Innovent Biologics and Hengrui Medicine Highlight New Drug Development Advances at ASCO: Oral Presentations by Six Chinese Researchers

May 31–June 4, 2019: The annual global oncology conference, the American Society of Clinical Oncology (ASCO) Annual Meeting, was held in Chicago, USA.

This year’s conference marks the 55th Annual Meeting of ASCO, themed “Caring for Every Patient, Learning from Every Patient,” and has attracted more than 40,000 elites in global clinical oncology research. During the annual meeting, authors of approximately 2,450 research abstracts were selected to deliver oral presentations, while more than 2,500 additional abstracts will be published online.

At this year’s ASCO Annual Meeting, six Chinese scholars will successively present in the ASCO Oral Presentation session. They are Professor Chen Mingyuan, Professor Ma Jun, and Professor Xu Ruihua from Sun Yat-sen University Cancer Center; Professor Zhang Li from the Institute of Hematology, Chinese Academy of Medical Sciences; Professor Jiang Zefei from the Fifth Medical Center of the Chinese PLA General Hospital; and Professor Tao Rong from Xinhua Hospital.

Arterial Network Medicine (WeChat ID: biobeat1) has summarized the key points from reports by six Chinese scholars for our readers. Their research not only enriches combination therapy regimens for oncology but has also drawn widespread attention due to their proprietary Me-Better innovative drugs.

Reporter: Professor Chen Mingyuan, Sun Yat-sen University Cancer Center

Clinical Trial Information: NCT00705627

Clinical Trial Phase: Phase III

ASCO Abstract No.: 6004

Professor Chen Mingyuan from the Sun Yat-sen University Cancer Center presented a Phase III clinical study on locally advanced nasopharyngeal carcinoma (NPC) at the conference. According to the Chinese version of the NCCN Guidelines, the standard treatment regimen for locally advanced NPC is radiotherapy combined with concurrent cisplatin, and the concurrent use of nimotuzumab is also a therapeutic option.

Objective: To evaluate the efficacy and safety of induction chemotherapy (IC) with cisplatin and fluorouracil (PF) followed by concurrent chemoradiotherapy (CCRT), compared with CCRT alone, in the treatment of advanced nasopharyngeal carcinoma (NPC). The primary endpoints were disease-free survival (DFS) and distant metastasis-free survival (DMFS).

Results: This study included 476 randomized patients. After a median follow-up of 82.6 months, the 5-year disease-free survival (DFS) rate was 73.4% (95% CI 67.7–79.1) in the induction chemotherapy (IC) group, followed by 63.1% (95% CI 56.8–69.4) in the concurrent chemoradiotherapy (CCRT) group, and lastly in the CCRT-alone group (P=0.005). The 5-year distant metastasis-free survival (DMFS) rate in the IC group (82.8%, 95% CI 77.9–87.7) was also significantly higher than that in the CCRT group (73.1%, 95% CI 67.2–79.0; P=0.013). The results indicated that IC improved overall survival (OS): the 5-year OS rate was 80.8% in the IC group, compared with 76.8% in the CCRT-alone group (P=0.045). There was no significant difference in the incidence of grade 3–4 late adverse events between the two groups during the follow-up period.

Study Conclusion: Induction chemotherapy (IC) with cisplatin and fluorouracil (PF) after CCRT can improve disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival (OS) compared to CCRT alone.

Reporter: Professor Ma Jun, Sun Yat-sen University Cancer Center

Clinical Trial Information: NCT01872962

Clinical Trial Phase: Phase III

ASCO Abstract No.: 6003

Professor Ma Jun from the Sun Yat-sen University Cancer Center reported the findings of a Phase III multicenter randomized controlled trial, presenting clinical trial data on gemcitabine plus cisplatin induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent radiotherapy alone in patients with locally advanced nasopharyngeal carcinoma. The study results are scheduled to be published simultaneously in The New England Journal of Medicine and have been honored as Best of ASCO.

According to statistics, approximately 70% of patients with nasopharyngeal carcinoma present at an intermediate or advanced stage at the time of diagnosis. These patients face a high risk of treatment failure and are prone to distant metastasis after therapy. Professor Ma Jun’s team aims to reduce the risk of distant metastasis and improve patient survival rates by intensifying systemic chemotherapy.

Currently, the gemcitabine (IC) plus cisplatin (GP) regimen has become the standard first-line treatment for patients with recurrent/metastatic nasopharyngeal carcinoma (NPC); however, its efficacy in locally advanced disease remains unclear.

Six years ago, Professor Ma Jun’s team initiated a clinical study evaluating induction chemotherapy with gemcitabine plus cisplatin followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma. The study enrolled previously untreated, non-metastatic stage III–IVB (excluding T3-4N0M0, according to the 7th edition of the AJCC staging system) nasopharyngeal carcinoma patients aged 18–64 years without severe comorbidities. The primary endpoint was recurrence-free survival (RFS).

