publication date: May. 22, 2020

Drugs & Targets

Opdivo + Yervoy combination receives FDA approval for first-line mNSCLC (PD-L1 tumor expression ≥1%)

FDA has approved the combination of Opdivo (nivolumab) plus Yervoy (ipilimumab) as first-line treatment for patients with metastatic non-small cell lung cancer whose tumors express PD-L1(≥1%), as determined by an FDA-approved test, with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations.

Opdivo and Yervoy are sponsored by Bristol-Myers Squibb Co.

FDA has also approved the PD-L1 IHC 28-8 pharmDx, sponsored by Agilent Technologies Inc., as a companion diagnostic device for selecting patients with NSCLC for treatment with nivolumab plus ipilimumab.

Efficacy was investigated in CHECKMATE-227 (NCT02477826), a randomized, open-label, multi-part trial in patients with metastatic or recurrent NSCLC and no prior anticancer therapy. In Part 1a of the trial, 793 patients with PD-L1 tumor expression ≥1% were randomized to receive either the combination of nivolumab plus with ipilimumab (n=396) or platinum-doublet chemotherapy (n=397).

The trial demonstrated a statistically significant improvement in overall survival for patients with PD-L1 tumor expression ≥1% receiving nivolumab plus ipilimumab compared to those treated with  platinum-doublet chemotherapy. Median OS was 17.1 months (95% CI: 15, 20.1) versus 14.9 (95% CI: 12.7, 16.7) (HR 0.79; 95% CI: 0.67, 0.94; p=0.0066).

Median progression-free survival per blinded independent central review was 5.1 months (95% CI: 4.1, 6.3) in the nivolumab plus ipilimumab arm and 5.6 months (95% CI: 4.6, 5.8) in the platinum-doublet chemotherapy arm (HR 0.82; 95% CI: 0.69, 0.97). Confirmed overall response rate per BICR was 36% (95% CI: 31, 41) and 30% (95% CI: 26, 35), respectively. Median response duration was 23.2 months in the nivolumab plus ipilimumab arm and 6.2 months in the platinum-doublet chemotherapy arm.


Pomalidomide receives accelerated approval to for Kaposi sarcoma

FDA has expanded the indication of pomalidomide (Pomalyst) to include adult patients with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy, and Kaposi sarcoma in adult patients who are HIV-negative.

Pomalyst is sponsored by Celgene Corp.

Efficacy was investigated in Study 12-C-0047, an open-label, single-arm clinical trial, conducted by NCI. Twenty-eight patients (18 HIV-positive, 10 HIV-negative) received 5 mg of pomalidomide orally once daily on days 1 through 21 of each 28-day cycle until disease progression or unacceptable toxicity. All HIV-positive patients continued highly active antiretroviral therapy.

The main efficacy outcome measure was overall response rate, which included complete response, clinical complete response, and partial response. Response was assessed by the investigator according to the AIDS Clinical Trial Group Oncology Committee response criteria for Kaposi sarcoma. Among the 18 HIV-positive patients, the ORR was 67% (95% CI: 41, 87) with a median response duration of 12.5 months (95% CI: 6.5, 24.9). Among the 10 HIV-negative patients, the ORR was 80% (95% CI: 44, 98) with a median response duration of 10.5 months (95% CI: 3.9, 24.2).


Rucaparib receives FDA approval for BRCA-mutated metastatic castration-resistant prostate cancer

FDA has granted an accelerated approval to rucaparib (Rubraca) for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy.

Rubraca is sponsored by Clovis Oncology Inc.

Efficacy was investigated in TRITON2 (NCT02952534), an ongoing, multi-center, single arm clinical trial in 115 patients with BRCA-mutated (germline and/or somatic) mCRPC who were treated with androgen receptor-directed therapy and taxane-based chemotherapy. Patients received rucaparib 600 mg orally twice daily and concomitant GnRH analog or had prior bilateral orchiectomy.

Objective response rate and duration of response were assessed in 62 patients with measurable disease. The confirmed ORR was 44% (95% CI: 31, 57). Median DOR was not evaluable (NE; 95% CI: 6.4, NE). The range for the DOR was 1.7-24+ months. Fifteen of the 27 (56%) patients with confirmed objective responses had a DOR of ≥6 months.


