On June 4, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported clinical data from two pivotal trials of its anti-PD-1 antibody tislelizumab at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO 2021), including the Phase 3 RATIONALE 302 trial of tislelizumab compared to chemotherapy in previously treated patients with advanced or metastatic esophageal squamous carcinoma (ESCC) and the pivotal Phase 2 trial of tislelizumab in patients with previously treated, locally advanced unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) solid tumors. ASCO (Free ASCO Whitepaper) 2021 takes place virtually on June 4-8, 2021 (Press release, BeiGene, JUN 4, 2021, View Source [SID1234583505]).

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"We are delighted to share the promising results from two pivotal trials of tislelizumab at this year’s ASCO (Free ASCO Whitepaper), RATIONALE 302 in ESCC and a pivotal Phase 2 trial in MSI-H or dMMR solid tumors, which we plan to discuss with health authorities," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "We and our collaborator Novartis are committed to advancing tislelizumab in a broad global clinical program both as a monotherapy and in combination with other cancer therapeutics. We hope that, with a growing body of clinical evidence, tislelizumab can become a meaningful immunotherapy that can potentially benefit more patients worldwide."

Primary Results of RATIONALE 302 Trial of Tislelizumab vs. Chemotherapy in Previously Treated Advanced or Metastatic ESCC

Poster No. 4012

RATIONALE 302 is a randomized, open-label, multicenter global Phase 3 trial (NCT03430843) designed to evaluate the efficacy and safety of tislelizumab when compared to investigator’s choice chemotherapy as a second-line treatment for patients with advanced or metastatic ESCC. The primary endpoint is overall survival (OS) in the intent-to-treat (ITT) population; a key secondary endpoint is OS in patients with high PD-L1 expression (defined as visually-estimated combined positive score [vCPS] ≥10%); and other secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety. A total of 512 patients were enrolled in the trial in 11 countries or regions across Asia, Europe, and North America, randomized 1:1 to either the tislelizumab arm or the chemotherapy arm (investigator’s choice of paclitaxel, docetaxel, or irinotecan).

"Advanced or metastatic ESCC typically has a poor prognosis, with the five-year survival rate estimated at five percent. In the RATIONALE 302 trial, tislelizumab significantly prolonged survival for these patients with consistent survival benefit observed across pre-defined subgroups, including PD-L1 expression and patient race," commented Lin Shen, M.D., Peking University Cancer Hospital and Institute and a principal investigator of the trial. "In addition, tislelizumab demonstrated a favorable safety profile compared to chemotherapy, with no new safety signals identified. We hope that this anti-PD-1 antibody can become a new treatment option for those with advanced or metastatic ESCC following prior systemic treatment."

At the data cutoff on December 1, 2020, the median follow-up time in the tislelizumab arm and the chemotherapy arm was 8.5 months and 5.8 months, respectively.

Tislelizumab demonstrated a statistically significant and clinically meaningful improvement in OS, compared to chemotherapy, in both the ITT population (primary endpoint) and in patients with high PD-L1 expression (key secondary endpoint). Efficacy results included:

In the ITT population, the median OS in the tislelizumab arm was 8.6 months (95% CI: 7.5, 10.4), compared to 6.3 months (95% CI: 5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70 [95% CI: 0.57, 0.85]). The OS rates at six months and 12 months were 62.3% and 37.4% in the tislelizumab arm, respectively, compared to 51.8% and 23.7% in the chemotherapy arm;
In patients with high PD-L1 expression, the median OS in the tislelizumab arm was 10.3 months (95% CI: 8.5, 16.1), compared to 6.8 months (95% CI: 4.1, 8.3) in the chemotherapy arm (p=0.0006; HR=0.54 [95% CI: 0.36, 0.79]). The OS rates at six months and 12 months were 67.4% and 44.0% in the tislelizumab arm, respectively, compared to 50.8% and 27.0% in the chemotherapy arm;
In the trial, the PFS curves for two arms separate late. The median PFS was 1.6 months (95% CI: 1.4, 2.7) in the tislelizumab arm, compared to 2.1 months (95% CI: 1.5, 2.7) in the chemotherapy arm (HR=0.83 [95% CI: 0.67, 1.01]). The PFS rates at six months and 12 months were 21.7% and 12.7% in the tislelizumab arm, compared to 14.9% and 1.9% in the chemotherapy arm;
Tislelizumab was associated was a higher ORR of 20.3% (95% CI: 15.6, 25.8), compared to 9.8% (95% CI: 6.4, 14.1) on chemotherapy, and
Tislelizumab demonstrated a more durable anti-tumor response, with a median DoR of 7.1 months (95% CI: 4.1, 11.3), compared to 4.0 months (95% CI: 2.1, 8.2) on chemotherapy.
Compared to chemotherapy, tislelizumab demonstrated a favorable safety profile with no new safety signals identified. Safety results included:

