 The FDA has granted a priority review to a supplemental new drug application (sNDA) for TAS-102 (trifluridine/tipiracil; Lonsurf) for use in previously treated patients with advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction (GEJ).

FDA Approves TAS-102 for Gastric/GEJ Cancer

The sNDA is based on data from the phase III TAGS trial, in which TAS-102 reduced the risk of death by about one-third compared with placebo in patients with heavily pretreated gastric or GEJ cancer.

 The TAGS trial also showed improvements in progression-free survival (PFS) and disease control, and demonstrated a predictable and manageable safety profile.

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the sNDA by February 24, 2019.

"We look forward to working with the FDA as they consider the application for Lonsurf under priority review," Martin Birkhofer, MD, senior vice president and chief medical officer, Taiho Oncology, Inc, the manufacturer of TAS-102, said in a press release. 

TAGS was conducted to confirm findings from a phase II Japanese study in patients with metastatic gastric cancer in which TAS-102 was evaluated after failure of standard chemotherapies (fluoropyrimidines, platinums, and taxanes) or irinotecan and found to lead to a median OS of 8.7 months and a disease control rate of 65.5%.

The global phase III TAGS double-blind study enrolled 507 adults with histologically confirmed, nonresectable metastatic gastric/GEJ cancer and an ECOG performance status of 0 or 1 who received ≥2 prior chemotherapy regimens. Patients were randomized 2:1 to receive TAS-102 (35 mg/m

 twice daily on days 1 to 5 and 8 to 12 of each 28-day cycle) or placebo plus best supportive care, and were treated until progression, intolerability, or patient withdrawal.

The primary cancer site was gastric in 71% and GEJ in 29%. Fifty-five percent had ≥3 metastatic sites. Sixty-three percent in each arm had ≥3 prior treatments and 44% in each arm had prior gastrectomy. More than 90% received prior platinum, fluoropyridine, and taxane treatment. About one-third in each arm had prior ramucirumab.

Median OS, the primary endpoint, was 5.7 months for patients assigned to TAS-102 compared with 3.6 months for patients randomized to placebo. The 2.1-month improvement in median OS with TAS-102 over placebo translated into a hazard ratio for death of 0.69 (

 = .0003). The 12-month OS rate for the TAS-102 group was 21% versus 13% for the placebo group.

Multivariate analysis the following factors to be prognostic for OS (

 <.05): ECOG performance status of 1 (vs 0), 2 prior regimens (vs 33), age <65 years (vs ≥65 years), 1 or 2 metastatic sites (vs 3), and negative HER2 status (vs positive or undetermined). After adjusting for these factors, the treatment effect for TAS-102 was maintained (HR, 0.69; 95% CI, 0.56-0.85).

Median progression-free survival (PFS), a secondary endpoint, was also significantly improved with TAS-102 compared with placebo (2.0 vs 1.8 months; HR, 0.57; 

 < .0001). The 6-month PFS rates were 15% and 6%, respectively. The PFS advantage for TAS-102 was maintained when assessed by subgroups based on age, region, ethnicity, ECOG performance status, primary site, number of metastatic sites, and prior treatment with ramucirumab, among others.

The objective response rate with TAS-102 was 4% compared with 2% for placebo. In the active treatment group, there was 1 complete response (CR), 12 partial responses (PRs), and 115 patients with stable disease (SD), for a disease control rate of 44%. The disease control rate in the placebo group was 14% (0 CR, 3 PRs, 18 patients with SD). The absolute difference between groups in the disease control rate was 30% (

Time to deterioration of ECOG performance status to 2, a secondary endpoint, was longer in the TAS-102 group compared with the placebo group (median, 4.3 vs 2.3 months; HR, 0.69; 

Grade ≥3 adverse events (AEs) of any cause occurred in 80% of patients on TAS-102 versus 58% of those assigned to placebo. TAS-102 was associated with more treatment-related AEs of any grade (81% vs 57%). There was 1 treatment-related death in each group. Grade ≥3 febrile neutropenia of any cause was reported in 6 (2%) patients treated with TAS-102.

