Dylann Cohn-Emery

A rolling submission of the Biologics License Application (BLA) was initiated for toripalimab for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma (NPC). The developer, Shanghai Junshi Biosciences Co., Ltd announced plans to submit the BLA back in September 2020, after the agent showed promise in the phase 1b/2 POLARIS-02 trial (NCT02915432) and was granted Breakthrough Therapy Designaton.

“There has been limited development of treatment approaches for patients with advanced NPC in the United States [US]," Patricia Keegan, MD, chief medical officer of Junshi Biosciences, said in a statement. “We are determined to advance effective treatments in the US by leveraging the successful experience with toripalimab, a safe and effective treatment for previously treated NPC that is now approved for marketing in China.”

In POLARIS-02, the safety and efficacy of toripalimab was assessed in patients with recurrent or metastatic nasopharyngeal carcinoma, head and neck cancer, gastric cancer, and esophageal cancer. There was a cohort of 190 patients with nasopharyngeal carcinoma included in the study.

Toripalimab led to an objective response rate (ORR) of 20.5% (95% CI, 15.0%-27.0%) with a median duration of response (DOR) of 12.8 months (95% CI, 9.4–not estimable). In terms of survival, the median progression-free survival (PFS) was 1.9 months (95% CI, 1.8-3.5), and the median overall survival (OS) was 17.4 months (95% CI, 11.7-22.9).

Those enrolled were 18 years of age or older with histologically or cytologically documented recurrent or metastatic disease haryngeal carcinoma that was refractory to previous standard chemotherapy, an ECOG performance status of 0 or 1, and measurable disease, per the eligibility protocol of the study. 

The primary end point of the study was ORR per independent review committee, according to RECIST v1.1 criteria. The key secondary end points were safety, DOR, disease control rate, PFS, and OS.

The Breakthrough Therapy Designation given to toripalimab, an anti–PD-1 monoclonal antibody, in September 2020 was based on preliminary clinical evidence suggesting it could show substantial improvement over the current therapies in this setting. The designation will expedite the development and review of this agent for patients with NPC.

“We appreciate the FDA’s recognition of this potentially important new treatment through its Breakthrough Therapy Designation, which enables the acceleration of the review process,” Keegan continued. “We will work closely with the FDA to facilitate the review of the US marketing application in order to make toripalimab available for patients in the US as soon as possible.”

Toripalimab is the first of its type to be approved for marketing in China, has been studied in over 30 clinical trials globally, and has over 15 indications. If this drug is approved for the treatment of recurrent or metastatic NPC and the collaboration between Shanghai Junshi Biosciences Co., Ltd. and Coherus Biosciences, Inc. is closed successfully, the companies will file additional toripalimab BLA supplements with the FDA over the next 3 years for multiple disease types including non–small cell lung cancer, as well as more rare cancers. The collaboration was started in February 2021 to develop and commercialize toripalimab in the US and Canada.

“Toripalimab could address a significant unmet medical need as a new treatment for advanced NPC, and we are encouraged by the initiation of the BLA submission,” Denny Lanfear, chief executive officer of Coherus Biosciences, Inc., said in a press release. “With an extensive clinical development program across a range of tumor types, a broad therapeutic profile is developing for toripalimab. We look forward to working with Junshi Biosciences to bring this new anti–PD-1 antibody to patients in the US and Canada.”

The FDA has granted toripalimab 1 Breakthrough Therapy, 1 Fast Track, and 3 Orphan Drug Designations for the treatment of patients with NPC, mucosal melanoma, and soft tissue sarcoma.

In December 2018, toripalimab was given conditional approval from the National Medical Products Administration (NMPA) for the treatment of patients with unresectable or metastatic melanoma in the second line. Since then, it has been included in the 2019 and 2020 Guidelines for Chinse Society of Clinical Oncology for the Diagnosis and Treatment of Melanoma. The NPMA accepted a supplemental new drug application for this agent in May 2020 to treat patients with metastatic urothelial carcinoma also in the second line and subsequently received a priority review designation from the NMPA in July 2020.

Toripalimab was included in the National Reimbursement Drug List in December 2020. In February 2021, a supplemental New Drug Application was accepted by NMPA for toripalimab combined with chemotherapy in the first line for patients with advanced recurrent or metastatic NPC. That month, the NMPA also granted a conditional approval to this drug for the same patient population after progression on 2 or more lines of prior systemic therapy.

