression and essentially restore response.

The global, placebo-controlled, double-blinded SKYSCRAPER-02 trial enrolled patients with histologically or cytologically confirmed ES-SCLC who have not previously received systemic treatment.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, acceptable hematologic and end-organ function, and they needed to be treatment free for at least 6 months since their last chemoradiation.

If patients had symptomatic or actively progressing central nervous system metastases, malignancies other than SCLC within 5 years before randomization, active or a history of autoimmune disease or immune deficiency, or human immunodeficiency virus, active hepatitis B or C virus, or severe infection at the time of randomization, they were excluded.

A total of 490 patients were enrolled to the trial, and they were randomized 1:1 to receive intravenous (IV) tiragolumab at 600 mg on day 1 of each 21-day cycle plus atezolizumab and carboplatin/etoposide or placebo plus atezolizumab and carboplatin/etoposide. All patients received IV atezolizumab at 1200 mg on day 1 of each 21-day cycle, IV carboplatin on day 1 of each 21-day cycle for 4 cycles followed by etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for 4 cycles.

The co-primary end points of the trial were OS and PFS in the primary analysis set, which was comprised of all randomized patients whose cancer had not spread to the brain. Important secondary end points included OS and PFS in all randomized patients and safety.

Previously, tiragolumab was granted a breakthrough therapy designation from the FDA for use in combination with atezolizumab in the first-line treatment of patients with metastatic NSCLC whose tumors are PD-L1 high and do not harbor any 

The phase 2 CITYSCAPE trial (NCT03563716) enrolled treatment-naïve patients with stage IV non–small cell lung cancer (NSCLC) who had 

 wild-type disease. To participate, patients needed to have a PD-L1 tumor proportion score (TPS) of 1% or higher per 22C3 immunohistochemistry and local or central assay.

A total of 135 patients were randomized 1:1 to receive IV tiragolumab at 600 mg every 3 weeks in combination with IV atezolizumab at 1200 mg every 3 weeks (n = 67), or IV placebo at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 68). Treatment was administered until progressive disease or clinical benefit was lost. Key stratification factors included PD-L1 TPS (1% to 49% vs more than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no).

The co-primary end points of this research were objective response rate (ORR) and PFS. Secondary end points included duration of response, OS, and safety.

At a median follow-up of 30.4 months, the combination produced a median PFS of 5.6 months (95% CI, 4.2-10.4) per investigator assessment vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone in the intention-to-treat (ITT) population. The median OS in the investigative and control arms was 23.2 months (95% CI, 14.1-31.5) and 14.5 months (95% CI, 9.6-20.4), respectively.

At the time of the primary analysis, which had a data cutoff date of June 30, 2019, and a median follow-up of 5.9 months, the tiragolumab combination produced a clinically meaningful improvement in ORR and PFS in the ITT population vs atezolizumab monotherapy. That benefit was maintained with the additional follow-up, with a greater magnitude of improvement noted in the patient subset who had a PD-L1 TPS of 50% or less.

The phase 3 SKYSCRAPER-01 trial (NCT04294810) is currently ongoing to confirm the results yielded in CITYSCAPE. Here, the safety and efficacy of tiragolumab plus atezolizumab is being compared with atezolizumab alone in patients with previously untreated locally advanced, unresectable or metastatic PD-L1–selected NSCLC without an 

“We look forward to seeing additional data from the upcoming phase 3 trial in PD-L1–high NSCLC based on encouraging results from the CITYSCAPE study,” Garraway added.

Ad hoc announcement pursuant to Art. 53 LR Roche provides update on phase III SKYSCRAPER-02 study in extensive-stage small cell lung cancer. News release. Roche; March 30, 2022. Accessed March 30, 2022. 

A study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer (SKYSCRAPER-02). ClinicalTrials.gov. Updated March 17, 2022. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04256421

Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche; January 5, 2021. Accessed March 30, 2022. 

Cho BC, Rodriguez-Abreu S, Hussein M, et al. LBA2 updated analysis and patient-reported outcomes (PROs) from CITYSCAPE: a randomised, double-blind, phase II study of the anti-TIGIT antibody tiragolumab + atezolizumab (TA) versus placebo + atezolizumab (PA) as first-line treatment for PD-L1+ NSCLC. 

. 2021;32(suppl 7):S1428. doi:10.1016/j.annonc.2021.10.217

A study of tiragolumab in combination with atezolizumab compared with placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (SKYSCRAPER-01). ClinicalTrials.gov. Updated December 7, 2021. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04294810

This article was published on OncLive as “Tiragolumab Plus Atezolizumab/Chemo Misses PFS End Point in Extensive-Stage SCLC"

An update from the phase 3 SKYSCRAPER-02 trial found that tiragolumab to atezolizumab did not significantly improve progression-free survival in extensive-stage small cell lung cancer. 