Dosing modification (dose delay or reduction) to manage adverse events was required in 58% of the TAS-102 group. Treatment had to be discontinued due to adverse events in 13%. G-CSF treatment to manage neutropenia was necessary in 16%. The most common AEs leading to dosing modification were neutropenia and/or decreased neutrophil count (37%), anemia and/or decreased hemoglobin level (9%), and leukopenia and/or decreased white blood cell count (6%).

Yoon-Koo Kang, MD, PhD, a professor in the Department of Oncology at the Asan Medical Center of the University of Ulsan College of Medicine in Seoul, Korea, commented that although TAGS was a global trial, Asian patients were underrepresented, with Japanese patients constituting only 15% of the total patient population. Kang was not involved in the TAGS study.

Other agents explored in third or later lines of treatment include nivolumab (Opdivo; RECOURSE, 33% Japanese enrollment) and apatinib (YN968D1; TERRA, conducted in China, Korea, and Thailand). Those 2 therapies have HRs for OS relative to placebo similar to the 0.69 observed with TAS-102 as well as similar PFS, Kang noted.

The need for biomarkers to define the best third and later line of treatment for advanced gastric cancer is urgent, he said. Sequential use of these agents is possible if they are tolerated. TAS-102 in combination with immunotherapy or antiangiogenic agents should be investigated, he added.

Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase 3, randomised, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. LBA25.

Bando H, Doi T, Muro K, et al. A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201). 

. 2016;62:46-53. doi: 10.1016/j.ejca.2016.04.009.

Articles

The FDA has granted a priority review to a supplemental new drug application for TAS-102 for use in previously treated patients with advanced or metastatic gastric adenocarcinoma, including cancer of the gastroesophageal junction. 

FDA Grants Priority Review to TAS-102 for Gastric/GEJ Cancer

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with the VEGF inhibitor axitinib (Inlyta) significantly improved survival versus sunitinib (Sutent) as a first-line treatment for patients with advanced or metastatic renal cell carcinoma (RCC), according to findings from the phase III KEYNOTE-426 trial.

Merck (MSD), the manufacturer of pembrolizumab, announced in a press release that the study had met the coprimary endpoints of significant improvement in overall survival (OS) and progression-free survival (PFS), as well as the secondary endpoint of significantly improved objective response rate (ORR). The OS, PFS, and ORR benefits were observed with the combination across risk groups and regardless of PD-L1 expression level.

“Keytruda, in combination with the tyrosine kinase inhibitor Inlyta, resulted in significant and clinically meaningful improvements in overall survival, progression-free survival, and objective response in this phase III study. This marks the first time that combination treatment with an anti—PD-1 therapy has achieved the dual primary endpoints of overall survival and progression-free survival as first-line therapy in advanced renal cell carcinoma,” Roger M. Perlmutter, MD, PhD, president, Merck Research Laboratories, said in a statement.

“Fewer than 10% of those diagnosed with advanced renal cell carcinoma survive for 5 years, and hence there is significant need for improved therapies for this disease. We are very grateful to the investigators and patients for their involvement in this important study, the results of which will be filed with global regulatory authorities in the near future,” added Perlmutter.

The open-label phase III KEYNOTE-426 trial (NCT02853331) randomized 861 patients with advanced or metastatic RCC to frontline treatment with pembrolizumab (200 mg IV every 3 weeks) plus axitinib (5 mg orally twice daily) for up to 24 months, or sunitinib (50 mg orally once daily for 4 weeks followed by no treatment for 2 weeks, continuously). Merck noted that safety data for pembrolizumab and axitinib were consistent with earlier findings from studies of each agent.

Previously reported data from an open-label phase Ib single-arm clinical trial showed that antitumor activity with the combination of axitinib and pembrolizumab was superior to that expected from axitinib or PD-1/PD-L1 pathway inhibitor monotherapy in treatment-naïve patients with advanced RCC.