1. Junshi Biosciences and Coherus BioSciences announce initiation of rolling submission of BLA for toripalimab to the U.S. FDA for the treatment of nasopharyngeal carcinoma. News release. Coherus BioSciences, Inc. Published March 3, 2021. Accessed March 4, 2021.

2. Wang F-H, Wei X-I, Feng J, et al. Efficacy, safety, and correlative biomarkers of toripalimab in previously treated recurrent or metastatic nasopharyngeal carcinoma: a phase 2 clinical trial (POLARIS-02). 

. 2021;39(7):704-712. doi:10.1200/JCO.20.02712

Articles

A rolling submission of the Biologics License Application was initiated for toripalimab for the treatment of patients with recurrent or metastatic nasopharyngeal carcinoma.

Toripalimab Rolling Submission of BLA Initiated for Nasopharyngeal Carcinoma

A preplanned analysis of the Regorafenib Dose Optimization Study (ReDOS; NCT02368886) in patients with metastatic colorectal cancer (mCRC) showed using pre-emptive clobetasol to treat hand–foot skin reactions (HFSR) was more effective than treating this adverse event (AE) reactively.

“Regorafenib [Stivarga] causes HFSR. Pre‐emptive clobetasol, a high‐potency topical corticosteroid, appears to lessen the severity of this AE,” wrote the authors led by Aminah Jatoi, MD of the Mayo Clinic, in the published manuscript. “Although further study is needed, the favorable AE profile of this intervention might prompt clinicians to discuss this option with their patients.”

Clobetasol 0.05% cream was given to 61 patients pre-emptively and 55 patients reactively. In the first 2 cycles of receiving regorafenib, 30% of patients had no evidence of HFSR with pre-emptive treatment versus 13% of patients who were treated with reactive clobetasol (

=.03). For the first cycle only, the investigators observed 54% of patients had no HFSR with pre-emptive treatment and 45% had no HFSR with reactive treatment (

=.35). There were 33% and 15% of patients who had no HFSR with pre-emptive and reactive clobetasol, respectively (

With pre-emptive clobetasol, grade 1 HFSR was 30%, grade 2 was 8%, and grade 3 was 3% during the second cycle; these rates were 43%, 18%, and 7%, respectively, with reactive clobetasol (

=.12). There were no AEs due to the clobetasol cream.

HFSR compromised almost all daily living activities with worse quality of life according to patient-reported outcomes from those who received reactive treatment versus pre-emptive.

ReDOS, a phase 2 trial in refractory mCRC, randomized patients 1:1:1:1 to lower dose regorafenib with pre-emptive or reactive clobetasol compared with standard-dose regorafenib with pre-emptive or reactive clobetasol. Patients were directed to apply the clobetasol to their palms and soles twice a day for 8 weeks, which was demonstrated to be more effective before the development of HFSR than after.

“Pre‐emptive clobetasol might lessen regorafenib‐induced hand–foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort,” the authors concluded.

In the original publication of the trial results, the dose-escalation dosing strategy showed comparable activity and lower rates of AEs in patients with mCRC.

 Patients received regorafenib starting at 80 mg a day with weekly escalations of 40 mg, going up to 160 mg a day by the end of the escalation, or the standard dose of 160 mg a day for 21 days of a 28-day cycle. With a median follow-up of 1.18 years, the trial met its primary end point of the proportion of evaluable patients initiating cycle 3. Out of the 54 patients in the dose-escalation group, 23 (43%) initiated cycle 3 versus 16 (26%) of the 62 patients receiving the standard dose (one-sided 

The most common grade 3/4 AEs seen in this study were fatigue in 13% and 18% of the dose-escalation group and standard-dose group, respectively, HFSR in 15% and 16%, abdominal pain in 17% and 6%, and hypertension in 7% and 15%. There were 14 patients with at least 1 drug-related serious AE, 6 receiving dose escalation, and 8 receiving the standard dose. The standard-dose group had 1 probably treatment-related death due to myocardial infarction.

Jatoi et al noted that although these findings warrant further research in a larger cohort of patients, the results show that pre-emptive clobetasol can be offered by clinicians as an option for their patients with mCRC and hand–foot skin reactions.

