Merck's Keytruda Expands Strongly and Amgen Showcases Extensive BiTE Platform Data — Seven Major Pharma Highlights from ASCO

From May 31 to 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.

The annual ASCO meeting is always a showcase of abundant achievements in the field of oncology diagnosis and treatment, with major pharmaceutical companies competing to release their landmark research data. VCBeat’s New Medicine (biobeat1) has compiled the 2019 ASCO results from major pharmaceutical companies. Among them, Merck & Co. presented five-year follow-up results on PD-1 inhibitor therapy; Amgen disclosed clinical data from its largest-ever oncology pipeline; and AstraZeneca, in collaboration with Merck & Co., achieved significant results in the Phase III clinical trial of Olaparib (brand name Lynparza) for pancreatic cancer. For more highlights, see below:

Merck & Co. announced five-year data from KEYNOTE-001 (a Phase Ib clinical trial of pembrolizumab). The data demonstrated that pembrolizumab (generic name: pembrolizumab; brand name: Keytruda) is safe and effective, and can significantly improve overall survival in patients with advanced non-small cell lung cancer (aNSCLC).

About This Study

Pembrolizumab is a PD-1 monoclonal antibody launched by Merck & Co. The clinical trial KEYNOTE-001 disclosed herein enrolled a total of 550 patients with advanced non-small cell lung cancer (aNSCLC), among whom 101 were treatment-naïve, while the remaining 449 had previously received pharmacological or targeted therapy. All patients received pembrolizumab at a dose of 2 mg/kg every three weeks or 10 mg/kg every two to three weeks. In recent years, this dosing regimen has been revised to a fixed dose of 200 mg, irrespective of body weight.

Specifically, 23.2% of patients who had not previously received chemotherapy and 15.5% of those who had received chemotherapy remained alive five years after treatment with pembrolizumab (Keytruda). Among them, patients with high PD-L1 expression demonstrated the best outcomes.

These data indicate that immunotherapy has significantly improved the 5-year survival rate. Ten years ago, the 5-year survival rate for patients with locally advanced and metastatic non-small cell lung cancer (NSCLC) was less than 1%, whereas it has now reached an overall 18%. Researchers stated that this is the longest follow-up study to date on pembrolizumab in patients with advanced NSCLC (aNSCLC).

# Key Research Findings

The median follow-up time for patients was 60.6 months, approximately 5 years. At the cutoff date, 18% of the enrolled participants (100 individuals) remained alive. The survival rate was 23% for treatment-naïve patients, whereas it was 15.5% for those who had received prior treatment.

Among patients who had not previously received other treatments, the 5-year survival rate was 29.6% for those with PD-L1 expression exceeding 50%, and 15.7% for those with PD-L1 expression below 50%. Among patients who had previously received other treatments, the 5-year survival rate was 25% for those with PD-L1 expression exceeding 50%, 12.6% for those with PD-L1 expression between 1% and 49%, and only 3.5% for those with PD-L1 expression below 1%.

In patients who had previously received other treatments, 42% had a duration of response of 16.8 months. In contrast, among patients who had not previously received other treatments, 23% had a duration of response as long as 38.9 months.

In addition to non-small cell lung cancer, Merck & Co. announced that the KEYNOTE-062 Phase III randomized clinical trial of pembrolizumab for advanced gastric and gastroesophageal junction (G/GEJ) cancers met its primary endpoint. The trial demonstrated that first-line treatment with pembrolizumab yielded overall survival rates comparable to those of standard chemotherapy (non-inferiority) in patients with PD-L1-positive/HER2-negative advanced G/GEJ cancers. Furthermore, a significant improvement in overall survival was observed among patients with high PD-L1 expression treated with pembrolizumab. Specifically, 39% of patients receiving pembrolizumab were alive at two years, compared with a two-year survival rate of 22% for those receiving standard chemotherapy.

The trial also evaluated chemotherapy alone versus pembrolizumab plus standard chemotherapy. The final results showed that this regimen did not improve survival compared with chemotherapy alone.