In addition, fewer liver function test abnormalities and less fatigue were reported compared with other combinations of VEGF inhibitors and PD-1 checkpoint inhibitors, lead investigator Michael B. Atkins, MD, said when presenting the findings in February at the 2018 Genitourinary Cancers Symposium.

“The regimen was highly active,” he said, with 38 of 52 patients (73.1%) enrolled in the dose-finding and dose-expansion phases of the study having objective responses with the axitinib/pembrolizumab combination. Best overall response was a complete response in 4 patients (7.7%), partial response in 34 (65.4%), and stable disease in 8 (15.4%). The median progression-free survival was 20.9 months (95% CI, 15.4 to not evaluable). Median overall survival was not reached at a minimum follow-up of 17.6 months.

Prior studies in which VEGF inhibitors were combined with PD-1 checkpoint inhibitors were plagued by excess toxicity. Many of these toxicities were related to off-target effects of multitargeted tyrosine kinase inhibitors. The possibility that a more selective VEGF inhibitor would improve tolerability when combined with a PD-1 inhibitor while offering synergistic antitumor activity was the basis for the phase Ib study that Atkins reported at the symposium.

In the study, 11 treatment-naïve patients were enrolled in a dose-finding phase to estimate the maximum-tolerated dose and 41 in a dose-expansion phase. Axitinib at 5 mg was administered orally twice daily and pembrolizumab at 2 mg/kg was given intravenously every 3 weeks.

Tumors were assessed using RECIST v1.1 at baseline, week 12, and then every 6 weeks. The primary endpoint was dose-limiting toxicity during the first 2 cycles (6 weeks). “Per protocol, according to the investigators’ judgment, patients with evidence of disease progression experiencing what was thought to be clinical benefit were eligible for continued treatment,” said Atkins, deputy director, Georgetown-Lombardi Comprehensive Cancer Center.

To be included in the study, patients had to have treatment-naïve clear cell kidney cancer, prior nephrectomy, at least 1 measureable lesion by RECIST v1.1, an ECOG performance status of 0 or 1, and controlled hypertension.

Of the 11 patients treated in the dose-finding phase, 3 dose-limiting toxicities were reported. One patient had a transient ischemic attack. “Axitinib was held, she recovered from the event, axitinib was restarted at a lower dose, and she remains on therapy with a response almost 3 years later,” Atkins said. Two others could not complete at least 75% of the planned axitinib dose, 1 due to a grade 2/3 headache and another due to grade 3 headache, fatigue, asthenia, and dehydration. The maximum-tolerated dose, therefore, was estimated to be axitinib at 5 mg twice daily and pembrolizumab at 2 mg/kg every 3 weeks.

The entire cohort of 52 patients had a median age of 63 years (range, 28-75). Forty-six percent had a favorable International Metastatic Renal Cell Carcinoma Database risk score, although 26.9% of patients had Fuhrman grade 4 tumors. The median time from nephrectomy and initiation of therapy was 20.3 months.

As of the data cutoff on March 31, 2017, there were 25 patients on treatment, 22 were receiving the combination and 3 were receiving pembrolizumab only. Eight patients with confirmed disease progression were still receiving treatment for continued clinical benefit. Of the 27 patients who discontinued both study treatments, 10 did so for adverse events, 9 because of disease progression, 5 because of mixed disease progression and adverse events, and 3 for other reasons.

The median duration of axitinib/pembrolizumab treatment was 14.5 months. Some 61.5% of patients had their axitinib dose reduced to <5 mg twice weekly for at least 2 consecutive doses. One patient had an axitinib dose increase to 7 mg twice daily. The median dose of axitinib was 8.8 mg/day and the median dose of pembrolizumab was 2.0 mg/kg per cycle.

More than 90% of patients had tumor shrinkage. “Except in rare cases, continued treatment beyond disease progression was characterized more by stabilization or slow, continued progression rather than regression,” said Atkins.