244 patients (95.7%) experienced at least one treatment-emergent adverse event (TEAE) of any grade in the tislelizumab arm, compared to 236 patients (98.3%) in the chemotherapy arm;
In the tislelizumab arm, 187 patients (73.3%) experienced at least one treatment-related adverse event (TRAE) of any grade, with the most common (≥10%) being aspartate aminotransferase (AST) increased (11.4%), anemia (11.0%), and hypothyroidism (10.2%);
In the chemotherapy arm, 225 patients (93.8%) experienced at least one TRAE of any grade, with the most common (≥10%) being white blood cell count decreased (40.8%), neutrophil count decreased (39.2%), anemia (34.6%), decreased appetite (31.3%), diarrhea (27.5%), nausea (27.5%), vomiting (17.9%), alopecia (17.5%), malaise (14.6%), fatigue (13.8%), neutropenia (12.9%), leukopenia (12.5%), asthenia (11.7%), constipation (10.4%), and weight decreased (10.4%);
Grade ≥3 TEAEs and TRAEs were reported in 118 patients (46.3%) and 48 patients (18.8%) in the tislelizumab arm, compared to 163 patients (67.9%) and 134 patients (55.8%) in the chemotherapy arm;
Serious TEAEs and TRAEs were reported in 105 patients (41.2%) and 36 patients (14.1%) in the tislelizumab arm, compared to 105 patients (43.8%) and 47 patients (19.6%) in the chemotherapy arm;
TEAEs or TRAEs leading to treatment discontinuation occurred in 49 patients (19.2%) and 17 patients (6.7%) in the tislelizumab arm, compared to 64 patients (26.7%) and 33 patients (13.8%) in the chemotherapy arm; and
Death due to TEAEs or TRAEs occurred in 14 patients (5.5%) and five patients (2.0%) in the tislelizumab arm, compared to 14 patients (5.8%) and seven patients (2.9%) in the chemotherapy arm.
Results from Pivotal Phase 2 Trial in MSI-H or dMMR Solid Tumors

Poster No. 2569

This single-arm, open-label, multicenter pivotal Phase 2 trial (NCT03736889) was designed to evaluate the efficacy and safety of tislelizumab as a monotherapy in patients with previously treated, locally advanced unresectable or metastatic MSI-H or dMMR solid tumors, with an enrollment of 80 patients in China. The primary endpoint of this trial is ORR as assessed by independent review committee (IRC) per RECIST v1.1; secondary endpoints include time to response (TTR), DoR, disease control rate (DCR), and PFS as assessed by investigator and IRC, OS, and safety and tolerability.

"MSI-H and dMMR are found in many solid tumors, in particular cancers of the gastrointestinal tract, and existing literature supports a tissue-agnostic treatment approach with checkpoint inhibitors," said Jian Li, M.D., Beijing Cancer Hospital and a principal investigator of the trial. "In this pivotal Phase 2 trial, we observed consistent responses across tumor types with tislelizumab and it was generally well tolerated. We will continue patient follow-up for longer term evaluation, and hope that tislelizumab could potentially become a new treatment option for patients with MSI-H/dMMR solid tumors."

At the data cutoff on December 7, 2020, the median follow-up time was 11.78 months. Seventy-four patients were included in the primary efficacy analysis set, including 46 patients (62.2%) with colorectal cancer (CRC) and 28 patients with endometrial cancer, gastric or gastroesophageal junction (G/GEJ) cancer, and other tumor types.

Tislelizumab demonstrated a statistically significant and durable anti-tumor activity and showed consistent efficacy across tumor types, demonstrating the benefit of tissue-agnostic treatment. Efficacy results included:

The ORR as assessed by IRC was 45.9% (95% CI: 34.3, 57.9; p<0.0001) in the primary efficacy analysis set, 39.1% (95% CI: 25.1, 54.6) in patients with CRC, 57.1% (95% CI: 37.2, 75.5) in patients with other tumor types;
Four patients (5.4%) achieved a complete response (CR), including two (4.3%) with CRC, of which one was a patient with G/GEJ cancer and the other was a patient with endometrial cancer;
Among the 34 patients (45.9%) who achieved a response, the median TTR was 10.5 weeks with no report of progressive disease; except for one patient who started new therapy, 33 of these patients still had an ongoing response with a DoR rate of 100% at 12 months, but the median DoR was not reached; and
The median PFS and OS were not reached, and the PFS rate and OS rate at 12 months were 59.3% (95% CI: 46.2, 70.2) and 75.3% (95% CI: 62.6, 84.2), respectively, and consistent between patients with CRC and patients with other tumor types;
In the safety analysis set of all 80 patients, tislelizumab was generally well tolerated with no new safety signals identified. Safety results were consistent with expected manifestations of the disease and known effects of anti-PD-1 antibodies, including:

80 patients (100%) experienced at least one TEAE of any grade; and 79 patients (98.8%) experienced at least one TRAE of any grade, with the most common (≥15%) being anemia (43.8%), alanine aminotransferase (ALT) increased (28.8%), blood bilirubin increased (25.0%), AST increased (23.8%), white blood cell count decreased (22.5%), hypothyroidism (18.8%), rash (18.8%), and neutrophil count decreased (15.0%);
Grade ≥3 TEAEs and TRAEs were reported in 38 patients (47.5%) and 34 patients (42.5%), respectively;
Serious TEAEs and TRAEs were reported in 27 patients (33.8%) and 21 patients (26.3%), respectively;
Treatment discontinuation due to TEAEs and TRAEs each occurred in four patients (5.0%); and
Death due to TEAEs and TRAEs occurred in five patients (6.3%) and three patients (3.8%), respectively.
To learn more about BeiGene’s research and development and activities around ASCO (Free ASCO Whitepaper), please visit View Source

About Tislelizumab

Tislelizumab (BGB-A317) is a humanized IgG4 anti-PD-1 monoclonal antibody specifically designed to minimize binding to FcγR on macrophages. In pre-clinical studies, binding to FcγR on macrophages has been shown to compromise the anti-tumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T effector cells. Tislelizumab is the first drug from BeiGene’s immuno-oncology biologics program and is being developed internationally as a monotherapy and in combination with other therapies for the treatment of a broad array of both solid tumor and hematologic cancers.

