Immuno-Oncology Outlook: Bavencio Leads PD-1/L1 Pack In Ovarian Cancer
Executive Summary
Merck KGaA/Pfizer's Bavencio is likely to be the first checkpoint inhibitor to gain approval in ovarian cancer but Roche's Tecentriq is hot on its heels. The ovarian cancer pipeline boasts seven other late-stage drugs, including antibody-drug conjugates and small molecules, that are ready to ramp up competition on the market.
The ovarian cancer market will experience significant growth over the next five years as novel therapies complete pivotal trials and make their way through regulatory agencies; the value of the US market is expected to expand at the fastest rate.
According to forecasts from Datamonitor Healthcare, combined ovarian cancer drug sales in the US, Japan, and five major EU markets (France, Germany, Italy, Spain and the UK) will increase from $121m in 2014 to $667m in 2023 at a compound annual growth rate of 20.91%.
Ovarian Cancer Treatment Options
- Roche's VEGF inhibitor Avastin (bevacizumab)
- AstraZeneca's PARP inhibitor Lynparza (olaparib)
- Clovis' PARP inhibitor Rubraca (rucaparib)
- Tesaro's PARP inhibitor Zejula (niraparib)
To date, in the US, only four drugs have been approved for the treatment for ovarian cancer – but the development pipeline presents promising drug candidates. Poly ADP-ribose polymerase (PARP) inhibition remains an attractive target for drugs in this indication – with three PARP inhibitors already approved – but developers are also assessing newer immunological pathways.
"With about 22,000 diagnosed patients and about 15,000 deaths annually, there is a clear need and opportunity for innovation in advanced ovarian cancer," Sankalp Sethi, manager at ZS, a global sales and marketing firm, told Scrip. He noted that the next big wave in ovarian cancer treatment after PARP inhibition monotherapy is combination therapy – which is spurring development of other cancer immunotherapies in this space.
"PARPs alone are currently in Phase I/II trials in combination with anti-PD-L1, anti-CTLA-4, VEGF inhibitors, MEK inhibitors and chemotherapy, to name a few," he said. "By 2019, we will likely have approvals for combination regimens – with PARPs as the backbone – that continue to improve survival for ovarian cancer patients, especially HRD-negative and platinum-resistant patients where the unmet need is substantial."
After PARP Comes PD-L1
Outside the PARP space, all five programmed cell death protein-1 (PD-1) or PD-ligand 1 (PD-L1) therapies already on the market for other cancers are being tested in clinical trials in various ovarian cancer settings.
Sethi noted that there is "ample potential in this market for new therapies and combinations, especially those aimed at the up-to-half of patients not substantially benefitting from the current wave of PARP targeted therapies."
Merck KGAA and Pfizer Inc.'s jointly developed PD-L1 inhibitor Bavencio (avelumab) is positioned to be the first of this class to win approval in ovarian cancer. The drug is in Phase III trials for the treatment of advanced ovarian cancer patients in the first-line and maintenance settings, as well as the platinum-resistant/refractory setting.
Immuno-Oncology Outlook Series
This is the fourth article in Scrip's series on immunotherapy expanding into new cancer types.
Bavencio is slightly ahead of its closest competitor, Roche's PD-L1 drug Tecentriq (atezolizumab), in ovarian cancer but Roche's drug is snapping at the Merck KGaA/Pfizer drug's heels and is already in Phase III. Tecentriq is targeting the same patient populations as Bavencio – addressing first-line and maintenance indications – but Roche does not have a late-stage trial ongoing in the platinum-resistant/refractory setting. Tecentriq is being trialed as a treatment for recurrent, platinum-sensitive patients.
If Bavencio and Tecentriq successfully make it through regulatory processes and are approved for use in ovarian cancer, the treatments face competition not only from each other but from established therapies like Avastin and the PARP inhibitors, as well as new therapies being tested. Tecentriq and Bavencio share some weaknesses, including the possibility treatment may be limited to PD-L1-positive patients only, intravenous delivery and potentially hefty price tags that could slow or block uptake.
Other drugs in Phase III for ovarian cancer include: Eisai Co. Ltd.'s farletuzumab, PharmaMar SA's lurbinectedin, ImmunoGen Inc.'s mirvetuximab soravtansine, AstraZeneca's Recentin (cediranib), AbbVie Inc.'s veliparib, Gradalis Inc.'s Vigil vaccine and Mateon Therapeutics' Zybrestat.
Datamonitor Healthcare analysts expect Bavencio to receive approval in relapsed platinum-resistant/refractory ovarian cancer patients in the US in the third quarter of next year and in Japan and five major EU countries in 1Q 2019.