From 2013 to 2016, the research team spent 33 months completing patient enrollment and treatment. The study enrolled a total of 480 patients from 12 centers, with a median follow-up duration of 43 months.

The results showed that the 3-year RFS rates for the GPIC+CCRT group and the CCRT group were 85.8% and 77.2%, respectively; the 3-year OS rates were 94.6% and 90.3%, respectively; and the locoregional relapse-free survival (LR-RFS) rates were 91.8% and 91.0%, respectively. The addition of gemcitabine plus cisplatin induction chemotherapy increased the 3-year disease-free survival rate by nearly 9% and reduced the risk of treatment failure by approximately 50%.

Research findings indicate that the GPIC regimen followed by concurrent chemoradiotherapy significantly improves disease control and overall survival (OS) in patients with high-risk locally advanced nasopharyngeal carcinoma, with good tolerability and a favorable toxicity profile. This study provides evidence supporting GP plus concurrent chemoradiotherapy (CCRT) as the first-line standard treatment for patients with high-risk locally advanced nasopharyngeal carcinoma.

In recent years, significant progress has been made in the comprehensive treatment of nasopharyngeal carcinoma (NPC). In addition to the incorporation of induction chemotherapy prior to concurrent chemoradiotherapy, immunotherapy has also achieved remarkable outcomes in the field of NPC. Among patients with metastatic or recurrent NPC, the response rate to PD-1 antibodies is 20–30%. Furthermore, unlike traditional chemotherapy, PD-1 antibodies confer highly durable therapeutic benefits once a response is achieved. Professor Ma Jun stated that, based on these findings, he believes that PD-1 antibodies will further improve survival rates and save more lives among patients with newly diagnosed, non-metastatic, advanced-stage NPC, building upon existing treatment regimens.

Reporter: Professor Xu Ruihua, Sun Yat-sen University Cancer Center

Clinical Trial Information: NCT01824459

Clinical Trial Phase: Phase III

Pharmaceutical Company: Taihao Pharmaceutical

ASCO Abstract No.: 4017

Professor Xu Ruihua from the Sun Yat-sen University Cancer Center reported the results of a Phase III clinical trial. The data showed that, for patients with previously untreated advanced diffuse-type or mixed-type gastric adenocarcinoma and gastroesophageal junction adenocarcinoma, the S-1 plus oxaliplatin (SOX) regimen demonstrated superior efficacy and a more favorable toxicity profile compared to the S-1 plus cisplatin (SP) regimen.

The prognosis for diffuse-type or mixed-type gastric adenocarcinoma and adenocarcinoma of the gastroesophageal junction is often poor, necessitating more effective therapeutic approaches. In Asia, the SP regimen is the standard first-line chemotherapy for advanced gastric cancer. However, clinical data suggest that oxaliplatin-based chemotherapy regimens may be more effective and better tolerated than cisplatin-based regimens.

From July 2013 to July 2018, this Chinese, multicenter, randomized, parallel-group, open-label, phase 3 trial enrolled a total of 576 patients aged 18–75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, normal organ function, and histologically confirmed, unresectable advanced diffuse-type or mixed-type gastric adenocarcinoma or gastroesophageal junction adenocarcinoma.

Patients were randomly assigned in a 1:1 ratio to either the SOX group (S-1: 40–60 mg, twice daily, days 1–14, every 3 weeks; oxaliplatin: 130 mg/m², day 1, every 3 weeks) or the SP group (S-1: 40–60 mg, days 1–14, every 3 weeks; cisplatin: 60 mg/m², day 1, every 3 weeks).

The primary endpoint was overall survival (OS) in the full analysis set; secondary endpoints included progression-free survival (PFS), time to treatment failure (TTF), and safety. The results showed that the median number of chemotherapy cycles was 4 in both groups. Compared with the SP group, the SOX regimen demonstrated improved OS (13.0 months vs. 11.8 months; HR=0.764, 95% CI 0.636–0.918), PFS (5.7 months vs. 4.9 months; HR=0.752, 95% CI 0.632–0.895), and TTF (5.2 months vs. 4.7 months; HR=0.763, 95% CI 0.641–0.909).

The results of this clinical study indicate that the addition of GP induction chemotherapy to concurrent chemoradiotherapy significantly improves failure-free survival in patients with locally advanced nasopharyngeal carcinoma, with good tolerability and a favorable toxicity profile.