About This Study

This trial enrolled 763 patients with a median age of 62 years, among whom 69% had gastric cancer and 30% had gastroesophageal junction cancer. Twenty-six percent of the patients had previously undergone resection surgery for gastric tumors.

Researchers assessed the patients’ PD-L1 Combined Positive Score (CPS) to characterize PD-L1 expression in their tumors. Patients with a PD-L1 CPS greater than 1 were more likely to benefit from pembrolizumab, while a PD-L1 CPS of 10 or higher indicated an even greater likelihood of benefit. In the current trial, all patients had a PD-L1 CPS of 1 or higher, with 281 patients (37% of those enrolled) scoring 10 or higher.

Researchers randomly assigned an equal number of patients to receive one of three regimens as initial treatment: intravenous pembrolizumab, pembrolizumab plus chemotherapy, or placebo plus chemotherapy. The median follow-up duration was 11.3 months.

Primary Research Findings

Pembrolizumab Monotherapy: The trial met its primary endpoint, demonstrating that overall survival with pembrolizumab was non-inferior (comparable) to that with standard chemotherapy. Favorable survival outcomes were observed in enrolled patients with a PD-L1 Combined Positive Score (CPS) of 10 or higher. Specific findings include:

Patients with PD-L1 CPS > 1: Survival was non-inferior (comparable) to chemotherapy [hazard ratio = 0.91]. The median overall survival was 10.6 months for patients receiving pembrolizumab and 11.1 months for those receiving chemotherapy.

Patients with PD-L1 CPS >10: Pembrolizumab demonstrated superior survival compared with chemotherapy [hazard ratio=0.69]. The median overall survival was 17.4 months for patients receiving pembrolizumab versus 10.8 months for those receiving chemotherapy. At 2 years, the survival rate was 39% in the pembrolizumab group compared with 22% in the chemotherapy group.

Pembrolizumab plus chemotherapy: For the combination therapy of pembrolizumab and chemotherapy, overall survival and progression-free survival (time to disease progression) are comparable to chemotherapy alone, regardless of the CPS score.

AstraZeneca and Merck & Co. have announced partial results from the global, multicenter Phase III clinical trial of olaparib (brand name Lynparza) for pancreatic cancer. The trial found that maintenance therapy with olaparib significantly delayed disease progression in patients with BRCA-mutated metastatic pancreatic cancer compared with placebo. In the trial, patients whose cancer had not progressed after initial platinum-based chemotherapy received olaparib. After two years, 22.1% of patients receiving olaparib were free of disease progression, compared with 9.6% of those receiving placebo.

About Olaparib

Olaparib, jointly developed by AstraZeneca and Merck & Co., is a small-molecule targeted therapy that inhibits PARP. PARP plays a critical role in DNA transcription and repair. Olaparib is currently approved by the FDA for first-line maintenance treatment in patients with BRCA mutations who have responded to platinum-based chemotherapy. BRCA mutations are germline mutations that increase the incidence of ovarian, breast, and prostate cancers. Approximately 5%–6% of pancreatic cancers are caused by mutations in one or two BRCA genes. Previous studies have shown that the response rate (tumor shrinkage) to Olaparib treatment in pancreatic cancer patients with BRCA1/2 mutations, following gemcitabine-based chemotherapy, was 22%.

About This Study

In this study, researchers screened 247 patients with BRCA mutations from a cohort of 3,315 pancreatic cancer patients. Subsequently, 154 patients were allocated in a 3:2 ratio, with 92 receiving olaparib and the remaining 62 receiving placebo. Two-thirds of the participants harbored BRCA2 mutations, while the remainder had BRCA1 mutations. Treatment was initiated 4–8 weeks after the patients’ last dose of platinum-based chemotherapy.

Primary Research Findings

Compared with patients receiving placebo, Olaparib reduced the risk of disease progression by 47%. The median progression-free survival was 7.4 months in patients treated with Olaparib, versus only 3.8 months in those receiving placebo. At one year, 33.7% of patients in the Olaparib group showed no signs of disease progression, compared with 14.5% in the placebo group. At two years, 22.1% of patients in the Olaparib group remained free of cancer progression, versus 9.6% in the placebo group. Overall, the probability of remaining progression-free was approximately twice as high in patients treated with Olaparib as in the placebo group.

