On June 4, 2018 SELLAS Life Sciences Group, Inc. (NASDAQ:SLS) ("SELLAS" or "the Company") reported that interim Phase 1 data of GPS in combination with nivolumab in patients with WT1+ ovarian cancer in second or third remission after salvage chemotherapy at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Sellas Life Sciences, JUN 4, 2018, View Source [SID1234527155]). The presentation, "A phase I study of concomitant galinpepimut-S (GPS) in combination with nivolumab (nivo) in patients (pts) with WT1+ ovarian cancer (OC) in second or third remission," is being delivered by Roisin E. O’Cearbhaill, M.D., Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, during the "Gynecologic Cancer" session from 1:15 to 4:45 p.m. CT. The primary endpoint of the study is safety and assessment of toxicity, and treatment is continued until disease progression or toxicity. The secondary endpoint is immune response, and the exploratory endpoints include landmark 1-year PFS rate compared to historical controls and correlative analyses between clinical and immune responses.

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Exploratory efficacy interim data from this open-label Phase 1 investigator-sponsored trial showed that GPS, when combined with a PD-1 inhibitor, demonstrated PFS of 64% at one year in an intent to treat (ITT) group of 11 evaluable patients with WT1+ ovarian cancer in second or greater remission. Among patients who received at least three doses of GPS in combination with nivolumab, PFS at one year was 70% (7/10). The historical rates with best standard treatment do not exceed 50% in this disease setting. The most common adverse events were Grade 1 or 2, including fatigue and injection site reactions. Dose limiting toxicity was observed in one patient, following the second dose of the combination. No additional adverse event burden was observed for the combination as compared to nivolumab monotherapy. WT1 is a tumor antigen that is expressed in about half of ovarian cancers. The combination induced a high frequency of T- and B-cell immune responses.

Based on these safety, clinical activity and immunogenicity data, SELLAS expects to initiate a Phase 1/2 clinical study of GPS in combination with the PD-1 inhibitor pembrolizumab in a variety of tumor types, including WT1+ ovarian cancer in the third quarter of 2018.

"Patients with advanced relapsed ovarian cancer, in which WT1 is highly expressed, have few treatment options with limited efficacy," said Angelos Stergiou, MD, ScD h.c., President & Chief Executive Officer of SELLAS. "The interim data being presented today further support the therapeutic potential of GPS in high-risk cancer populations, including ovarian cancer. In this Phase 1 trial, the combination of GPS and nivolumab showed promising clinical and immune response activity with no additional adverse event burden as compared to nivolumab monotherapy, warranting further evaluation. These data bolster our commitment to developing GPS, alone and in combination, across a wide range of cancers, and we look forward to initiating our Phase 1/2 basket trial investigating the combination of GPS with pembrolizumab in five WT1+ tumor types, including ovarian, small cell lung, colorectal and triple negative breast cancer and acute myeloid leukemia."

Of the 11 patients evaluated:

7 patients were in second remission and 4 patients were in third remission
10 patients received six total doses of GPS (800 mcg) over 12 weeks in combination with seven infusions of I.V. nivolumab (3 mg/kg) over 14 weeks
all underwent toxicity assessments with each dose of GPS, and three weeks after the completion of therapy at Week 15. Non-progressors at Week 15 were permitted to receive four additional GPS doses, administered every eight weeks.
With regard to clinical and immune responses:

in 11 evaluable patients, the landmark 1-year PFS rate was 64% in the ITT group and 70% in the ten patients who received at least three doses of GPS + nivolumab. Historical rates do not exceed 50% in this disease setting
serum levels of antigen-specific IgG, against both individual WT1 peptides within GPS and the full-length WT1 protein, were induced in 86% of patients
achievement of high titers of WT1-specific IgG post-GPS results from Immunoglobulin (Ig) M to IgG class switching, the latter being a surrogate marker of induction of activated T-helper (Th) cells after vaccination
antigen-specific T-cell responses to individual WT1 peptides were observed between Weeks 6-15, primarily CD4 T-cells and, to a smaller extent, CD8 T-cells
"Effective consolidation or maintenance strategies are needed to prevent further recurrence or to prolong remission in patients with ovarian cancer after successful salvage from a previous relapse. In this setting, immune-directed therapy with a combination of blocker nivolumab and GPS, a multivalent, heteroclitic peptide vaccine targeting WT1, an antigen expressed in about half of ovarian cancers, led to high rates of antigen-specific immunization. We anticipate that this enhanced immunogenicity will translate into a reduction in relapses in larger studies," mentioned Dr. O’Cearbhaill. She added "these encouraging interim data suggest that the combination of GPS plus PD-1 inhibitors deserves further study in WT1+ ovarian cancer."