The China National Medical Products Administration (NMPA) has granted tislelizumab approval in three indications, including full approval for first-line treatment of patients with advanced squamous non-small cell lung cancer (NSCLC) in combination with chemotherapy; and conditional approval for the treatment of patients with classical Hodgkin’s lymphoma (cHL) who received at least two prior therapies and for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) with PD-L1 high expression whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Full approval for these indications is contingent upon results from ongoing randomized, controlled confirmatory clinical trials.

In addition, three supplemental Biologics License Applications for tislelizumab have been accepted by the Center for Drug Evaluation (CDE) of the NMPA and are under review for first-line treatment of patients with advanced non-squamous NSCLC in combination with chemotherapy, for second- or third-line treatment of patients with locally advanced or metastatic NSCLC who progressed on prior platinum-based chemotherapy, and for patients with previously treated with at least one systemic therapy hepatocellular carcinoma.

BeiGene has initiated or completed 17 potentially registration-enabling clinical trials in China and globally, including 13 Phase 3 trials and four pivotal Phase 2 trials.

In January 2021, BeiGene and Novartis entered into a collaboration and license agreement granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

Tislelizumab is not approved for use outside of China.

About the Tislelizumab Clinical Program

Clinical trials of tislelizumab include:

Phase 3 trial comparing tislelizumab with docetaxel in the second- or third-line setting in patients with NSCLC (NCT03358875);
Phase 3 trial comparing tislelizumab to salvage chemotherapy in patients with relapsed or refractory classical Hodgkin Lymphoma (cHL; NCT04486391);
Phase 3 trial in patients with locally advanced or metastatic urothelial carcinoma (NCT03967977);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced squamous NSCLC (NCT03594747);
Phase 3 trial of tislelizumab in combination with chemotherapy versus chemotherapy as first-line treatment for patients with advanced non-squamous NSCLC (NCT03663205);
Phase 3 trial of tislelizumab in combination with platinum-based doublet chemotherapy as neoadjuvant treatment for patients with NSCLC (NCT04379635);
Phase 3 trial of tislelizumab combined with platinum and etoposide versus placebo combined with platinum and etoposide in patients with extensive-stage small cell lung cancer (NCT04005716);
Phase 3 trial comparing tislelizumab with sorafenib as first-line treatment for patients with hepatocellular carcinoma (HCC; NCT03412773);
Phase 2 trial in patients with previously treated unresectable HCC (NCT03419897);
Phase 2 trial in patients with locally advanced or metastatic urothelial bladder cancer (NCT04004221);
Phase 3 trial comparing tislelizumab with chemotherapy as second-line treatment for patients with advanced esophageal squamous cell carcinoma (ESCC; NCT03430843);
Phase 3 trial of tislelizumab in combination with chemotherapy as first-line treatment for patients with ESCC (NCT03783442);
Phase 3 trial of tislelizumab versus placebo in combination with chemoradiotherapy in patients with localized ESCC (NCT03957590);
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment for patients with gastric cancer (NCT03777657);
Phase 2 trial of tislelizumab in patients with relapsed or refractory cHL (NCT03209973);
Phase 2 trial in patients with MSI-H/dMMR solid tumors (NCT03736889); and
Phase 3 trial of tislelizumab combined with chemotherapy versus placebo combined with chemotherapy as first-line treatment in patients with nasopharyngeal cancer (NCT03924986).
BeiGene Oncology

BeiGene is committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D team of approximately 2,300 colleagues dedicated to advancing more than 90 clinical trials involving more than 13,000 patients and healthy volunteers. Our expansive portfolio is directed by a predominantly internalized clinical development team supporting trials in more than 40 countries. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. The Company currently markets three medicines discovered and developed in our labs: BTK inhibitor BRUKINSA in the United States, China, Canada, and additional international markets; and non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab and PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations, including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis Pharma AG granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On June 4, 2021 BeiGene, Ltd. (NASDAQ: BGNE; HKEX: 06160), a global biotechnology company focused on developing and commercializing innovative medicines worldwide, reported that its PARP inhibitor pamiparib showed efficacy in patients with HER2-negative breast cancer and demonstrated numerically higher but not statistically significant progression-free survival in gastric cancer (Press release, BeiGene, JUN 4, 2021, View Source [SID1234583504]). The results in gastric cancer may have been influenced by the fact that the study did not meet the planned enrollment target. These data were presented in poster sessions at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (ASCO 2021) taking place virtually on June 4-8, 2021, and included initial reporting from a Phase 2 trial evaluating pamiparib in locally advanced or metastatic HER2-negative (HER2[-]) breast cancer with germline BRCA1/2 mutation (gBRCA1/2m) and initial reporting of a randomized Phase 2 trial of pamiparib as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer who responded to platinum-based first-line chemotherapy.

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"We are pleased to share results from our pamiparib clinical development program, focused on diseases with high prevalence, as we work towards our mission of improving outcomes for patients in need," commented Yong (Ben) Ben, M.D., Chief Medical Officer, Immuno-Oncology at BeiGene. "We are encouraged by the positive results for pamiparib in HER2-negative breast cancer, a devastating disease and leading cause of cancer death among women, and while it did not achieve statistical significance in gastric cancer, we hope these findings can improve understanding among the scientific community and reinforce the tolerability of pamiparib as we advance its global development."