Reporter: Professor Zhang Li, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences

Clinical Trial Information: NCT02204644

Clinical Trial Phase: Phase III

Pharmaceutical Company: Jiangsu Hansoh Pharmaceutical

ASCO Abstract No.: 7004

At the conference, Professor Zhang Li from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, presented the results of a Phase III clinical study on chronic myeloid leukemia (CML). CML is a malignant neoplasm affecting the blood and bone marrow. The targeted therapy drug imatinib (IM) is the first-line treatment for CML in the chronic phase, while allogeneic hematopoietic stem cell transplantation (Allo-SCT) is an effective curative option. Flumatinib (FM), a derivative of imatinib (IM), is a novel BCR-ABL1 tyrosine kinase inhibitor and holds promise as the next-generation therapeutic agent for CML in the chronic phase following IM. Developed by Jiangsu Hansoh Pharmaceutical, the drug has currently submitted a New Drug Application (NDA) for a Class 1 innovative drug.

Objective: This study aimed to evaluate the efficacy and safety of first-line FM treatment in patients with chronic-phase chronic myeloid leukemia (CML-CP), using IM as the comparator. The primary endpoints were the rates of major molecular response (MMR, defined as BCR-ABL IS ≤0.1%) at 6 and 12 months.

Results: A total of 400 patients were enrolled in the study, with comparable baseline characteristics across groups. The full analysis set comprised 393 patients, who received either flumatinib 600 mg/day (n=196) or imatinib 400 mg/day (n=197).

Compared with imatinib, flumatinib induced significantly higher MMR rates at 6 months [33.7% (95% CI 27.06–40.29) vs. 18.3% (12.88–23.67); P=0.0005] and 12 months [48.5% (41.47–55.47) vs. 33.0% (26.43–39.56); P=0.0021], as well as a higher MMR rate at 3 months [8.2% (4.33–12.00) vs. 2.0% (0.06–4.00); P=0.0058].

Moreover, a significantly higher proportion of patients in the flumatinib group achieved complete molecular response (BCR-ABL IS ≤0.0032%) at 12 months compared with those in the imatinib group.

The early molecular response rate (BCR-ABL IS ≤10%) [82.1% (76.78–87.50) vs. 53.3% (46.33–60.27); P<0.0001] and the early complete cytogenetic response rate at 6 months [60.71% (53.88–67.55) vs. 49.75% (42.76–56.73); P=0.0332] were also significantly higher in the FM group than in the IM group.

Studies have shown that flumatinib and imatinib have similar safety profiles, with comparable incidence rates of grade 3/4 treatment-emergent adverse events (TEAEs) in both groups (56.57% vs. 41.38%). However, compared to the imatinib group, the flumatinib group had significantly lower incidence rates of certain non-hematological and hematological adverse events, such as rash (4.59% vs. 12.63%; P=0.0064), eyelid edema (0.51% vs. 14.65%; P<0.0001), leukopenia (30.61% vs. 62.63%; P<0.0001), and malnutrition (30.10% vs. 59.60%; P<0.0001). No specific TEAEs were identified in either group.

Study Conclusion: For the treatment of chronic-phase chronic myeloid leukemia (CML-CP) in China, flumatinib demonstrates comparable safety to imatinib, but exhibits superior efficacy at 3, 6, and 12 months. Therefore, the study results indicate that flumatinib can serve as a first-line therapy for such patients.

Reporter: Professor Jiang Zefei, The Fifth Medical Center of Chinese PLA General Hospital

Clinical Trial Information: NCT02973737

Clinical Trial Phase: Phase III

Pharmaceutical Company: Jiangsu Hengrui Medicine

ASCO Abstract No.: 1001

Professor Jiang Zefei from the Fifth Medical Center of the Chinese PLA General Hospital reported the results of a Phase III study at ASCO. Clinical trial data demonstrated that, in Chinese patients with HER2-positive metastatic breast cancer previously treated with trastuzumab (brand name: Herceptin) and taxanes, pyrotinib (generic name: Pyrotinib) combined with capecitabine significantly improved progression-free survival (PFS) compared with placebo plus capecitabine.

Pyrotinib, developed by Jiangsu Hengrui Medicine at a cost exceeding RMB 500 million, is an oral dual inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) tyrosine kinases.

In May 2011, Jiangsu Hengrui and Shanghai Hengrui jointly submitted an Investigational New Drug (IND) application (Class 1.1 chemical drug) to the China Food and Drug Administration; in April 2012, they obtained the clinical trial approval for Class 1.1 chemical drugs in China; in August 2017, they submitted a New Drug Application (NDA) in China for the treatment of HER2-positive metastatic breast cancer; in August 2018, pyrotinib was officially approved for marketing.

The market launch of pyrotinib not only adds another blockbuster domestically developed innovative drug, but also provides an important clinical treatment option for breast cancer patients in China.

Previously, as an irreversible pan-ErbB receptor tyrosine kinase inhibitor, pyrotinib demonstrated robust antitumor activity and acceptable tolerability in Phase 1/2 trials for HER2+ metastatic breast cancer.