About Galinpepimut-S (GPS):
GPS is a heteroclitic multivalent, multi-peptide cancer immunotherapeutic agent composed of four peptides, addressing over 20 epitopes, and derived from the WT1 protein, which has been ranked by the National Cancer Institute as a top priority among cancer antigens for immunotherapy. Importantly, because the WT1 antigen is overexpressed in many malignancies, and is not found in most normal tissues, GPS has the potential to be a broad immunotherapy, effective across a multitude of diverse cancer types and patient populations.

On June 4, 2018 At the American Society Clinical Oncology’s 2018 annual meeting, scientists from National Institute of Cancer Research Taiwan reported results from a phase 1 clinical study, showing that Polaris lead therapeutic candidate ADI‑PEG 20 in combination with pembrolizumab has activity for advanced solid tumors (Press release, Polaris Pharmaceuticals, JUN 4, 2018, View Source [SID1234527208]).

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The study results showed that ADI‑PEG 20 could be safely combined with pembrolizumab at its full dose (200 mg) for the treatment of advanced solid tumors. In the dose escalation cohort, two patients, one with thymus cancer and one with nasopharyngeal carcinoma, both in the fourth-line systemic treatment, had a partial response (PR). The main toxicity has been transient and manageable neutropenia. The study is currently enrolling patients in two recommended phase 2 dose cohorts: one for advanced cancers with low PD-L1 expression and one for head and neck cancer. Overall, the study has an objective response rate (ORR) of 27.8% (5/18) in evaluable patients at this time.

In the advanced cancers with low PD-L1 expression cohort, only patients with less than 50% PD-L1 expression are eligible for entry. Of the first 8 evaluable patients in this group, the current ORR is 37.5% as 3 PRs have been observed in heavily pre-treated patients: a third-line mucosal melanoma, a fifth-line cholangiocarcinoma and a fourth-line esophageal carcinoma. These preliminary results suggest that ADI-PEG 20 could potentially be synergistic with program death compounds, and various combinations that include ADI‑PEG 20 and other immunotherapies should be further explored in multiple cancer types.

"Preclinical data indicated that ADI‑PEG 20 could up-regulate PD-L1 expression, turning immune ‘cold’ tumors to express PD-L1 and thus more receptive to programmed death inhibition with agents such as pembrolizumab. We are gratified to see this same scenario occur in patients," said John Bomalaski, M.D., Executive Vice President, Medical Affairs, of Polaris. "Based on this encouraging data, we now have multiple trials planned with ADI‑PEG 20 and various checkpoint inhibitors, including combinations with both programmed death and CTLA-4 inhibitors. The enhancement of sensitivity to programmed death inhibition, combined with ADI-PEG 20’s efficacy, tolerability, and different mechanism of action make it an ideal agent for incorporation into checkpoint agent therapy," he added.

About ADI-PEG 20

ADI‑PEG 20 is a biologic being developed by Polaris Group to treat cancers carrying a major metabolic defect that renders them unable to internally synthesize arginine. Because arginine is essential for protein synthesis and survival of cells, these cancer cells become dependent upon the external supply of arginine to survive and grow. ADI‑PEG 20 is designed to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. Multiple cancers have been reported to have a high degree of arginine-dependency and can potentially be treated with ADI‑PEG 20.