Results from Phase 2 Trial of Pamiparib in Locally Advanced or Metastatic HER2-Negative Breast Cancer with gBRCAm

Poster No. 1087

This single-arm, open label, multi-center Phase 2 trial (NCT03575065) was designed to evaluate the safety and efficacy of pamiparib in patients with locally advanced or metastatic HER2-negative breast cancer, with deleterious or suspected deleterious gBRCA1/2m, who received no more than two prior lines of chemotherapy. A total of 88 patients were enrolled, including 62 patients with triple-negative breast cancer (TNBC cohort) and 26 patients with hormone receptor-positive (HR[+]) and HER2(-) breast cancer (HR[+] cohort). Fifty-five patients in the TNBC cohort and 21 patients in the HR(+) cohort had measurable disease at baseline per independent review committee (IRC). The primary endpoint of the trial was objective response rate (ORR) as assessed by IRC per RECIST v1.1; secondary endpoints included investigator-assessed ORR, duration of response (DoR), best overall response (BOR), progression-free survival (PFS), clinical benefit rate (CBR), and disease control rate (DCR) as assessed by IRC and investigator, and overall survival (OS), as well as safety and tolerability.

"Studies have suggested that breast cancer with germline BRCA mutations may be susceptible to PARP inhibition. These Phase 2 results demonstrated pamiparib’s efficacy in patients with HR(+)/HER2(-) breast cancer, as well as in triple-negative breast cancer, one of the most aggressive forms of the disease with the poorest outcomes," said Binghe Xu, M.D., Ph.D., Cancer Hospital Chinese Academy of Medical Sciences and a principal investigator of the trial. "In addition to demonstrating positive response rates, the trial suggested pamiparib may show promise in progression-free survival benefits and we look forward to further research of pamiparib in this patient population, who are in great need of additional treatment options."

At the data cut-off on October 9, 2020, the median follow-up time was 13.8 months (TNBC cohort, 10.9 months; HR[+] cohort, 18.5 months).

Pamiparib demonstrated meaningful and durable clinical activity in patients across both cohorts. Efficacy results included:

Confirmed ORR as assessed by IRC, the primary efficacy endpoint, was 61.9% (95% CI: 38.4, 81.9) in the HR(+) cohort and 38.2% (95% CI: 25.4, 52.3) in the TNBC cohort;
Four patients achieved a complete response (CR), including three in the TNBC cohort and one patient in the HR(+) cohort;
18 patients in the TNBC cohort and 12 patients in the HR(+) cohort demonstrated a partial response (PR);
DCR as assessed by IRC was 90.5% (95% CI: 69.6, 98.8) in the HR(+) cohort and 72.7% (95% CI: 59.0, 83.9) in the TNBC cohort;
Additionally, CBR as assessed by IRC was 71.4% (95% CI: 47.8, 88.7) in the HR(+) cohort and 43.6% (95% CI: 30.3, 57.7) in the TNBC cohort;
Patients in the HR(+) cohort had a median DoR of 7.5 months (95% CI: 5.6, 14.8) and patients in the TNBC cohort had a median DoR of 7.0 months (95% CI: 3.9, not estimable [NE]);
The median PFS was 9.2 months (95% CI: 7.4, 11.9) in the HR(+) cohort and 5.5 months (95% CI: 3.7, 7.3) in the TNBC cohort; and
In the trial, the median OS in the TNBC cohort was 17.1 months (95% CI:13.7, NE) and was not reached in the HR(+) cohort (NE; 95% CI: 18.1, NE).
Pamiparib was generally well-tolerated, and results from the safety analysis for all 88 patients across both cohorts included:

87 patients (98.9%) experienced at least one treatment-emergent adverse event (TEAE) of any grade and 54 patients (61.4%) experienced at least one Grade ≥3 TEAE;
87 patients (98.9%) experienced at least one treatment-related TEAE of any grade, and 53 patients (60.2%) experienced at least one Grade ≥3 treatment-related TEAE, with the most common (≥5%) being anemia (39.8%), neutrophil count decrease (29.5%), white blood cell count decrease (21.6%), platelet count decrease (9.1%), leukopenia (5.7%), and neutropenia (5.7%);
Serious TEAEs were reported in 19 patients (21.6%) and serious treatment-related TEAEs were reported in 15 patients (17.0%);
Two patients experienced treatment discontinuation due to TEAEs, both considered treatment-related; and
TEAEs leading to death occurred in one patient (1.1%) and no treatment-related TEAEs leading to death were reported.
Results from Phase 2 Trial of Pamiparib vs. Placebo in Locally Advanced or Metastatic Gastric Cancer

Poster No. 3109

PARALLEL 303 is a double-blind, randomized, multicenter Phase 2 trial (NCT03427814) comparing the safety and efficacy of pamiparib vs placebo as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line chemotherapy. A total of 136 patients were enrolled and due to slow enrollment and a change in the standard of care for this patient population, the trial did not meet the planned target enrollment of approximately 540 patients. Patients were randomized 1:1 to receive pamiparib 60 mg orally twice daily (n = 71) or placebo (n = 65) in 28-day cycles. The primary endpoint was PFS as assessed by investigator per RECIST v1.1; secondary endpoints included time to subsequent treatment (TSST), ORR, DoR, and time to response (TTR) as assessed by investigator, OS, and safety. At the time of data analysis, OS data were immature.

"Many patients with gastric cancer become resistant to currently available therapies in later stages of disease, so continued research is crucial to find medicines that may improve outcomes and survival," said Fortunato Ciardiello, M.D., Ph.D., Second University of Naples, Italy and a principal investigator of the trial. "Though the PARALLEL 303 study did not achieve statistical significance, these results help us advance understanding of the role that PARP inhibition has in metastatic gastric cancer and reinforces pamiparib’s safety profile and potential clinical benefit for appropriate patients."

At the data cutoff on December 7, 2020, median follow-up time was 8.0 months (pamiparib arm, 7.9 months; placebo arm, 8.0 months).