The median time to response was 2.8 months (range 0.7-15.2 months) and the median duration of tumor response was 18.6 months. Nineteen of the 38 responders were continuing to respond at the time of data cutoff, including 17 patients who were still on therapy. Ten patients who discontinued both agents because of toxicity were censored even though their disease had not progressed, and 5 were still responding to treatment, Atkins noted.

“There were only 6 deaths total, 4 related to the disease under study and 2 for unrelated reasons,” he said.

About two-thirds (65.4%) had grade ≥3 toxicities. “Most of these were axitinib-related, with 23% having hypertension,” Atkins said. The other most common grade ≥3 adverse events were diarrhea (9.6%), fatigue (9.6%), and an increase in the level of ALT (7.7%). The most common immune-related grade ≥3 adverse events were diarrhea (7.7%), an increase in ALT (3.8%), an increase in the level of AST (3.8%), and fatigue (3.8%).

Merck’s KEYTRUDA® (pembrolizumab) in Combination with Pfizer’s Inlyta® (axitinib) Significantly Improved Overall Survival (OS) and Progression-free Survival (PFS) as First-Line Therapy for Advanced or Metastatic Renal Cell Carcinoma. Merck. Published October 18, 2018. Accessed October 18, 2018. https://bit.ly/2yLtWaC.

Atkins MB, Plimack ER, Puzanov I, et al. Safety and efficacy of axitinib (axi) in combination with pembrolizumab (pembro) in patients (pts) with advanced renal cell cancer (aRCC). Presented at: 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, Calif. Abstract 579.

Combining the PD-1 inhibitor pembrolizumab with the VEGF inhibitor axitinib significantly improved survival versus sunitinib as a first-line treatment for patients with advanced or metastatic renal cell carcinoma. 

Pembrolizumab/Axitinib Improves Survival in Frontline RCC

The HPV vaccine Gardasil 9 (HPV 9-valent Vaccine, Recombinant) is now approved by the FDA for use in males and females aged 9 through 45 years.

Gardasil 9 has been shown to prevent cancers and other diseases caused by the 9 types of HPV: 6, 11, 16, 18, 31, 33, 45, 52, and 58. The FDA initially approved Gardasil 9 in 2014 for use in males and females aged 9 through 26 years.

“Today’s approval represents an important opportunity to help prevent HPV-related diseases and cancers in a broader age range,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research,” said in a press release. 

“The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90% of these cancers, or 31,200 cases every year, from ever developing,” added Marks.

The FDA approved the vaccine Gardasil, the predecessor to Gardasil 9, in 2006. Gardasil, which prevents malignancies causes by types of HPV, is no longer distributed in the United States. However, efficacy data for Gardasil can be extrapolated to Gardasil 9, since the 2 vaccines are manufactured similarly and Gardasil is targets 4 of the 9 HPV types covered by Gardasil 9.

In a large trial of women aged 27 to 45, Gardasil demonstrated an efficacy rate of 88% in preventing persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV 6, 11, 16, and 18. The study included approximately 3200 women and the average follow-up was 3.5 years.

The FDA used these data, as well as up updated long-term follow-up data from the study, as the basis for increasing the approved age up to 45 for Gardasil 9 in women. The new approval of Gardasil 9 for men aged 27 to 45 was based on inferred efficacy from the 3200-women Gardasil trial and efficacy results for Gardasil in men aged 16 to 26. The FDA also reviewed immunogenicity data from a study in which a 3-dose regimen of Gardasil over 6 months was assessed in 160 men aged 27 to 45 years.

Gardasil 9 was shown to be safe and tolerable in a combined male and female population of approximately 13,000 individuals. Adverse reactions that were most frequently reported included injection site pain, swelling, redness and headaches.