On June 4, 2018 Patients with metastatic uveal melanoma (mUM) treated with IMCgp100 continued to experience a durable tumour response with a median follow up of 19.1 months, without yet reaching median overall survival (OS), according to new Phase I research to be reported at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago.2 IMCgp100 is the wholly-owned, lead programme from Immunocore Limited, a leading T-cell receptor (TCR) company focused on delivering first-in-class biological therapies that transform lives (Press release, Immunocore, JUN 4, 2018, View Source [SID1234527140]).

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Although rare, uveal melanoma is the most common form of adult eye cancer.3 When it metastasises beyond the eye, less than half of patients will survive for one year.4 Of the 19 HLA-A*0201+ patients enrolled in Phase I of the Phase I/II dose escalation trial, 17 were evaluated for efficacy. Among these patients, treatment with IMCgp100 was associated with an objective response rate of 18% (90% confidence interval [4,30]) and a one-year overall survival rate of 74% (95% confidence interval [48,88]) at the time of data cut-off.2

"Survival rates in uveal melanoma have remained largely unchanged for decades, and it is difficult to treat once it advances to metastatic disease," said Dr. Takami Sato, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University and lead investigator. "These data provide compelling evidence that IMCgp100 may offer hope to this underserved patient population."

Additional exploratory survival analyses also indicated prolonged OS was associated with a number of pharmacodynamic outcomes, including lymphocyte trafficking, providing encouraging evidence supporting the proposed mechanism of action of IMCgp100.2

"Immunocore is focused on transforming the lives of patients with some of the most challenging diseases, such as metastatic uveal melanoma, for which there is currently no standard of care," said Andrew Hotchkiss, Chief Executive Officer at Immunocore. "Although these are early findings, we are encouraged by the emerging clinical data and focused on advancing our pivotal trials."

The most common adverse events in the Phase I arm included pruritus (severe itching of the skin; 90%), pyrexia (fever) and fatigue (84%), and hypotension (74%).2 Dose limiting toxicities were observed in 3 patients; all were reversible abnormalities in liver function tests (Grade 3 or 4 ALT/AST changes). There were no IMCgp100-related AEs that resulted in discontinuation or death.2

About Metastatic Uveal Melanoma
Uveal melanoma is an aggressive form of melanoma which affects the eye, with a poor prognosis and no standard of care.5 Although it is the most common primary intraocular malignancy in adults,3 the diagnosis is rare, with approximately 4,000 new patients diagnosed globally each year (1,500 cases/year in US).1 Up to 50% of people with uveal melanoma will eventually develop metastatic disease.5,6 When the cancer spreads beyond the eye, only approximately 40% of patients will survive for one year.4

About the IMCgp100-102 Phase I/II Trial
In this study, IMCgp100 is administered on a weekly basis with an intra-patient escalation dosing regimen. The dose escalation portion of the study has been completed, which identified the recommended Phase II intra-patient dose. The Phase II portion of the study is ongoing evaluating both the safety and efficacy in patients with metastatic uveal melanoma. The currently enrolling cohort is assessing IMCgp100 in patients who have experienced disease progression after 1 or 2 prior lines of therapy, which may include up to 1 line of liver directed therapy. Approximately 150 patients will be enrolled in the Phase II portion and the estimated enrolment completion date is September 2019.

About the IMCgp100 Programme
IMCgp100 is a novel bi-specific biologic T cell redirection therapy that specifically targets the melanoma-associated antigen gp100, and which is now in pivotal studies for mUM. IMCgp100 was granted Orphan Drug Designation by the US Food and Drug Administration in 2016 and Promising Innovative Medicine designation under UK Early Access to Medicines Scheme in 2017. For more information about enrolling IMCgp100 clinical trials for metastatic uveal melanoma, please visit ClinicalTrials.gov (NCT02570308, NCT03070392).

About ImmTAC Molecules
Immunocore’s proprietary TCR (T Cell Receptor) technology generates a novel class of bi-specific biologics called ImmTAC (Immune mobilising monoclonal TCRs Against Cancer) molecules that enable the immune system to recognise and kill cancerous cells. ImmTAC molecules are based on synthetic, soluble TCRs engineered to recognise intracellular cancer antigens with ultra-high affinity and selectively kill cancer cells via an anti-CD3 immune-redirecting effector function. ImmTAC molecules can access up to nine-fold more target antigens than typical antibody-based approaches, including monoclonal antibodies. Based on the demonstrated mechanism of T cell infiltration into human tumours, the ImmTAC mechanism of action holds the potential to tackle solid "cold" low mutation rate tumours, the majority of tumours that do not adequately respond to currently available immunotherapies.