Pamiparib demonstrated a numerically higher median PFS of 3.7 months (95% CI, 1.9, 5.3 months), compared to 2.1 months (95% CI, 1.9, 3.8 months) in the placebo arm, however the trial did not achieve statistical significance (p=0.1428; HR=0.799 [95% CI, 0.5, 1.2]). Additional efficacy results included:

The median OS in the pamiparib arm was 10.2 months (95% CI: 8.7, 16.3), compared to 12.0 months in the placebo arm (95% CI: 8.2, not estimable [NE]);
The ORR in the pamiparib arm was 7.7% (95% CI: 1.6, 20.9), compared to 6.3% (95% CI: 0.8, 20.8) in the placebo arm;
The median DoR in the pamiparib arm was 3.6 months (95% CI: 3.5, NE), compared to NE (95% CI: 5.6, NE) in the placebo arm; and
The median TTR in the pamiparib arm was 3.7 months (range: 1.8, 7.3), compared to 1.9 months (range: 1.9, 1.9) in the placebo arm.
In the trial, pamiparib was generally well-tolerated, with no new safety signals observed. Safety results included:

65 patients (91.5%) experienced at least one TEAE of any grade in the pamiparib arm, compared to 61 patients (93.8%) in the placebo arm;
Serious TEAEs and TEAEs of Grade ≥3 were reported in 14 patients (19.7%) and 29 patients (40.8%) respectively in the pamiparib arm, compared to 10 patients (15.4%) and 20 patients (30.8%) in the placebo arm;
In the pamiparib arm, the most common (≥10%) TEAEs included anemia (36.6%), nausea (32.4%), decreased appetite (26.8%), vomiting (23.9%), asthenia (21.1%), diarrhea (18.3%), upper abdominal pain (16.9%), aspartate aminotransferase increased (AST; 12.7%), alanine aminotransferase increased (ALT; 11.3%), abdominal pain (11.3%), constipation (11.3%), and white blood cell count decreased (11.3%);
In the placebo arm, the most common (≥10%) TEAEs included abdominal pain (18.5%), nausea (16.9%), peripheral sensory neuropathy (13.8%), asthenia (16.9%), anemia (12.3%), decreased appetite (12.3%), dysphagia (12.3%), upper abdominal pain (10.8%), constipation (10.8%), and diarrhea (10.8%);
Treatment discontinuation due to TEAEs occurred in eight patients (11.3%) in the pamiparib arm, compared to two patients (3.1%) in the placebo arm; and
Death due to TEAEs occurred in two patients (2.8%) in the pamiparib arm, none of which were deemed treatment-related, compared to two patients (3.1%) in the placebo arm, of which one (1.5%) was deemed treatment-related.
To learn more about BeiGene’s research and development and activities around ASCO (Free ASCO Whitepaper), please visit View Source

About Pamiparib

Pamiparib is an inhibitor of PARP1 and PARP2 which has demonstrated pharmacological properties such as brain penetration and PARP-DNA complex trapping in preclinical models. Discovered by BeiGene scientists, pamiparib is currently in global clinical development as a monotherapy or in combination with other agents for a variety of solid tumor malignancies. To date, more than 1,200 patients have been enrolled in clinical trials of pamiparib.

In China, pamiparib received conditional approval for the treatment of patients with germline BRCA (gBRCA) mutation-associated recurrent advanced ovarian, fallopian tube, or primary peritoneal cancer who have been treated with two or more lines of chemotherapy in May 2021. Full approval for this indication is contingent upon results from ongoing corroborative trials confirming the clinical benefit of pamiparib in this population.

About the Pamiparib Clinical Program

Clinical trials of pamiparib include:

Phase 3 trial in China of pamiparib as maintenance versus placebo in patients with platinum-sensitive recurrent ovarian cancer (NCT03519230);
Phase 2 trial of pamiparib in patients with metastatic castration-resistant prostate cancer with homologous recombination deficiency (NCT03712930);
Phase 2 trial in China of pamiparib in patients with metastatic HER2-negative breast cancer with BRCA mutation (NCT03575065);
Phase 2 trial of pamiparib in patients with advanced or inoperable gastric cancer (NCT03427814);
Phase 1/2 trial in China of pamiparib in patients with advanced ovarian cancer, fallopian cancer, and primary peritoneal cancer or advanced triple negative breast cancer (NCT03333915);
Phase 1b/2 trial of pamiparib in combination with radiation therapy and/or temozolomide in patients with first-line or recurrent/refractory glioblastoma (NCT03150862);
Phase 1b trial of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors (NCT03150810); and
Phase 1b trial of pamiparib in combination with tislelizumab for a variety of solid tumor malignancies (NCT02660034).
BeiGene Oncology

BeiGene is committed to advancing best and first-in-class clinical candidates internally or with like-minded partners to develop impactful and affordable medicines for patients across the globe. We have a growing R&D team of approximately 2,300 colleagues dedicated to advancing more than 90 clinical trials involving more than 13,000 patients and healthy volunteers. Our expansive portfolio is directed by a predominantly internalized clinical development team supporting trials in more than 40 countries. Hematology-oncology and solid tumor targeted therapies and immuno-oncology are key focus areas for the Company, with both mono- and combination therapies prioritized in our research and development. The Company currently markets three medicines discovered and developed in our labs: BTK inhibitor BRUKINSA in the United States, China, Canada, and additional international markets; and non-FC-gamma receptor binding anti-PD-1 antibody tislelizumab and PARP inhibitor pamiparib in China.

BeiGene also partners with innovative companies who share our goal of developing therapies to address global health needs. We commercialize a range of oncology medicines in China licensed from Amgen and Bristol Myers Squibb. We also plan to address greater areas of unmet need globally through our collaborations, including with Amgen, Bio-Thera, EUSA Pharma, Mirati Therapeutics, Seagen, and Zymeworks. BeiGene has also entered into a collaboration with Novartis Pharma AG granting Novartis rights to develop, manufacture, and commercialize tislelizumab in North America, Europe, and Japan.