1. Jatoi A, Ou FS, Ahn DH, et al. Pre-emptive versus reactive topical clobetasol for regorafenib-induced hand-foot reactions: a preplanned analysis of the ReDOS trial. 

. Published February 18, 2021. Accessed February 24, 2021. doi:10.1002/onco.13730

2. Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. 

. 2019;20(8):1070-1082. doi:10.1016/S1470-2045(19)30272-4

A preplanned analysis of the Regorafenib Dose Optimization Study in patients with metastatic colorectal cancer showed using pre-emptive clobetasol to treat hand–foot skin reactions was more effective than treating this adverse event reactively.

Pre-Emptive Treatment May Be Superior to Reactive Treatment of Hand–Foot Reactions in mCRC

-mutated high-risk HER2-negative early breast cancer demonstrated a superior invasive disease-free survival (iDFS) when compared with placebo in the phase 3 OlympiA trial (NCT02032823), according to a press release from AstraZeneca and Merck & Co., Inc.

The randomized, double-blind, parallel-group, multicenter trial has been moved to early primary analysis and reporting by recommendation of the Independent Data Monitoring Committee (IDMC) because of data from a planned interim analysis. These data showed the study crossed the superiority boundary for the primary end point of iDFS and showed that olaparib has a sustainable and clinically relevant treatment effect versus placebo for the trial’s patient population.

“We are delighted that our global academic and industry partnership has been able to help investigate a possible personalized treatment for women with hereditary breast cancer,” Andrew Tutt, MD, PhD, global chair of the OlympiA phase 3 trial and professor at the Institute of Cancer Research and Kings College London, said in a statement. The OlympiA trial is a partnership between the Breast International Group, NRG Oncology, the US National Cancer Institute, Frontier Science & Technology Research Foundation, AstraZeneca, and Merck.

“The most common cause of hereditary breast cancer is an inherited mutation in the 

 genes which also may cause the disease to develop at a significantly earlier age than is usual,” Tutt continued. “The OlympiA trial has allowed us to go beyond using genetic testing to identify patients who are at risk of this disease and explore the potential of [olaparib] to prevent disease recurrence for these patients. We look forward to analyzing and presenting the full results of the trial at a forthcoming medical meeting.”

There were 1836 patients with HER2-negative or triple-negative breast cancer, germline 

 mutations, who have completed adequate breast and axilla surgery, as well as 6 or more cycles of neoadjuvant or adjuvant chemotherapy, with an ECOG performance status of 0 or 1 randomized 1:1 on this study. These patients either received olaparib orally twice a day at 300 mg or placebo orally twice a day.

Any patients who had previously received a PARP inhibitor, had second primary malignancy, concomitant use of CYP3A inhibitors, or evidence of metastatic breast cancer were excluded from the trial.

“Breast cancer remains one of the most common cancers globally and despite advances in treatment, many patients with high-risk disease will, unfortunately, develop a recurrence. We look forward to reviewing the results,” José Baselga, executive vice president of Oncology R&D, said in a press release.

Previously, olaparib was approved by the FDA for the treatment of adult patients with germline 

-mutated metastatic breast cancer based on the OlympiAD trial (NCT02000622).

 These patients had been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting before receiving olaparib.

For the OlympiA trial, the IDMC did not bring up any new safety concerns when recommending the study for early analysis. The investigators continue to assess the key secondary end points of overall survival and distant disease-free survival. Other end points include the incidence of new cancers, health-related quality of life, and safety and tolerability.

“Analysis of the OlympiA trial, based upon the IDMC recommendation, could represent a potential step forward for patients with early-stage, high-risk primary breast cancer with a germline 

 mutation,” Roy Baynes, senior vice president, head of global clinical development, and chief medical officer of Merck, said in a statement.

1. IDMC has concluded that OlympiA trial of Lynparza (olaparib) crossed superiority boundary for invasive disease-free survival vs. placebo at planned interim analysis. News release. AstraZeneca and Merck & Co., Inc. February 17, 2021. Accessed February 18, 2021. https://bit.ly/37uivWK

2. FDA approves olaparib for germline BRCA-mutated metastatic breast cancer. FDA. January 12, 2018. Accessed February 19, 2021. https://bit.ly/37uWhnJ

Patients with BRCA-mutated high-risk HER2-negative early breast cancer demonstrated a superior invasive disease-free survival when compared with placebo in the phase 3 OlympiA trial.