On June 4, 2018 TESARO, Inc.(NASDAQ:TSRO), an oncology-focused biopharmaceutical company, reported the results of the TOPACIO and QUADRA trials during an investor briefing held in conjunction with the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, TESARO, JUN 4, 2018, View Source [SID1234527156]).

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"The promising data presented at this year’s ASCO (Free ASCO Whitepaper) meeting demonstrated the potential of ZEJULA not only as a monotherapy treatment for women with advanced ovarian cancer, but also in combination with an anti-PD-1 antibody, to provide a meaningful clinical benefit to patients beyond those with BRCA mutations," said Mary Lynne Hedley, Ph.D., President and COO of TESARO. "Our oncology development strategy is focused on rational therapeutic combinations and niraparib and TSR-042, our anti-PD-1 antibody, are the foundation of this strategy. The TOPACIO results support the advancement of combination studies in ovarian cancer and breast cancers and we have initiated preparations for registrational trials of niraparib in combination with TSR-042 in these settings. QUADRA results demonstrated that ZEJULA is active as a late-line treatment for patients beyond those with BRCA mutations, which is the only treatment setting in which PARP inhibitors are approved today, and we intend to submit an sNDA in the fourth quarter of 2018."

TOPACIO Data Demonstrate Encouraging Activity of Niraparib in Combination with anti-PD-1 in Platinum-Resistant/Refractory Ovarian Cancer

Prior clinical studies have shown that monotherapy with PARP inhibitors or anti-PD-1 antibodies has limited efficacy in the treatment of patients with platinum-resistant/refractory ovarian cancer or triple-negative breast cancer beyond those patients with BRCA mutant tumors, and these patients generally face a poor prognosis. TOPACIO is a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of niraparib plus KEYTRUDA (pembrolizumab) in patients with recurrent, platinum-resistant/refractory ovarian cancer or triple-negative breast cancer (TNBC). Following dose finding in Phase 1, niraparib was administered orally, once-daily, at a dose of 200 milligrams in combination with 200 milligrams of pembrolizumab administered intravenously on day one of each 21-day treatment cycle in two patient cohorts: platinum-resistant or refractory ovarian cancer and TNBC. Endpoints included objective response rate (ORR), duration of response (DOR) and disease control rate (DCR; CR+PR+SD).

At the time of data cutoff, of the 62 patients enrolled with ovarian cancer, 60 were evaluable for an initial response assessment. The population had been treated with a median of 2 (range of 1 to 5) prior lines of therapy; 50% had platinum-resistant ovarian cancer, 29% were platinum-refractory, 63% had received prior bevacizumab, and 21% were platinum ineligible. Data indicate an ORR (CR and PR) of 25% and a DCR of 67% in the evaluable population; ORR in the BRCAmut cohort was 25% with a DCR of 63%; ORR in the BRCAwt cohort was 24% with a DCR of 65%. Response rates were not dependent on biomarker status or platinum status. ORR was 23% (7/30) in platinum-resistant ovarian cancer patients, 24% (4/17) in platinum-refractory patients and 31% (4/13) in patients who were platinum ineligible per investigator’s assessment (typically due to prior platinum hypersensitivity, toxicities or other reasons that platinum could not be tolerated). Median DOR was 9.3 months, with 9 patients remaining on treatment. The most common grade ≥ 3 adverse events (AEs) included anemia (21%) and thrombocytopenia (9%) at a 200-milligram starting dose of niraparib. Following a successful discussion with FDA, a registration study with TSR-042 plus niraparib is being planned.