On June 4, 2021 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported two e-poster presentations at the 2021 ASCO (Free ASCO Whitepaper) Annual Meeting (Press release, Deciphera Pharmaceuticals, JUN 4, 2021, View Source [SID1234583503]). The presentations include intra-patient dose escalation (IPDE) data from the INVICTUS Phase 3 study of QINLOCK in patients with advanced gastrointestinal stromal tumor (GIST), as well as preliminary results from the Company’s ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in patients with endometrial cancer.

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Both e-poster presentations are now available on-demand via the ASCO (Free ASCO Whitepaper) Meeting Library and on the Company’s website at www.deciphera.com/presentations-publications.

"We are committed to understanding the full benefit QINLOCK may provide to patients with GIST and the data presented at ASCO (Free ASCO Whitepaper) further demonstrate the important clinical benefits QINLOCK can provide in this population," said Matthew L. Sherman, MD, Executive Vice President and Chief Medical Officer of Deciphera. "Importantly, consistent with our Phase 1 data, these exploratory results from the Phase 3 study show that dose escalation to QINLOCK 150 mg BID after disease progression on QINLOCK 150 mg QD can offer substantial additional clinical benefit with a tolerable safety profile. As the body of data supporting QINLOCK’s efficacy and safety continues to grow, we are pleased with QINLOCK’s potential to offer clinically meaningful benefit for GIST patients in multiple settings of the disease."

Dr. Sherman continued, "Results presented today from the endometrial cancer cohort of the Phase 1b/2 study of rebastinib, our selective TIE2 inhibitor, in combination with paclitaxel continue to demonstrate rebastinib’s anti-tumor activity as well as its evolving safety profile. We look forward to sharing updated data from the platinum-resistant ovarian cancer cohort of this study in the third quarter of 2021 and finalizing the pivotal development plan for rebastinib in combination with paclitaxel in the second half of 2021."

INVICTUS Dose Escalation Data

The INVICTUS Phase 3 clinical study is a randomized (2:1), double-blind, placebo-controlled, international, multicenter study to evaluate the safety, tolerability, and efficacy of QINLOCK compared to placebo in patients with advanced GIST whose previous therapies have included at least imatinib, sunitinib, and regorafenib. The Company previously reported primary results from the randomized portion of the INVICTUS study, in which QINLOCK significantly improved PFS and showed a clinically meaningful overall survival (OS) benefit. An exploratory analysis was conducted to assess the safety and efficacy of QINLOCK dose escalation to 150 mg BID among patients randomized to QINLOCK 150 mg QD in the INVICTUS study.

As of an August 10, 2020 cutoff date, of the 85 patients randomized to QINLOCK 150 mg QD in the INVICTUS study, 43 dose escalated to 150 mg BID after disease progression by blinded independent central review using modified RECIST version 1.1.

Among the 43 patients in the QINLOCK arm who dose escalated, initial median PFS, or mPFS1, was 4.6 months (95% CI 2.7–6.4) and the subsequent median PFS, or mPFS2, from the day of dose escalation to second disease progression or death was 3.7 months (95% CI 3.1–5.3). The ratio of mPFS2/mPFS1 was 80%.
Median OS was 18.4 months in patients randomized to QINLOCK 150 mg QD with progressive disease and who dose escalated to 150 mg BID (n=43) and 14.2 months in those randomized to QINLOCK 150 mg QD with progressive disease and not dose escalating (n=22) (HR 0.74, 95% CI 0.37–1.49).
QINLOCK 150 mg BID was well tolerated with a similar safety profile to QINLOCK 150 mg QD, with new or worsening Grade 3–4 TEAEs of anemia in 6 (14%) and abdominal pain in 3 (7%) patients.
Updated Preliminary Data from the Ongoing Phase 1b/2 Study of Rebastinib in Combination with Paclitaxel in Endometrial Cancer

The Phase 1b/2 study of rebastinib in combination with paclitaxel is a two-part, open-label, multicenter study assessing the safety, tolerability, anti-tumor activity, and pharmacokinetics of rebastinib in patients with advanced or metastatic solid tumors. As previously announced, both the endometrial and platinum-resistant ovarian cancer cohorts in Part 2 of the study advanced into the second stage of the Simon two-stage design based on demonstrating at least five responses in each cohort.

As of a March 19, 2021 cutoff date, 38 patients with endometrial cancer initiated treatment with rebastinib in combination with weekly paclitaxel 80 mg/m2. All 38 patients received prior taxane, with 44% of patients having received four or more prior anti-cancer regimens, with a median of three prior therapies across all patients. 16 patients were treated with rebastinib at a starting dose of 100 mg BID (11 reduced to 50 mg BID) and 22 patients were treated with a starting dose of 50 mg BID. Of the 38 patients with endometrial cancer who initiated treatment with rebastinib, the median duration of treatment was 3.7 months.

Of the 33 patients in the modified intent-to-treat (mITT) population:

There were 11 partial responses (8 confirmed) and 12 patients with stable disease for an objective response rate of 33% (unconfirmed and confirmed) and 24% (confirmed only) with a median duration of response of 7.4 months,
The median progression-free survival (PFS) was 6.2 months.
The majority of the common (≥15%) treatment-emergent adverse events (TEAEs) were Grade 2 or lower.
Nine patients experienced SAEs at least possibly related to rebastinib including muscular weakness (n=3), nausea (n=2), acute myocardial infarction (n=1), atrial flutter (n=1), dehydration (n=1), noninfective encephalitis (n=1), peritonsillitis (n=1), and stress cardiomyopathy (n=1).
The Company expects to present updated data from the ongoing Phase 1b/2 study of rebastinib in combination with paclitaxel in the platinum-resistant ovarian cancer cohort in the third quarter of 2021 and finalize the pivotal development plan for rebastinib in combination with paclitaxel in the second half of 2021, subject to favorable data and discussions with regulators.