Olaparib Prolongs Invasive Disease-Free Survival in BRCA-Mutant, HER2- Breast Cancer

The VEGF tyrosine kinase inhibitor tivozanib hydrochloride demonstrated a significantly increased quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) as third- or fourth-line therapy in patients with metastatic renal cell carcinoma (RCC) compared with sorafenib (Nexavar) in the phase 3 TIVO-3 trial (NCT02627963).

“The difference in Q-TWiST in TIVO-3 was primarily driven by benefits of tivozanib in TWiST, partially offset by superiority of sorafenib in time after progression/relapse
[REL],” the investigators wrote in their abstract for the 2021 American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium.

To quantify the net health benefits of tivozanib, the investigators applied Q-TWiST methods because of the similar survival of the 2 agents reported previously.

Investigators calculated mean Q-TWiST by applying utility coefficients of 0.5, 1.0, and 0.5 to the 36-month restricted mean health states of time with toxicity, time without symptoms and toxicity, and REL, respectively.

 The relative Q-TWiST gain was defined as the mean absolute Q-TWiST difference divided by the sorafenib mean overall survival (OS).

The mean Q-TWiST was 15.04 months for tivozanib versus 12.78 months for sorafenib (

=.0493). The relative gain for tivozanib was 11.2%. With more follow-up, there were better Q-TWiST means. Q-TWiST at 36 months of follow-up, which was the primary end point of this analysis, the mean was 2.25 (95% CI, 0.01-4.51) in favor of tivozanib. Mean TWiST was significantly longer for tivozanib versus sorafenib (10.30 months vs 5.35 months; TABLE).

For this multicenter, randomized, controlled, open-label trial, 350 patients were split evenly between the 2 drugs and stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy.

 These patients had to progress on 2 or 3 prior systemic regimens, at least 1 of which had to be a VEGFR tyrosine kinase inhibitor other than sorafenib or tivozanib.

Patients either received 1.5 mg of tivozanib mg orally once a day on 4-week cycles or sorafenib at 400 mg orally twice a day continuously. The primary end point was progression-free survival (PFS) by independent review in the intention-to-treat population.

In the previous report of TIVO-3, tivozanib increased PFS compared with sorafenib but did not show a difference in OS. The PFS difference at a 19-month median follow-up was significant between tivozanib and sorafenib at 5.6 and 3.9 months, respectively (HR, 0.73; 95% CI, 0.56-0.94; 

The most common grade 3/4 treatment-related adverse events (TRAEs) in the originally published data were hypertension in 20% of patients receiving tivozanib and 14% of patients receiving sorafenib. Serious TRAEs were observed in 11% versus 10% of patients respectively, but no treatment-related deaths were reported.

“As a third- or fourth-line treatment for RCC, tivozanib significantly increased Q-TWiST relative to sorafenib, primarily through an increase in TWiST, which is generally considered to be the state with highest utility to patients. Consequently, Q-TWiST may be considered an alternative patient-centered measure of benefit of tivozanib in these settings,” the investigators wrote in their conclusion.

1. Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib (T) versus sorafenib (S) in patients with advanced renal cell carcinoma (RCC) in the TIVO-3 study. 

2021;39(suppl 6):298. doi:10.1200/JCO.2021.39.6_suppl.298

2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. 

. 2020;21(1):95-104. doi: 10.1016/S1470-2045(19)30735-1

The VEGF tyrosine kinase inhibitor tivozanib hydrochloride demonstrated a significantly increased quality-adjusted time without symptoms of disease and toxicity as third- or fourth-line therapy in patients with metastatic renal cell carcinoma compared with sorafenib in the phase 3 TIVO-3 trial.

Dylann Cohn-Emery | Authors

Articles

Toripalimab Rolling Submission of BLA Initiated for Nasopharyngeal Carcinoma

Pre-Emptive Treatment May Be Superior to Reactive Treatment of Hand–Foot Reactions in mCRC

Olaparib Prolongs Invasive Disease-Free Survival in BRCA-Mutant, HER2- Breast Cancer

TIVO-3 Trial End Point Q-TWiST Increased With Tivozanib in RCC