For patients with platinum-resistant ovarian cancer, response to chemotherapy is 5-18%, including the most commonly prescribed regimen in the U.S., bevacizumab plus pegylated liposomal doxorubicin1. Platinum refractory patients typically have even lower response rates and NCCN treatment guidelines recommend clinical trials for these patients2. Historical response to PARP inhibitors is 5-10% in patients without BRCA mutations who have platinum resistant disease3 and 0-14% in those with BRCA mutations and platinum refractory disease4. Response rates of 10-15% have been reported with anti-PD-1 antibodies in this ovarian cancer population5.

TOPACIO Results in Advanced Triple-Negative Breast Cancer Show Encouraging Activity of Niraparib in Combination with anti-PD-1

At the time of data cutoff, of the 55 patients enrolled with TNBC, 46 were available for an initial response assessment, 15 of whom had BRCA mutations and 5 of whom were HRRmut. In the TNBC population evaluable for initial response assessment, ORR was 28% and DCR was 50%, while in the BRCAmut population, ORR was 60% and DCR was 80%, with mPFS of 8.3 months. In the combined BRCAmut plus HRRmut population, ORR was 55% and DCR was 80%, with mPFS of 6.4 months. Median DOR has not been reached with 62% (8/13) of responders remaining on treatment, including five patients with long-term, ongoing clinical benefit for approximately one year. The combination was well tolerated with the most commonly observed grade ≥ 3 AEs including anemia (15%) and thrombocytopenia (13%). Of note, the incidence of thrombocytopenia was substantially reduced with the 200-milligram dose of niraparib in both the ovarian cancer and TNBC cohorts in comparison to what has been observed in clinical trials with a starting dose of 300 milligrams niraparib. Following a successful discussion with FDA, a registration study of niraparib plus TSR-042 is being planned.

For patients with TNBC, the standard of care is chemotherapy6, which generally results in a median PFS in the range of three to five months, and median overall survival of ≤ 12 months7. PARP inhibitor monotherapy has demonstrated clinical activity in TNBC patients who are germline BRCA mutation carriers, but has not shown activity in breast cancer beyond gBRCAmut patients8. Anti-PD-1 antibody monotherapy has demonstrated modest activity in previously treated PD-1L positive TNBC, with an ORR of approximately 5-18% and median PFS of approximately two months9.

The TOPACIO trial is being conducted in collaboration with Merck Sharp & Dohme B.V., a subsidiary of Merck & Co., Inc., which is providing support for the trial.

QUADRA Results Demonstrate Durable Potential of ZEJULA in Late-Line Ovarian Cancer Setting Beyond Patients with BRCA Mutations

Previous studies have shown that meaningful activity of other PARP inhibitors in the late-line treatment of ovarian cancer is limited to populations with BRCA mutations. Efficacy of cytotoxic chemotherapy is limited in patients with heavily-pretreated ovarian cancer. QUADRA, a single arm study (n=463), was conducted to assess the activity of ZEJULA monotherapy in the fourth-line or greater treatment of patients with ovarian cancer, regardless of platinum or biomarker status. In QUADRA, less than 20% of patients had a BRCA mutation, 27% received niraparib as a sixth or later line therapy, two-thirds were platinum resistant or refractory (33% and 35%, respectively), and 48% were HRD positive. The majority of platinum sensitive patients who enrolled in QUADRA were considered platinum ineligible, and 62% had received prior bevacizumab. The median time from last chemotherapy until the first dose of niraparib was two months.

The primary efficacy population included fourth or fifth line patients who were previous PARPi naïve, platinum sensitive, and HRD positive (n= 45). The ORR in this population was 29% (95% CI 16-44, p=0.0003). Approximately one-third of patients (27%) enrolled in QUADRA were treated in the sixth or later line of therapy. For patients who were fourth or later line, HRD-positive and platinum sensitive (n=51), the ORR was 27%, the disease control rate (DCR; CR + PR + SD) was 69%, and DOR was 9.2 months. Among those treated in fourth or later line of therapy, clinical benefit (CR+PR+SD) rate for at least 16 weeks was 53% for patients with a BRCA mutation and 49% for patients who were HRD positive and platinum sensitive. Responses to niraparib were durable, with a median DOR of 9.4 months across the entire evaluable patient population. An estimated 44% of all responses lasted 12 months or more.