Novartis Announces Findings from the International Phase III MONALEESA-7 Trial of Ribociclib (Brand Name: Kisqali)The addition of ribociclib to standard endocrine therapy significantly improved overall survival in premenopausal patients with HR-positive/HER2-negative breast cancer, compared with endocrine therapy alone.

About Ribociclib

Ribociclib is a small-molecule targeted therapy that inhibits cyclin-dependent kinases 4 and 6 (CDK4/6). In July 2018, the U.S. Food and Drug Administration approved ribociclib in combination with an aromatase inhibitor for premenopausal and perimenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer. Advanced breast cancer is less common in premenopausal women than in older women, but its incidence is gradually increasing. Between 1978 and 2008, the incidence of advanced breast cancer among women aged 20 to 39 years in the United States increased by an average of 2% per year.

About This Study

MONALEESA-7 is the first clinical trial specifically targeting premenopausal women under 59 years of age with advanced breast cancer who have not previously received endocrine therapy. A total of 672 female patients participated in this study. After a median follow-up of 34.6 months, 173 (26%) patients remained on treatment, including 116 (35%) receiving ribociclib and 57 (17%) receiving placebo.

Primary Research Findings

The median progression-free survival for women receiving ribociclib was 23.8 months, compared with 13 months for those receiving placebo plus endocrine therapy. Researchers observed that after 42 months of follow-up, the survival rate was 70% in patients treated with ribociclib, versus only 46% in those receiving placebo plus endocrine therapy. Overall, the relative risk of death was reduced by 29%. Among women receiving ribociclib in combination with tamoxifen or nonsteroidal aromatase inhibitors, survival rates were 71% and 70%, respectively, whereas in the placebo group receiving tamoxifen or aromatase inhibitors alone, survival rates were 55% and 43%, respectively.

Pfizer and Astellas Announce Interim Analysis of the International Randomized Phase III ENZAMET Clinical Trial for Enzalutamide (Brand Name: Xtandi). The results showed that after three years, 80% of patients with metastatic hormone-sensitive prostate cancer (mHSPC) receiving enzalutamide maintained efficacy with standard-of-care treatment, compared to 72% of men treated with other non-steroidal antiandrogens (NSAAs) plus standard therapy.

# About Enzalutamide

Enzalutamide was first approved by the FDA in 2012 for patients with metastatic hormone-sensitive prostate cancer (mHSPC) who had previously received docetaxel treatment, and later in 2014 for the same indication in patients who had not received docetaxel. Patients with mHSPC typically undergo orchidectomy or receive hormonal analog injections to reduce blood androgen levels. Additional therapies may then be added based on individual circumstances, including abiraterone (another nonsteroidal antiandrogen [NSAA]) or docetaxel chemotherapy. If the cancer continues to progress, further hormonal therapy and chemotherapy can be administered. These interventions have been shown to extend patient survival.

About This Study

In this trial, a total of 1,125 male patients were enrolled, of whom 503 had previously received early-line docetaxel therapy and 602 had not received docetaxel. Enrolled patients were randomly assigned between March 2014 and March 2017 to receive injectable testosterone suppression therapy combined with either daily oral enzalutamide (160 mg) or one of three other standard nonsteroidal antiandrogens (NSAAs): bicalutamide, nilutamide, or flutamide.

Primary Research Findings

After three years of clinical trials, the survival rate for patients receiving Enzalutamide plus testosterone suppression therapy was 80%, compared to 72% for those receiving other nonsteroidal antiandrogens (NSAAs) plus testosterone suppression therapy. Overall, mortality was reduced by approximately 33% in patients treated with Enzalutamide versus those treated with other NSAAs.