On June 4, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported promising phase 2 results for CABOMETYX (cabozantinib) in combination with Bristol Myers Squibb’s OPDIVO (nivolumab) in patients with advanced or metastatic non-clear cell renal cell carcinoma (nccRCC) from an investigator-sponsored trial (Press release, Exelixis, JUN 4, 2021, View Source [SID1234583502]). The combination regimen showed promising efficacy and an acceptable safety profile in patients with metastatic nccRCC with papillary, unclassified or translocation-associated histologies. The data will be presented as part of the Poster Discussion Session: Genitourinary Cancer – Kidney and Bladder at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held virtually, June 4-8, 2021. All posters will be available on demand beginning at 6:00 a.m. PT on Friday, June 4.

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"The strong objective response rate associated with cabozantinib in combination with nivolumab in this trial is a meaningful finding for this patient community, who are typically not the focus of major clinical trials for kidney cancer," said Dr. Chung-Han Lee, medical oncologist at Memorial Sloan Kettering Cancer Center, and principal investigator for the study. "We look forward to building on these results with additional insights into which types of non-clear cell renal cell carcinoma may be most likely to respond to this combination regimen."

This single-institution, non-randomized, open-label, investigator-sponsored, phase 2 trial of CABOMETYX 40 mg in combination with OPDIVO (240 mg every two weeks or 480 mg every four weeks) was conducted by Memorial Sloan Kettering Cancer Center. The trial enrolled patients with advanced or metastatic nccRCC who had not received prior immune checkpoint inhibitor (ICI) therapy. A total of 47 patients were treated; 40 patients with papillary, unclassified, or translocation-associated RCC in cohort 1, and seven patients with chromophobe histology in cohort 2. Median follow-up was 13.1 months.

In cohort 1, CABOMETYX in combination with OPDIVO demonstrated an objective response rate (ORR) of 47.5% (95% confidence interval [CI]: 31.5–63.9). Among the 32 patients with papillary histology, ORR was 47% (95% CI: 29–65). Objective responses were seen in five of six patients with NF2 mutations, four of five patients with FH mutations and one of six patients with SETD2 mutations. Median duration of response was 13.6 months. Median progression-free survival was 12.5 months (95% CI: 6.3–15.9), and median overall survival was 28 months (95% CI: 16.3–non-estimable). A best response of stable disease was observed for five of seven patients in cohort 2.

"Following the recent FDA approval of CABOMETYX in combination with OPDIVO as a first-line treatment for patients with advanced renal cell carcinoma, we’re excited to see these new data specifically in non-clear cell RCC, a heterogeneous group of kidney cancers," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "These positive phase 2 results build on our understanding of CABOMETYX’s potential use in papillary RCC, one of these subtypes, and may help physicians choose an appropriate first-line systemic therapy for their patients with advanced non-clear cell renal cell carcinoma."

CABOMETYX or OPDIVO was discontinued due to adverse events in 17% and 13% of patients, respectively. Both therapies were discontinued due to adverse events in 9% of patients. Grade 3/4 treatment-related adverse events were observed in 32% of patients. The most common grade 3/4 treatment-related adverse events were hypertension (13%) and diarrhea (6%).

More information about this trial (NCT03635892) is available at ClinicalTrials.gov.

About RCC

The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.2

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.3 Other subtypes, collectively grouped as nccRCC, constitute a diverse mixture of malignancies.4 Papillary histology accounts for about 15% of all renal cell carcinomas.5,6 Genomic and molecular characterization of papillary RCC has implicated MET signaling as a key driver of this cancer.6,7 Targeting VEGFR and other tyrosine kinases, including MET and AXL, has led to improved outcomes in RCC compared with sunitinib and further supported the investigation of MET-targeting tyrosine kinase inhibitors in nccRCC.

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with HCC who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information View Source

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

Dr. Lee has provided advisory services to Exelixis and Bristol Myers Squibb.

On June 4, 2021 Exelixis, Inc. (NASDAQ: EXEL) reported results from a post-hoc exploratory analysis demonstrating that the efficacy benefits seen in the phase 3 CheckMate -9ER trial with CABOMETYX (cabozantinib) in combination with Bristol Myers Squibb’s OPDIVO (nivolumab) compared with sunitinib as a first-line treatment for advanced renal cell carcinoma (RCC) were observed across analyzed subgroups, including those based on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk status, site of metastases and extent of tumor burden at baseline (Press release, Exelixis, JUN 4, 2021, View Source [SID1234583501]). The data will be presented as part of the Poster Session: Genitourinary Cancer – Kidney and Bladder at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, which is being held virtually, June 4-8, 2021. All posters will be available on demand beginning at 6:00 a.m. PT on Friday, June 4.

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Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"To inform treatment decisions, we are eager to gain a deeper understanding of how baseline disease characteristics may impact clinical outcomes for patients treated with cabozantinib in combination with nivolumab, and this analysis supports that the combination regimen may be an appropriate option in the first-line setting for a wide range of patients with renal cell carcinoma," said Andrea Apolo, M.D., Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, who served on the study’s steering committee. "Some of the baseline characteristics, including the presence of bone metastases, are associated with worse outcomes, making it encouraging to see that the combination regimen demonstrated efficacy benefits in these patients."