Median overall survival (OS) in all patients treated fourth line or later was 17.2 months. Median OS was 16.6 months in HRD-negative or unknown patients, 19.0 months in HRD-positive patients and 26.0 months in patients with BRCA mutations.

At a starting dose of 300 milligrams of ZEJULA, the most commonly observed grade 3 or higher adverse events were consistent with prior clinical experience and included anemia (26.3%) and thrombocytopenia (20.5%), which were generally managed via dose modifications. TESARO intends to submit a sNDA to FDA in the fourth quarter of 2018.

Investor Briefing and Webcast
TESARO will host an investor and analyst briefing in Chicago on Monday, June 4 at 6:15PM local time in conjunction with the ASCO (Free ASCO Whitepaper) Annual Meeting. A reception will begin at 6:00PM CT, preceding the presentation. During this briefing, TESARO management will provide a business overview and pipeline update and will answer questions from investors and analysts. This event will be webcast live and archived for 30 days, and may be accessed from the TESARO Investor Events and Presentations webpage at www.tesarobio.com.

About the QUADRA Clinical Trial
QUADRA is an open-label, single arm trial designed to evaluate the safety and efficacy of ZEJULA in the treatment setting of ovarian cancer. Patients were enrolled and received a starting dose of 300 milligrams of niraparib once per day. The primary endpoint of this study was objective response rate (ORR) per RECIST in the fourth and fifth-line HRD positive patients who were PARP inhibitor naïve, and platinum sensitive. Other endpoints include durability of response, disease control rate, progression free survival (PFS), overall survival (OS) and safety and tolerability.

About ZEJULA (Niraparib)
Niraparib is marketed in the United States and Europe under trade name ZEJULA. ZEJULA (niraparib) is a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. In preclinical studies, ZEJULA concentrates in the tumor relative to plasma, delivering greater than 90% durable inhibition of PARP 1/2 and a persistent antitumor effect.

ZEJULA (niraparib) Select Important Safety Information
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) was reported in patients treated with ZEJULA in some clinical studies. Discontinue ZEJULA if MDS/AML is confirmed.
Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time.

Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

Based on its mechanism of action, ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose. Because of the potential for serious adverse reactions in breastfed infants from ZEJULA, advise a lactating woman not to breastfeed during treatment with ZEJULA and for one month after receiving the final dose.

On June 4, 2018 Hutchison China MediTech Limited ("Chi-Med") (AIM/Nasdaq: HCM) reported that further data from the FRESCO Phase III study in 416 patients with locally advanced or metastatic colorectal cancer ("CRC") were presented at the 2018 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) ("ASCO") Annual Meeting, held in Chicago, Illinois from June 1 to 5, 2018 (Press release, Hutchison China MediTech, JUN 4, 2018, https://www.chi-med.com/fresco-data-at-asco-2018/ [SID1234527125]).

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Fruquintinib is a highly selective and potent oral inhibitor of vascular endothelial growth factor ("VEGF") receptors 1, 2 and 3. The FRESCO dataset is a part of the New Drug Application ("NDA") filed and accepted by the China National Drug Administration (the "CNDA"). Additional clinical trials are ongoing in China for lung cancer (the third-line FALUCA Phase III study and the first-line Iressa combination Phase II study) and gastric cancer (the second-line FRUTIGA Phase III study), as well as in the United States (Phase I bridging study).

The two presentations were as follows:

Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, Phase III trial comparing fruquintinib versus placebo plus best supportive care in Chinese patients with metastatic colorectal cancer

Presenter: Ruihua Xu
Other Authors: Jin Li, Yu-Xian Bai, Yanhong Deng, Lei Yang, Haijun Zhong, Zhendong Chen, Hongming Pan, Weijian Guo, Yongqian Shu, Ying Yuan, Jianming Xu, Lin Shen, Ning Wang, Xin Wang, Haidong Chi, Jack Peng, Ye Hua, Weiguo Su, Shukui Qin
Time & Location: Sunday, June 3, 08:00 – 11:30 CDT; Hall A, Poster Board: #30
Session: Gastrointestinal (Colorectal) Cancer
Abstract No. & Link: #3537; abstracts.asco.org/214/AbstView_214_215579.html
Poster Link:[ ]: 16ealJfSDOCUUwuY6Icm22