According to Merck (MSD), the manufacturer of Gardasil 9, the “vaccine is indicated in the United States in females 9 through [45] years of age for the prevention of cervical, vulvar, vaginal, and anal cancers caused by HPV types 16, 18, 31, 33, 45, 52, and 58; precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV types 6 and 11. Gardasil 9 is also indicated in males 9 through [45] years of age for the prevention of anal cancer caused by HPV types 16, 18, 31, 33, 45, 52, and 58; precancerous or dysplastic lesions caused by HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; and genital warts caused by HPV types 6 and 11.”

The company also noted that “Gardasil 9 is contraindicated in individuals with hypersensitivity, including severe allergic reactions to yeast, or after a previous dose of Gardasil 9 or Gardasil."

FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. FDA. Published October 5, 2018. Accessed October 7, 2018. https://bit.ly/2zVRxa9.

FDA Grants Priority Review to Merck’s Supplemental Biologics License Application (sBLA) for GARDASIL®9 in Women and Men Ages 27 to 45 for the Prevention of Certain HPV-Related Cancers and Diseases. Merck. Published June 13, 2018. Accessed October 7, 2018. https://bit.ly/2zWvlgo.

The HPV vaccine Gardasil 9 is now approved by the FDA for use in males and females aged 9 through 45 years.

FDA Approves Gardasil 9 HPV Vaccine for Use Up to Age 45

The FDA has granted a priority review to a new drug application (NDA) for selinexor for the treatment of patients with penta-refractory multiple myeloma, according to Karyopharm Therapeutics, the manufacturer of the XPO1 inhibitor.

The NDA is based on results from the phase IIb STORM trial, which examined the combination of selinexor and dexamethasone in patients with penta-refractory multiple myeloma. Updated data from the study presented at the 2018 SOHO Annual Meeting showed that the doublet regimen was associated with an overall response rate (ORR) of 26.2% and a median overall survival (OS) of 8.6 months in patients with penta-refractory disease.

Sundar Jagannath, MD, director of the Multiple Myeloma Program and professor of medicine at The Tisch Cancer Institute, Mount Sinai Health System, delivered the STORM findings at SOHO. He explained that patients who had a response to treatment, even a minor response, did significantly better, with a median OS of 15.6 months. Historically, the median OS in this patient population is an estimated 3.6 months.

According to Karyopharm, the study defined 

as “patients who have previously received at least one alkylating agent, glucocorticoids, two immunomodulatory drugs (IMiDs; lenalidomide [Revlimid] and pomalidomide [Pomalyst]), two proteasome inhibitors (PIs; bortezomib [Velcade] and carfilzomib [Kyprolis]), and daratumumab (Darzalex), and whose disease is refractory to glucocorticoids, at least one PI, at least one IMiD, and daratumumab, and whose disease has progressed following their most recent therapy.”

Under the Prescription Drug User-Fee Act, the FDA is scheduled to make a decision on the NDA by April 6, 2019.

"As a potential new therapy with a novel mechanism and compelling clinical profile, we believe oral selinexor, if approved, will provide a meaningful therapeutic option for patients battling highly resistant, penta-refractory myeloma," Sharon Shacham, PhD, MBA, founder, president and chief scientific officer of Karyopharm, said in a statement. "The acceptance of this NDA for review and grant of Priority Review mark significant milestones for the selinexor program, and further underscores the high level of unmet need in this patient population.  We look forward to working with the FDA during the review process."

The STORM trial included 122 patients with penta-refractory multiple myeloma at 38 sites in the United States; 85 patients were treated per-protocol. The median patient age was 65 years (range, 40-85). Eligible patients had to have received prior treatment with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, an alkylator, and glucocorticoids.

Patients had undergone a median of 7 prior treatments (range, 3-18), and all were refractory to proteasome inhibitor/immunomodulatory drugs/ daratumumab/glucocorticoid. Ninety-six percent were refractory to carfilzomib/pomalidomide/daratumumab. Eighty-four percent had undergone stem cell transplant, and 28% had undergone ≥2 transplants.