Ripretinib receives FDA approval for advanced gastrointestinal stromal tumor

FDA has approved ripretinib (Qinlock) Deciphera Pharmaceuticals LLC for adult patients with advanced gastrointestinal stromal tumor who have received prior treatment with three or more kinase inhibitors, including imatinib.

Qinlock is sponsored by Deciphera Pharmaceuticals.

“Despite the progress that has been made over the past 20 years in developing treatments for GIST, including four FDA-approved targeted therapies—imatinib in 2002, sunitinib in 2006, regorafenib in 2013 and avapritinib earlier this year—some patients don’t respond to treatment and their tumors continues to progress,” Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, said in a statement.

Efficacy was evaluated in INVICTUS (NCT03353753), an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. Patients received ripretinib150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Crossover was permitted at disease progression for patients randomized to receive placebo.

The major efficacy outcome measure was progression-free survival based on assessment by blinded independent central review using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included overall response rate by BICR and overall survival.

The trial demonstrated a statistically significant improvement in PFS for patients in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001). The median PFS was 6.3 months (95% CI: 4.6, 6.9) for ripretinib compared with 1.0 month (95% CI: 0.9, 1.7) for placebo. The ORR was 9% (95% CI: 4.2, 18) in the ripretinib arm compared with 0% (95% CI: 0, 8) in the placebo arm, though this difference was not statistically significant. The median OS in the ripretinib arm was 15.1 months (95% CI: 12.3, 15.1) compared with 6.6 months (95% CI: 4.1, 11.6) in the placebo arm with a HR of 0.36 (95% CI: 0.21, 0.62), though OS was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints (i.e., PFS, then ORR, then OS).


Tecentriq receives FDA approval as first-line monotherapy in NSCLC indication

FDA has approved Tecentriq (atezolizumab) as a first-line (initial) treatment for adults with metastatic non-small cell lung cancer whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

Tecentriq is sponsored by Genentech.

“We are pleased to offer people with certain types of lung cancer a new chemotherapy-free option that can help prolong their lives and be administered on a flexible dosing schedule, including an option for once-a-month Tecentriq infusions,” Levi Garraway, chief medical officer and head of Global Product Development, said in a statement.

This approval is based on an interim analysis from the phase III IMpower110 study, which showed Tecentriq monotherapy improved overall survival by 7.1 months compared with chemotherapy (median OS=20.2 versus 13.1 months; hazard ratio [HR]=0.59, 95% CI: 0.40–0.89; p=0.0106) in people with high PD-L1 expression (TC3/IC3-wild-type [WT]). Safety for Tecentriq appeared to be consistent with its known safety profile, and no new safety signals were identified. Grade 3-4 treatment-related adverse events were reported in 12.9% of people receiving Tecentriq compared with 44.1% of people receiving chemotherapy.

Tecentriq is the first and only single-agent cancer immunotherapy with three  dosing options, allowing administration every two, three or four weeks. The supplemental Biologics License Application for the Tecentriq monotherapy was granted Priority Review.

In the U.S., Tecentriq has received four approvals across NSCLC, including as a single agent or in combination with targeted therapies and/or chemotherapies. It is also approved in combination with carboplatin and etoposide (chemotherapy) for the first-line treatment of adults with extensive-stage small cell lung cancer.


Olaparib receives FDA approval for HRR gene-mutated metastatic castration-resistant prostate cancer

FDA has approved olaparib (Lynparza) for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair  gene-mutated metastatic castration-resistant prostate cancer, who have progressed following prior treatment with enzalutamide or abiraterone.

Lynparza is sponsored by AstraZeneca Pharmaceuticals LP.

FDA has also approved FoundationOne CDx (sponsored by Foundation Medicine Inc.) for selection of patients with mCRPC carrying HRR gene alterations and BRACAnalysis CDx test (sponsored by Myriad Genetic Laboratories Inc.) for selection of patients with mCRPC carrying germline BRCA1/2 alterations as companion diagnostic devices for treatment with olaparib. 

Efficacy was investigated in PROfound (NCT02987543), an open-label, multicenter trial randomizing (2:1) 256 patients to olaparib 300 mg twice daily and 131 patients to investigator’s choice of enzalutamide or abiraterone acetate. All patients received a GnRH analog or had prior bilateral orchiectomy.