In FRESCO, fruquintinib demonstrated a statistically significant and clinically meaningful benefit in third-line metastatic CRC patients in China. This analysis explored possible effects of prior target therapy on the efficacy and safety of fruquintinib by analyzing the subgroups of patients with prior target therapy ("PTT") and those without prior target therapy ("non-PTT"). The results of this analysis showed that fruquintinib had clinically meaningful benefits in third-line metastatic CRC patients regardless of PTT without observed accumulative toxicity.

Results previously presented at the 20th Annual Meeting of the Chinese Society of Clinical Oncology showed that the benefits of fruquintinib were generally consistent across all subgroups. Among a total of 278 fruquintinib-treated patients, 111 received PTT. In the PTT subgroup, fruquintinib significantly prolonged overall survival ("OS") (Median OS: 7.69 months vs 5.98 months; HR = 0.63; p = 0.023) and progression-free survival ("PFS") (Median PFS: 3.65 months vs 1.84 months; HR = 0.24; p < 0.001) compared to placebo. Patients who received prior anti-VEGF treatment (N = 84) also benefited from fruquintinib in OS (Median 7.20 months vs 5.91 months; HR = 0.68; p=0.066) and PFS (Median 3.48 months vs 1.84 months; HR = 0.24; p < 0.001). In the non-PTT subgroup, the median OS was 10.35 months for fruquintinib vs 6.93 months for placebo (HR = 0.63; p = 0.01), and the median PFS for fruquintinib was 3.81 months vs 1.84 months for placebo (HR = 0.28; p < 0.001).

Additional data presented at this year’s ASCO (Free ASCO Whitepaper) showed that there were no observed accumulative Grade ≥3 treatment-emergent adverse events in the PTT subgroup. The Grade ≥3 treatment-emergent adverse events rates of fruquintinib were similar in PTT and non-PTT subgroup (61.3% and 61.1%). This subgroup analysis result is consistent with the previously reported FRESCO intent-to-treatment population result.

Quality-adjusted time without symptoms or toxicity (Q-TWiST) of patients with metastatic colorectal cancer treated with fruquintinib in the randomized Phase III FRESCO trial

Presenter: Yu-Xian Bai
Other Authors: Hongyan Li, Ning Wang, Xiaojun Guo, Wei Wang, Songhua Fan, Jian-Ming Xu, Lin Shen
Time & Location: Sunday, June 3, 08:00 – 11:30 CDT; Hall A, Poster Board: #37
Session: Gastrointestinal (Colorectal) Cancer
Abstract No. & Link: #3544; abstracts.asco.org/214/AbstView_214_224293.html
Poster Link[ ]: 4l9OppVsv6UKE20CM4uQYy

This ad-hoc analysis aimed to compare the quality-adjusted survival between the two arms of the FRESCO study using quality-adjusted time without symptoms or toxicity ("Q-TWiST") methodology and to investigate the Q-TWiST benefit of fruquintinib treatment among subgroups. Q-TWiST is a tool to evaluate relative clinical benefit-risk from patient’s perspective and has been widely used in oncology treatment assessment. The survival time for each patient was divided into 3 portions: TOX (time with ≥ Grade 3 toxicity before progression), TWiST (time without symptoms or ≥ Grade 3 toxicity), and REL (time from progression or relapse until death or end of follow-up).

Patients treated with fruquintinib had longer Q-TWiST periods compared to patients treated with placebo. Q-TWiST benefits were observed regardless of prior lines of chemotherapy and target treatment with anti-VEGF or anti-EGFR. The relative improvement of Q-TWiST with fruquintinib represents a clinically important quality-of-life benefit for metastatic CRC patients.

Further information about the ASCO (Free ASCO Whitepaper) annual meeting is available at am.asco.org.