Patients received 80 mg of oral selinexor plus 20 mg of oral dexamethasone twice weekly until progression. The primary endpoint was ORR.

Two patients, both of whom were negative for minimal residual disease, achieved stringent complete response. Two patients who relapsed following chimeric antigen receptor T-cell therapy achieved a partial response.

The median progression-free survival (PFS) was 3.7 months for the entire cohort. For partial responders, the median PFS was 5.3 months, and 4.6 months for those who had at least minimal response.

Duration of response was 4.4 months (range, <1-12.2). Jagannath said responses typically occurred in the first 4 weeks of treatment. The clinical benefit rate was 39.3% and the disease control rate was 78.7%.

“If you’re able to arrest the growth of the tumor, you’re able to get a survival benefit for these patients,” Jagannath said.

The most common grade 3/4 treatment-related hematological adverse event (AE) was thrombocytopenia (53.7%), followed by anemia (29.3%), neutropenia (17.9%), leukopenia (13.8%), and lymphopenia (8.9%). There was only 1 instance of grade 4 anemia and no grade 4 leukopenias recorded.

There were no grade 4 non-hematological AEs observed. The most common grade 3 non-hematological AEs were fatigue/asthenia (22.8%), hyponatremia (16.3%), and nausea (9.8%).

Selinexor links to and inhibits XPO1 (CRM1), a nuclear export protein. There is an accumulation of tumor suppressor proteins in the cell nucleus as a result of this activity, and, subsequently, the cell’s tumor suppressor function is regained and amplified, which investigators hypothesize induces apoptosis.

Jagannath J, Vogl DT, Dimopoulos MA, et al. Phase 2b results of the STORM study: oral selinexor plus low dose dexamethasone (sd) in patients with penta-refractory myeloma (penta-MM). 

. 2018;18(suppl; Abstract MM-255). doi: 10.1016/j.clml.2018.07.149.

Karyopharm Completes Rolling Submission of New Drug Application to U.S. Food and Drug Administration for Selinexor as a Treatment for Patients with Penta-Refractory Multiple Myeloma. Published August 6, 2018. Accessed October 6, 2018. https://bit.ly/2zVwIfi.

The FDA has granted a priority review to a new drug application for selinexor for the treatment of patients with penta-refractory multiple myeloma.

FDA Grants Selinexor Priority Review for Multiple Myeloma

As researchers continue to explore immune checkpoints as targets for anticancer therapies, the IDO pathway has emerged as the leading contender to yield the next batch of new drugs in the field. Clinical trial results thus far have been particularly promising for IDO inhibitors combined with antibodies that target the PD-1/ PD-L1 pathway.

The IDO protein, or indoleamine (2,3)-dioxygenase, has been identified as a checkpoint protein involved in generating the immunosuppressive tumor microenvironment that supports tumor growth. The enzyme has 2 isoforms, IDO1 and IDO2, that act as the first step in the metabolic pathway that breaks down the essential amino acid tryptophan.

IDO exerts its immunomodulatory effects by shutting down the effector T cells of the immune system. Increased IDO protein levels then drive growth arrest and apoptosis of the effector T cells, a group of immune cells that includes cytotoxic T cells, helper T cells, and natural killer cells that mediate the immune system’s ability to destroy pathogens. By reducing the number of effector T cells, IDO overexpression prevents the immune system from effectively destroying cancer cells.

Researchers have discovered that IDO is expressed on tumor cells and on cells in the surrounding microenvironment, such as dendritic cells in the tumor-draining lymph nodes (

). This offers multiple opportunities for targeting the tumorigenic activities of aberrant IDO signaling.

IDO overexpression has been observed in numerous solid tumors, prompting pharmaceutical developers to evaluate pathway inhibitors in a variety of clinical settings. At least 5 IDO inhibitors are in development (

), mostly in combination with other immunotherapies including therapeutic vaccines and checkpoint blockade agents, or with standard chemotherapies.