Tiragolumab/Atezolizumab Fails to Improve PFS in Extensive-Stage SCLC 

 fusion–positive non–small cell lung cancer (NSCLC) experienced favorable response rates following treatment with selpercatinib (Retevmo), according to data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) presented during the 2022 European Lung Cancer Congress.

Following treatment, the 247 patients who had previously received platinum chemotherapy experienced a confirmed objective response rate (ORR) of 61.1% (95% CI, 54.7%-67.2%). Among the 69 treatment-naïve patients, the confirmed ORR was 84.1% (95% CI, 73.3%-91.8%). In addition, the 26 patients with measurable central nervous system (CNS) at baseline achieved an ORR of 84.6%. Among this group, 22 patients experienced complete or partial response as their confirmed best response to treatment.

At a 20.3-month median follow-up, patients in the treatment-naïve population were found to have an estimated duration of response (DOR) of 20.2 months (55.2% censoring rate). In the pretreated population, at a median follow-up time of 21.2 months, the median DOR was 28.6 months (60.9%).

Furthermore, the agent is anticipated to elicit a median progression-free survival (PFS) in the treatment-naïve and pretreated populations of 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. Patients with measurable CNS disease experienced a median intracranial PFS of 19.4 months; however, these median estimated are not yet mature.

With a median follow-up of 20.3 months in the treatment-naïve population, the median duration of response (DOR) was estimated to be 20.2 months (55.2% censoring rate). At a median follow-up of 21.2 months in the platinum-pretreated population, the median DOR was estimated to be 28.6 months (60.9%).

The estimated median progression-free survival (PFS) in the treatment-naïve and pretreated populations were 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. In those with measurable CNS disease, the median intracranial PFS with selpercatinib was 19.4 months. However, the median estimates remain immature.

“The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic 

 fusion–positive NSCLC treated with [selpercatinib], including those with difficult-to-treat brain metastases,” David Hyman, MD, chief medical officer of oncology at Eli Lilly and Company, stated in a press release.

In May 2020, the FDA granted an accelerated approval to selpercatinib for the treatment of patients with 

 alteration–positive NSCLC, medullary thyroid cancer, and other thyroid cancers based on earlier data from LIBRETTO-001.

 The regulatory decision is contingent upon data from a confirmatory trial.

The multicenter phase 1/2 LIBRETTO-001 trial enrolled patients with a diagnosis of advanced or metastatic solid tumors harboring 

 alterations.3 Patients needed to have an ECOG performance status ranging from 0 to 2, a QTc of ≤470 msec, and acceptable organ function. Notably, those with asymptomatic CNS metastases were allowed to participate.

A total of 355 patients were eligible for the efficacy analysis; of these patients, 247 patients were previously treated with at least 1 line of platinum chemotherapy and 69 were treatment naïve. Those who received prior treatment had received a median of 2 prior regimens (range, 1-15); 58% of these patients had received anti–PD-1/PD-L1 agents.

The primary end point of the trial was ORR per RECIST v1.1 criteria by independent review, and secondary end points included DOR, PFS, and safety.

The safety findings observed in the cohort proved to be consistent with what is known about selpercatinib. A total of 356 patients who had received at least 1 dose of the agent comprised the safety population. The adverse effects that were experienced by 25% or more of patients included dry mouth, diarrhea, hypertension, increased alanine/aspartate aminotransferase levels, peripheral edema, constipation, rash, headache, and fatigue.

Thirty four percent of patients needed to discontinue treatment with selpercatinib, with 10% doing so because of toxicity. Eleven of these cases were determined to be associated with the study agent.

“We are continuing to build on the robust body of evidence supporting [selpercatinib], including through an ongoing randomized phase 3 confirmatory study, with a planned readout in 2023,” Hyman added.

The phase 3 LIBRETTO-431 (NCT04194944), which is comparing the safety and efficacy of selpercatinib with standard treatment in patients with 

 fusion–positive nonsquamous NSCLC that has spread to other parts of the body, is currently recruiting.

Lilly presents updated data on Retevmo (selpercatinib) in advanced RET fusion-positive non-small-cell lung cancer (NSCLC) at the 2022 European Cancer Congress. News release. Eli Lilly and Company; April 1, 2022. Accessed April 1, 2022. 

Patients with metastatic RET fusion–positive non–small cell lung cancer experienced encouraging responses with selpercatinib.

Kristi Rosa