As presented at the ASCO (Free ASCO Whitepaper) 2021 Genitourinary Cancers Symposium (ASCO GU) in February 2021, at a median follow-up of 23.5 months in the CheckMate -9ER intent-to-treat population, median progression-free survival (PFS) was doubled at 17.0 months for CABOMETYX in combination with OPDIVO compared with 8.3 months for sunitinib (hazard ratio [HR]: 0.52; 95% confidence interval [CI]: 0.43-0.64; P<0.0001). Median overall survival (OS) was not yet reached for the combination regimen versus 29.5 months with sunitinib (HR 0.66; 95% CI: 0.50-0.87; P=0.0034). Objective response rate (ORR) was 54.8% with CABOMETYX in combination with OPDIVO versus 28.4% with sunitinib, and complete response (CR) rate was 9.3% versus 4.3%, respectively.

In this new exploratory analysis presented at ASCO (Free ASCO Whitepaper) 2021 (abstract #4553), patient subgroups were pre-specified based on the following baseline characteristics: IMDC risk status (favorable-, intermediate- or poor-risk disease), site of metastases (liver, bone or lung), number of organ sites with tumor lesions (one or at least two) and size of tumor lesions (less than or greater than/equal to the median). Across subgroups, median PFS was longer and ORR rates were consistently higher for patients treated with CABOMETYX in combination with OPDIVO compared with sunitinib. CR rates were higher with CABOMETYX in combination with OPDIVO versus sunitinib in most subgroups, ranging up to 16.3% for CABOMETYX in combination with OPDIVO versus 8.4% for sunitinib in the subgroup with a lower than median tumor lesion size, and 19.7% for CABOMETYX in combination with OPDIVO versus 4.4% for sunitinib in the subgroup where metastatic spread was limited to one organ site. See table below for additional details.

"Following the FDA approval of CABOMETYX in combination with OPDIVO as a first-line treatment for advanced renal cell carcinoma in January, these data further underscore the combination regimen’s role as an important option for a broad range of patients in need of first-line treatment for RCC," said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. "Our goal is to provide this combination regimen to as many eligible patients as possible, and we’re glad to see these data support its use across RCC patients regardless of prognosis."

Median OS was not yet reached for CABOMETYX in combination with OPDIVO in any subgroup, but 15-month OS rates were higher with CABOMETYX in combination with OPDIVO compared with sunitinib in all subgroups. Hazard ratios favored CABOMETYX in combination with OPDIVO compared with sunitinib for most subgroups (see table). Note, the trial was not powered to assess efficacy in subgroups. For certain subgroups, particularly patients with favorable risk, few events were observed in either arm.

In CheckMate -9ER, CABOMETYX in combination with OPDIVO was generally well tolerated and reflected the known safety profiles of the tyrosine kinase inhibitor and immunotherapy components in previously untreated advanced RCC. The most common adverse reactions reported in at least 20% of patients treated with CABOMETYX in combination with OPDIVO were diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough and upper respiratory tract infection. A safety analysis with extended follow-up reported at ASCO (Free ASCO Whitepaper) GU this year identified no new safety signals; among patients treated with OPDIVO and CABOMETYX, 6.6% discontinued both agents due to treatment-related adverse events, 9.7% discontinued OPDIVO only, and 7.2% discontinued CABOMETYX only.

About CheckMate -9ER

CheckMate -9ER is an open-label, randomized (1:1), multi-national phase 3 trial evaluating patients with previously untreated advanced or metastatic renal cell carcinoma with a clear cell component. A total of 651 patients (22% favorable risk, 58% intermediate risk, 20% poor risk; 25% PD-L1 ≥1%) were randomized to CABOMETYX at a dose of 40 mg QD and OPDIVO (n = 323) versus sunitinib (n = 328). The primary endpoint is PFS. Secondary endpoints include OS and ORR. The primary efficacy analysis compares the doublet combination regimen of CABOMETYX and OPDIVO versus sunitinib in all randomized patients. The trial is sponsored by Bristol Myers Squibb and Ono Pharmaceutical Co. and co-funded by Exelixis, Ipsen and Takeda Pharmaceutical Company Limited.

About RCC

The American Cancer Society’s 2021 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the U.S.1 Clear cell RCC is the most common form of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for RCC is high; for patients with advanced or late-stage metastatic RCC, however, the five-year survival rate is only 13%.1 Approximately 32,000 patients in the U.S. and 71,000 worldwide will require systemic treatment for advanced kidney cancer in 2021.3

About 70% of RCC cases are known as "clear cell" carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called von Hippel-Lindau, which leads to higher levels of MET, AXL and VEGF.5,6 These proteins promote tumor angiogenesis (blood vessel growth), growth, invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape pathways that drive resistance to VEGF receptor inhibitors.6,7

About CABOMETYX (cabozantinib)

In the U.S., CABOMETYX tablets are approved for the treatment of patients with advanced RCC; for the treatment of patients with hepatocellular carcinoma who have been previously treated with sorafenib; and for patients with advanced RCC as a first-line treatment in combination with OPDIVO. CABOMETYX tablets have also received regulatory approvals in the European Union and additional countries and regions worldwide. In 2016, Exelixis granted Ipsen exclusive rights for the commercialization and further clinical development of cabozantinib outside of the United States and Japan. In 2017, Exelixis granted exclusive rights to Takeda Pharmaceutical Company Limited for the commercialization and further clinical development of cabozantinib for all future indications in Japan. Exelixis holds the exclusive rights to develop and commercialize cabozantinib in the United States.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, vomiting, weight decreased, constipation, and dysphonia.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.