Excitement about the potential for the drugs as a class is building. “Everything is starting to come together for these IDO inhibitors,” said Adil Daud, MD, a leading IDO researcher who is a clinical professor at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, in an interview with 

. “For the last few years, there has been a lot of basic science research done showing that IDO is a fundamental mechanism that keeps pregnancy going, is involved in the immune system, and senses the tumor microenvironment.

“Now, this current generation of inhibitors is in testing, and they seem to be relatively nontoxic when they’re added to PD-1,” he said. “I think that’s something exciting considering all the immune checkpoint combinations that people are talking about. It seems like they can be combined and have a reasonable rate of activity, with the caveat that, currently, we are just talking about phase II trials.”

The most advanced agent under study is epacadostat, an orally available inhibitor of IDO1. Findings from early-phase studies into epacadostat have been promising, particularly in melanoma, where the drug is being paired with the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) in separate studies.

In phase I study results, 11 of 19 evaluable treatment-naïve patients with melanoma who received the combination achieved an objective response (58%), including 5 patients (26%) with a complete response (CR) and 6 (32%) with a partial response (PR).

 The disease control rate, which consisted of CRs, PRs, and stable disease, was 74% (14 patients).

The combination has advanced into a pivotal phase III study. The KEYNOTE-252/ECHO-301 trial will randomize 600 patients in a 1:1 ratio to pembrolizumab with either epacadostat or placebo (NCT02752074). The trial is recruiting patients with stage III/IV melanoma who have not received prior or systemic therapy for metastatic or unresectable disease.

Similarly, the pairing of epacadostat and nivolumab has shown positive early results in patients with melanoma. The combination demonstrated an objective response rate (ORR) of 63% and a CR rate of 5% among 74 patients with treatment- naïve melanoma in the multiarm phase I/II ECHO-204 trial, according to findings presented at the 2017 American Society of Clinical Oncology Annual Meeting in June.

Epacadostat also has shown efficacy in combination with both PD-1 inhibitors in other tumor types. Updated results of the ongoing phase I/II ECHO-202/KEYNOTE-037 trial demonstrate that the combination of epacadostat and pembrolizumab resulted in ORRs of 34% (13 of 38 patients) in metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN), 35% (14 of 40 patients) in advanced urothelial cell carcinoma, and 33% (10 of 30 patients) in advanced renal cell carcinoma.

For safety data, a pooled analysis of 294 patients treated with the combination during the trial found that treatment-related adverse events (TRAEs) occurred in 67% of participants, including grade ≥3 AEs in 18%. The most common TRAEs included fatigue (29%), rash (17%), nausea (11%) and pruritus (10%). Four percent of study participants discontinued treatment due to TRAEs.

For nivolumab, findings from the ECHO-204 study indicate that combining the PD-1 inhibitor with epacadostat resulted in a 23% ORR and a 3% CR rate among 31 patients with SCCHN.

 However, the combination did not prove effective in cohorts of patients with refractory ovarian cancer and colorectal cancer also tested during the study.

Indoximod, a small molecule that acts directly on immune cells to reverse IDO pathway-mediated suppression, has generated evidence of activity, as seen in early-phase clinical study results. The addition of indoximod to pembrolizumab led to an ORR of 52% in patients with advanced melanoma, according to findings from a phase II trial reported at the 2017 American Association for Cancer Research Annual Meeting (AACR).

The combination was evaluated in the single-arm phase II NLG2103 trial in which indoximod was added to physician’s choice of FDA-approved checkpoint inhibitors for melanoma: ipilimumab (Yervoy), nivolumab, or pembrolizumab. Accrued patients had unresectable stage III/IV melanoma, had not received systemic treatment for at least 28 days, and had an ECOG performance status of 2 or lower.