Further back in the pipeline, other PD-1 inhibitors are being tested in ovarian cancer settings. Merck & Co. Inc.'s Keytruda (pembrolizumab) is in Phase II, while AstraZeneca PLC's Imfinzi (durvalumab) and Bristol-Myers Squibb Co.'s Opdivo (nivolumab) are in Phase I/II.
At A Glance: PD-1/PD-L1 Inhibitors In Development For Ovarian Cancer
Source: Scrip & Biomedtracker
|
Drug |
Trial Phase |
Target Patient Population In Most Advanced Trial |
Biomedtracker's Likelihood Of Approval Rating |
|
Bavencio |
Phase III |
The Phase III pivotal study JAVELIN Ovarian 100 is testing Bavencio in combination with or following chemotherapy in first-line epithelial ovarian cancer. In the Phase III JAVELIN Ovarian 200 trial, Bavencio is being used alone or in combination with pegylated liposomal doxorubicin in patients with platinum-resistant/refractory ovarian cancer. |
39% (4% above average for development stage) |
|
Tecentriq |
Phase III |
The Phase III ATALANTE trial is testing Tecentriq in patients with late relapse of epithelial ovarian, fallopian tube or peritoneal cancer that has previously been treated with platinum-based chemotherapy. Meanwhile, the Phase III IMagyn050 trial is testing Tecentriq in combination with paclitaxel, carboplatin and bevacizumab as a first-line treatment in patients with stage III or IV epithelial ovarian, fallopian tube or peritoneal cancer. |
35% (average rating) |
|
Keytruda |
Phase II |
The Phase II KEYNOTE-100 study uses monotherapy Keytruda in patients with advanced, recurrent ovarian cancer. In ovarian cancer Keytruda is also being tested in two other Phase II trials and a Phase I/II trial in combination with PARP inhibitor Zejula. |
16% (6% above average for development stage) |
|
Imfinzi |
Phase I/II |
Imfinzi is being trialed as a monotherapy in patients with advance solid tumors that are refractory to standard therapy, including ovarian cancer patients. This trial will report topline data in 2017. |
10% (average rating) |
|
Opdivo |
Phase I/II |
Opdivo is being used in three combination trials targeting advanced solid tumors, including ovarian cancer: ECHO-204, which is pairing BMS's drug with Incyte Corp.'s epacadostat an indoleamine dioxygenase (IDO) inhibitor; ORION-01, a combination of Opdivo and Quest PharmaTech Inc.'s OvaRex; and a Phase I/II trial in combination with Celldex Therapeutics Inc.'s anti-CD27 antibody varlilumab. |
10% (average rating) |
Challenges In Ovarian Cancer
One major hurdle for the development of immunotherapies in this oncological space is that IO drugs have limited efficacy data in ovarian cancer. "Late phase trials that show immunotherapies are efficacious and safe are needed to better establish their place in the treatment paradigm," Datamonitor Healthcare analyst Zachary McLellan told Scrip.
Additionally, the development of immune checkpoint inhibitors has lagged behind in the ovarian cancer treatment space in comparison with other indications like melanoma and non-small cell lung cancer.
McLellan said this is likely because ovarian cancer has traditionally been considered non-immunogenic. "More recent early-phase studies have shown certain immunological pathways could be effective in treating ovarian cancer, including the PD-1 pathway. There is still more development and validation to be done," he highlighted.
As the first PD-L1 inhibitors to market in ovarian cancer, Bavencio and Tecentriq are expected to garner strong sales. Approvals as a front-line and/or maintenance treatments would be the most lucrative opportunities for both drugs.
But McLellan said, "the high cost of the regimens, competition from established PARP inhibitors and cheap chemotherapies, and potential biomarker requirements could limit potential."
Novel IO Approach
During the American Society for Clinical Oncology's 2017 annual meeting, researchers presented Phase I data from an investigator-initiated trial of BTG PLC and Amgen Inc.'s investigational therapy ONX 0801 – a novel compound that inhibits thymidylate synthase, an enzyme involved in cell growth and division.
The drug had surprisingly good results in the trial, which tested the compound in 15 women with refractory ovarian cancer. ONX-0801 significantly shrunk tumors in seven of the 15 patients.
The Phase I trial for BTG945 was initiated by BTG and Onyx Pharmaceuticals Inc. (now a subsidiary of Amgen). The drug is the first in a new class of drugs, discovered at the Institute of Cancer Research in London, that attack ovarian cancer by mimicking folic acid to enter cancer cells.