From July 2016 to November 2017, this double-blind, multicenter, randomized phase 3 trial enrolled a total of 279 Chinese patients with HER2-positive metastatic breast cancer who had previously been treated with trastuzumab and taxanes. Patients were randomized in a 2:1 ratio to receive either pyrotinib (400 mg, once daily, every 21 days) plus capecitabine (1,000 mg/m², twice daily, on days 1–14) (n=185) or placebo plus capecitabine (1,000 mg/m², twice daily, on days 1–14) (n=94).

The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee. Patients in the placebo group received pyrotinib monotherapy after disease progression.

The study results showed that the median PFS was 11.1 months (95% CI 9.66–16.53) in the pyrotinib group and 4.1 months (95% CI 2.79–4.17) in the placebo group; the objective response rates (ORR) were 68.6% (95% CI 61.4–75.3) and 16% (95% CI 9.2–25), respectively.

Among them, 71 patients in the placebo group received pyrotinib monotherapy after disease progression, achieving an objective response rate (ORR) of 38% (95% CI: 26.7%-49.3%) and a median progression-free survival (PFS) extension of 5.5 months (95% CI: 4.07-6.90), suggesting that pyrotinib monotherapy also demonstrated robust antitumor activity. The most common (≥5%) treatment-related grade ≥3 adverse events in both groups were diarrhea (30.8% vs. 12.8%) and hand-foot syndrome (15.7% vs. 5.3%). (Clinical trial information: NCT02973737)

Phase III clinical trial results demonstrated that pyrotinib plus capecitabine yielded a statistically significant improvement in progression-free survival (PFS) among women with HER2-positive metastatic breast cancer (MBC) previously treated with taxanes and trastuzumab. Pyrotinib monotherapy exhibited antitumor activity.

Reporter: Professor Tao Rong, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine

Clinical Trial Information: NCT03228836

Clinical Trial Phase: Phase II

Pharmaceutical Company: Innovent Biologics

ASCO Abstract No.: 7504

At the conference, Professor Tao Rong from Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine presented the results of a Phase II study named ORIENT on sintilimab for the treatment of relapsed/refractory extranodal NK/T-cell lymphoma (r/r ENKTL). ENKTL accounts for more than 20% of peripheral T-cell lymphomas in Asia. However, patients with r/r ENKTL have a poor prognosis after failure of L-asparaginase-based regimens, with a median overall survival (OS) of less than 6 months. Sintilimab is a PD-1 inhibitor jointly developed by Innovent Biologics and Eli Lilly and Company. It was approved by the National Medical Products Administration on December 24, 2018, for the treatment of relapsed or refractory classical Hodgkin’s lymphoma in patients who have undergone at least two lines of systemic chemotherapy.

Objective: ORIENT is a multicenter, single-arm, Phase II study designed to evaluate the efficacy and safety of sintilimab monotherapy in Chinese patients with relapsed or refractory extranodal natural killer/T-cell lymphoma (r/r ENKTL). The primary endpoint was the objective response rate based on the 2014 Lugano criteria. The data cutoff date for this analysis was February 2, 2019.

Results: From August 31, 2017, to February 7, 2018, a total of 28 patients with pathologically confirmed relapsed/refractory extranodal natural killer/T-cell lymphoma (r/r ENKTL) were enrolled in this study. Of these, 60.7% were male, with a median age of 37 years (range: 19–65 years); 68% had stage IV disease, and 89.3% had an ECOG performance status (PS) ≥1. All patients had failed prior L-asparaginase-based regimens, with a median of 3 prior lines of therapy (range: 1–13) before receiving the current treatment; 78.6% had previously received radiotherapy, and 7.1% had failed hematopoietic stem cell transplantation.

The median duration of treatment was 14.04 months (range, 1.4–17.3), and at the data cutoff, 19 patients were still receiving sintilimab treatment.

Analysis revealed that 68% (19/28; 95% CI: 47.6%-84.1%) of patients achieved complete or partial response, including four patients who had previously experienced disease progression. The disease control rate (DCR) for all patients was 85.7%, which included five patients with stable disease or those in the disease progression phase. The 1-year overall survival (OS) rate was 82.1%, and the median OS was not reached.

Most treatment-related adverse events (TRAEs) were Grade 1–2 (67.9%), and no patients discontinued treatment due to adverse events. The most common TRAE was decreased lymphocyte count (46.4%), with 84.6% of cases being Grade 1–2. Serious adverse events (SAEs) occurred in 21.4% of patients, but none were related to sintilimab.

The early disease progression observed on PET scans in the study may represent pseudoprogression, as it is not associated with adverse outcomes; however, further research is warranted.

Study Conclusion: Overall, sintilimab is effective and well-tolerated in the treatment of relapsed/refractory extranodal NK/T-cell lymphoma (ENKTL), representing a promising therapeutic option for such patients.

Compiled by Cao Xian and Wang Shiwei