About Fruquintinib
Fruquintinib (HMPL-013) is a highly selective small molecule drug candidate that has been shown to inhibit VEGF receptors 24 hours a day via an oral dose, with lower off-target toxicities compared to other targeted therapies. Its tolerability, along with its clean drug-drug interaction profile demonstrated to date, may enable rational combination with other cancer therapies such as in our ongoing clinical trials of fruquintinib in combination with chemotherapy and targeted therapy. VEGF receptors play a pivotal role in tumor-related angiogenesis, and inhibition of VEGFR represents an important therapeutic strategy in blocking the development of new blood vessels essential for tumors to grow and invade.

About Fruquintinib in CRC in China
The CNDA, formerly the China Food and Drug Administration, acknowledged acceptance of the NDA for fruquintinib for the treatment of patients with advanced CRC in June 2017. Fruquintinib was subsequently awarded priority review status in view of its significant clinical value, according to a CNDA announcement in September 2017. The NDA is supported by data from the successful FRESCO study, which was highlighted in an oral presentation at the ASCO (Free ASCO Whitepaper) Annual Meeting held on June 5, 2017. Additional details about this study can be found at clinicaltrials.gov, using identifier NCT02314819. The FRESCO study followed an initial Phase I trial in 40 solid tumor patients, a Phase Ib study in 62 CRC patients, and a Phase II clinical trial in 71 CRC patients.

Other Fruquintinib Development Programs
Lung cancer in China: Fruquintinib is being studied in China in a Phase III registration study, known as FALUCA, in non-small cell lung cancer ("NSCLC") patients. FALUCA is a randomized, double-blind, placebo-controlled, multi-center study of fruquintinib targeted at treating patients with advanced non-squamous NSCLC who have failed two lines of systemic chemotherapy. The trial completed enrollment of 527 patients in February 2018 (clinicaltrials.gov identifier NCT02691299). It was initiated following a similar Phase II clinical trial in 91 third-line NSCLC patients. Results of the Phase II study were highlighted in an oral presentation at the 17th World Conference on Lung Cancer on December 6, 2016 (clinicaltrials.gov identifier NCT02590965).

Along with FALUCA, fruquintinib is concurrently being studied in a Phase II study in combination with Iressa (gefitinib) in the first-line setting for patients with advanced or metastatic NSCLC (clinicaltrials.gov identifier NCT02976116). Preliminary results were highlighted in an oral presentation at the 18th World Conference on Lung Cancer on October 16, 2017.

Gastric cancer in China: In October 2017, Chi-Med initiated a pivotal Phase III clinical trial of fruquintinib in combination with Taxol (paclitaxel), known as the FRUTIGA study, for the treatment of patients with advanced gastric or gastroesophageal junction ("GEJ") adenocarcinoma. The FRUTIGA study is a randomized, double-blind, placebo-controlled, multi-center trial expected to enroll over 500 gastric or GEJ adenocarcinoma patients who have progressed after first-line standard chemotherapy (clinicaltrials.gov identifier NCT03223376). The FRUTIGA study follows a Phase Ib/II clinical trial that demonstrated that combination therapy of fruquintinib and Taxol in such patients was generally well-tolerated with promising tumor response (clinicaltrials.gov identifier NCT02415023).

In China, fruquintinib is jointly developed with Eli Lilly and Company.

United States bridging trial: In December 2017, Chi-Med initiated a multi-center, open-label, Phase I clinical study to evaluate the safety, tolerability and pharmacokinetics of fruquintinib in U.S. patients with advanced solid tumors (clinicaltrials.gov identifier NCT03251378).
About Chi-Med
Chi-Med is an innovative biopharmaceutical company which researches, develops, manufactures and sells pharmaceuticals and healthcare products. Its Innovation Platform, Hutchison MediPharma Limited, focuses on discovering and developing innovative therapeutics in oncology and autoimmune diseases for the global market. Its Commercial Platform manufactures, markets, and distributes prescription drugs and consumer health products in China.

Chi-Med is majority owned by the multinational conglomerate CK Hutchison Holdings Limited (SEHK: 1). For more information, please visit: www.chi-med.com.

Iressa is a trademark of the AstraZeneca PLC group of companies. Taxol is a trademark of The Bristol-Myers Squibb Company group of companies.