Furthermore, according to further analysis by the researchers, patients treated with Enzalutamide demonstrated higher survival rates than those treated with other non-steroidal anti-androgens (NSAAs), regardless of whether they belonged to the group with larger tumor areas on imaging scans or the group with smaller tumor areas. Meanwhile, the impact of Enzalutamide on survival rates was more pronounced in the patient population that had not received docetaxel treatment, reaching 83%, compared to 70% for patients taking other NSAAs. The researchers also pointed out that docetaxel yielded minimal benefits for patients with smaller tumor areas, whereas Enzalutamide could substantially improve survival rates in this subset of patients.

Johnson & Johnson’s subsidiary, Janssen Pharmaceuticals, announced the results of the TITAN clinical trial evaluating apalutamide (brand name Erleada) for metastatic castration-sensitive prostate cancer (mCSPC). The results demonstrated that the combination of Erleada plus androgen deprivation therapy (ADT) significantly improved progression-free survival and overall survival compared with placebo plus ADT.

About Apalutamide

Apalutamide is a second-generation antiandrogen drug developed by Janssen Pharmaceuticals that effectively inhibits androgen receptor activation, nuclear translocation, binding to coactivators, and androgen receptor-mediated gene expression.

Apalutamide was initially approved by the FDA in February 2018 for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC) at high risk of metastasis. It was also the first drug approved for the treatment of nmCRPC. In January 2019, Apalutamide received approval in the European Union for the same indication. China’s Center for Drug Evaluation (CDE) also included Apalutamide in the second batch of urgently needed overseas new drugs, announced on May 29.

Primary Research Findings

According to the data disclosed by Janssen Pharmaceuticals, treatment with Erleada significantly prolonged progression-free survival, reducing the risk of death by 52%. Furthermore, in terms of overall survival, Erleada combined with androgen deprivation therapy reduced the risk of death by 33%. The findings of this study were simultaneously published in The New England Journal of Medicine (NEJM).

At this year’s ASCO meeting, Amgen disclosed the largest-ever dataset from its oncology pipeline in the company’s history. Its promising BiTE (bispecific T cell engager) immuno-oncology platform has achieved progress in Phase I trials. Among these disclosures was the first-in-human data for AMG 510, the first KRAS G12C inhibitor to enter clinical trials, which primarily targets locally advanced or metastatic solid tumors harboring KRAS G12C mutations.

Data from other early-stage pipeline candidates have fully demonstrated the potential of the BiTE tumor immunotherapy platform. The indications span malignant hematologic tumors and solid tumors, including prostate cancer, for which data are being disclosed publicly for the first time.

Study of AMG 420 Treatment for Patients with Relapsed or Refractory Multiple Myeloma

BiTE molecules are designed to bind patients’ T cells to tumor-specific antigens, thereby activating the T cells to eliminate detectable tumor cells. The data recently disclosed by Amgen also include results from the Phase I dose-escalation study of AMG420, a BiTE molecule that targets B-cell maturation antigen (BCMA). This study primarily enrolled patients with relapsed or refractory multiple myeloma.

The objective of this study was to evaluate the safety, tolerability, and antitumor activity of AMG420. A total of 42 enrolled patients received varying doses of AMG420 (0.2 to 800 μg/day). Among the doses tested in this study, 400 μg/day was identified as the maximum tolerated dose (MTD).

Among these 42 patients, 13 demonstrated a treatment response. Of the 6 patients who achieved complete remission (CR) with minimal residual disease (MRD) negativity, 5 were from the 400 μg/d dose group. Additionally, one patient receiving the 400 μg/d dose exhibited a significant partial response, and the remaining patient achieved a partial response. The overall response rate in the 400 μg/d dose group was 70% (7/10). The median time to response was 9 months (range: 5.8–13.6 months). Among the 13 responding patients, 11 responded within the first treatment cycle, with a median time to response of 1 month.

Nineteen patients (45%) experienced serious adverse events (AEs) during the trial. Sixteen patients required hospitalization, with four of them requiring prolonged hospital stays. No grade 3 or 4 total neurotoxicity events were observed in the trial. Infections (n=13) and peripheral neuropathy (n=2) occurred in more than one patient.