As of March 2017, 102 patients had enrolled, with 94 receiving pembrolizumab and 8 receiving either nivolumab or ipilimumab. In the pembrolizumab arm, patients received the PD-1 inhibitor intravenously at 2 mg/kg every 3 weeks, along with oral indoximod at 1200 mg twice daily in 21-day cycles. At the AACR meeting, data were reported for 60 evaluable patients who received pembrolizumab plus indoximod.

Across the entire cohort, 31 (52%) patients had a response, including 6 CRs (10%) and 25 PRs (42%). The stable disease rate was 22% and the progressive disease rate was 27%. When excluding the 9 patients with ocular melanoma, the ORR, CR rate, and PR rate increased to 59%, 12%, and 47%, respectively.

The most common all-grade adverse events (AEs) included fatigue (60%), headache (33%), nausea (32%), arthralgia (28%), diarrhea (28%), pruritus (26%), rash (23%), and cough (21%). Grade 3 AEs included 1 incident each of fatigue, diarrhea, and rash.

NewLink Genetics, which is developing indoximod, plans to launch a pivotal phase III clinical trial combining the agent with a PD-1 inhibitor in the second half of 2017, according to its website.

The agent also has demonstrated efficacy in combination with sipuleucel-T (Provenge) in a phase II study of patients with metastatic castration- resistant prostate cancer.

 In the study, 46 patients were randomized to receive twice-daily oral indoximod (n = 22) or placebo (n = 24) for 6 months following treatment with sipuleucel- T. The median radiographic progression-free survival was 10.3 months in the experimental arm compared with 4.1 months for the placebo group (

Among other IDO inhibitors in development, early study findings for BMS-986205 demonstrate promising signals. BMS-986205, which inhibits IDO1, restored human T-cell proliferation in dendritic cells while lowering levels of the immunosuppressive metabolite kynurenine in preclinical studies.

In a phase I/IIa study, BMS-986205 was escalated from 25 to 200 mg daily across several previously treated advanced malignancies. The median age of patients was 58 years, and approximately 40% were males. The ECOG performance status was 0 or 1, and most patients had stage IV disease (approximately 80%).

Single-agent oral BMS-986205 was administered once daily for a 2-week lead-in period, followed by nivolumab at 240 mg intravenously every 2 weeks. Expansion cohorts were opened for patients with cervical, SCCHN, and bladder cancer. BMS-986205 showed significant reduction in intratumoral kynurenine in samples from 13 patients.

The drug is being explored in a 3-arm trial in combination nivolumab at 2 doses or with nivolumab plus ipilimumab. The phase I/ II trial seeks to enroll more than 900 patients (NCT02658890).

Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO-202/KEYNOTE-037. Presented at: 2016 European Society for Medical Oncology Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 1110PD. www.incyte.com/ir/events-and-presentations.aspx.

Perez RP, Riese JM, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary phase I/II results of ECHO-204 [ASCO abstract 3003]. 

2017;35 (suppl). meetinglibrary.asco.org/record/153930/abstract.

Updated data from ECHO-202 trial of Incyte’s epacadostat in combination with Merck’s Keytruda (pembrolizumab) demonstrate clinical activity across multiple tumor types [news release]. Wilmington, DE, and Kenilworth, NJ: Incyte Corporation and Merck; June 5, 2017. incyte.com/ir/press-releases.aspx. Accessed August 8, 2107.

Zakharia Y, McWilliams R, Shaheen M, et al. Interim analysis of the phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma. [AACR abstract CT117]. 

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NewLink Genetics. IDO pathway inhibitor clinical development. newlinkgenetics.com/pipeline/. Accessed August 8, 2017.

Gopalji Jha G, Gupta S, Tagawa ST, et al. A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC) [ASCO abstract 3066]. 

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Siu LL, Gelmon K, Chu Q, et al. BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial. [AACR abstract CT116]. 2017;77(13 suppl). doi: 10.1158/1538-7445.AM2017-CT116.

As researchers continue to explore immune checkpoints as targets for anticancer therapies, the IDO pathway has emerged as the leading contender to yield the next batch of new drugs in the field.

OncLive Staff

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