Patients were divided into two cohorts based on their HRR gene mutation status. Patients with mutations in either BRCA1, BRCA2, or ATM were randomized in Cohort A (N=245); patients with mutations among 12 other genes involved in the HRR pathway were randomized in Cohort B (N=142); those with co-mutations (Cohort A gene and a Cohort B gene) were assigned to Cohort A.

The major efficacy outcome of the trial was radiological progression-free survival (Cohort A). Additional efficacy outcomes included confirmed objective response rate (ORR) (Cohort A) in patients with measurable disease, rPFS (combined Cohorts A+B), and overall survival (Cohort A).

A statistically significant improvement was demonstrated for olaparib compared to investigator’s choice in Cohort A for rPFS with a median of 7.4 months vs 3.6 months (HR 0.34; 95% CI: 0.25, 0.47; p<0.0001), for OS with a median of 19.1 months vs. 14.7 months (HR 0.69; 95% CI: 0.50, 0.97, p=0.0175) and for ORR 33% vs 2% (p<0.0001). A statistically significant improvement for olaparib compared to investigator’s choice was also demonstrated for rPFS in Cohort A+B, with a median of 5.8 months vs. 3.5 months (HR 0.49; 95% CI: 0.38, 0.63; p<0.0001).


BRACAnalysis CDx receives approval as companion diagnostic for Lynparza in mCRPC indication

FDA has approved the BRACAnalysis CDx test for use as a companion diagnostic to identify men with metastatic castration-resistant prostate cancer who are eligible for treatment with Lynparza (olaparib).

Lynparza is approved for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer who have progressed following prior treatment with enzalutamide or abiraterone. Lynparza is a novel PARP inhibitor jointly developed and commercialized by AstraZeneca, and Merck outside of the U.S. and Canada.

“This approval is our seventh regulatory approval for BRACAnalysis CDx in support of Lynparza and further demonstrates our commitment to improve the lives of patients with cancer,”Nicole Lambert, president Myriad Oncology and Women’s Health, said in a statement. 

BRACAnalysis CDx is the only FDA-approved germline test to identify men with BRCA1 and BRCA2 mutations, a subpopulation of HRR gene mutations. In the PROfound trial, patients with metastatic castration-resistant prostate cancer who have HRR gene mutations had a statistically-significant and clinically meaningful improvement of radiographic progression-free survival when treated with Lynparza versus abiraterone acetate or enzalutamide.

“Studies have demonstrated that PARP inhibitors are highly effective in men with BRCA1/BRCA2 mutations, in addition to other mutations in HRR pathways.  Once we identify who these men are, they will have more options for treatment,” Todd Cohen,board-certified urologist and vice president of Medical Affairs for Myriad Urology, said in a statement.  “NCCN guidelines recommend that men with metastatic castration-resistant prostate cancer undergo genetic testing alongside an assessment of HRR gene mutations in the tumor.”

The collaboration between Myriad and AstraZeneca began in 2007 and has resulted in eight regulatory approvals for BRACAnalysis CDx and myChoice CDx.


Karyopharm submits sNDA for Xpovio as treatment for multiple myeloma after at least one prior line of therapy

Karyopharm Therapeutics Inc. has submitted a supplemental New Drug Application to FDA, seeking approval for Xpovio (selinexor), its first-in-class, oral selective inhibitor of nuclear export compound, as a new treatment for patients with previously treated multiple myeloma.

“Earlier this year, we reported positive top-line results from the pivotal phase III BOSTON study evaluating the combination of Xpovio (selinexor), once-weekly Velcade (bortezomib) and low-dose dexamethasone as a second line treatment for patients with relapsed or refractory multiple myeloma,” Sharon Shacham, founder, president and chief scientific officer of Karyopharm, said in a statement.

The full study results, which were included in the sNDA, will be presented May 29 during the 2020 American Society of Clinical Oncology virtual scientific program. In the BOSTON study, the SVd arm demonstrated a statistically significant reduction in the risk of disease progression or death, along with a 47% increase in median progression-free survival, as well as a significantly higher overall response rate, as compared to the standard Velcade and dexamethasone regimen.

Karyopharm also plans to submit a Marketing Authorization Application to the European Medicines Agency requesting approval for Xpovio in this same indication later this year. The abstract for the phase III BOSTON clinical data to be presented at the 2020 ASCO annual meeting and can be found here.

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