Treatment-related serious adverse events included polyneuropathy (n=2, Grade 3) and edema (Grade 3). One patient experienced Grade 3 cytokine release syndrome (CRS). A total of two patients in the trial died from adverse events unrelated to treatment: one died from acute respiratory distress syndrome caused by concurrent influenza and aspergillosis, and the other died from liver failure induced by a viral infection during treatment.

Pasotuxizumab for Prostate Cancer: AMG 212 Phase I Clinical Trial

Pasotuxizumab is a bispecific antibody that binds to the PSMA antigen. In the trial, 16 patients with mCRPC (metastatic castration-resistant prostate cancer) were divided into five dose groups, with doses ranging from 5 to 80 µg/d.

The primary endpoint of this trial is to determine the safety and maximum tolerated dose of the drug, while the secondary endpoints include explorations of pharmacokinetics (PK), biomarkers, and tumor response.

The decline in prostate-specific antigen (PSA) levels indicated a correlation between antitumor activity and dose. Three patients (one each from the 20 μg/day, 40 μg/day, and 80 μg/day cohorts) achieved a PSA reduction of ≥50%. One patient with a durable response received treatment at a dose of 40 μg/day for 14 months, while another patient with a durable response received treatment at a dose of 80 μg/day for 19.4 months. The latter patient exhibited complete resolution of soft-tissue metastases, significant regression of bone metastases, and sustained, marked improvement in disease-related symptoms. Trial enrollment was halted before the maximum tolerated dose (MTD) was reached. The primary reason for discontinuing the trial was to facilitate the initiation of another study by Amgen.

The most common adverse reactions in the trial were fever (94%, n=15) and chills (69%, n=11). One patient experienced a drug-related serious adverse reaction (fatigue), and three patients (19%) developed cytokine release syndrome (CRS). No Grade 5 adverse events occurred in this trial.

Other Clinical Trial Information on the BiTE Platform

At the conference, Amgen also announced two additional clinical trials based on its BiTE platform.

First is AMG596, a BiTE molecule targeting EGFRvIII (epidermal growth factor receptor variant III) in glioblastoma. AMG596 is currently undergoing Phase I clinical trials to evaluate its safety, tolerability, and pharmacodynamics. The study is expected to enroll 82 patients, who will be divided into two groups: one group consisting of patients with recurrent glioblastoma, and the other comprising patients with newly diagnosed glioblastoma who have already completed standard maintenance therapy.

Another drug disclosed by Amgen is AMG757, a BiTE molecule targeting DLL3 (Delta-like ligand 3), for the treatment of small cell lung cancer. AMG757 is currently undergoing an open-label, dose-escalation, multiple-dose Phase I clinical trial. The target population consists of adult patients with small cell lung cancer who have experienced disease progression or recurrence after receiving at least one platinum-based chemotherapy regimen. The primary endpoint of this study is to evaluate the safety and tolerability of the drug and to determine the dosage for subsequent Phase II trials. The secondary endpoints are to characterize the pharmacokinetics (PK) and to preliminarily assess antitumor activity.

In the field of antibody-based therapeutics, pembrolizumab has continued to robustly expand its indications, achieving promising results even in the challenging areas of gastric cancer and gastroesophageal junction cancer. Amgen’s bispecific antibody platform has also demonstrated strong performance, with multiple studies selected for poster presentations.

In addition to the increasingly hot field of antibody drugs, small-molecule targeted therapies remain a key focus for major pharmaceutical companies. Several previously approved small-molecule targeted drugs are being evaluated for expanded indications. New progress has also been made in multiple hard-to-treat tumor types, including pancreatic cancer, metastatic hormone-sensitive prostate cancer (mHSPC), and castration-resistant prostate cancer (CRPC). It is believed that with continued advances in drug research, more difficult-to-treat cancers will achieve breakthroughs, thereby overcoming the current lack of effective therapeutic options.

Compiled by Hao Han, Zhou Mengya