ASH 2019 Highlights: AstraZeneca, Roche, Johnson & Johnson Unveil Latest Data on Key Oncology Therapies

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The 61st American Society of Hematology (ASH) Annual Meeting (ASH 2019) was held in Orlando, Florida, USA, from December 7 to 10 this year. The ASH Annual Meeting is the largest and most comprehensive international scientific exchange event in the field of hematology worldwide, covering both malignant and non-malignant hematologic diseases. Each year, it attracts more than 25,000 hematologists and other related healthcare professionals from over 100 countries around the globe. At this meeting, several pharmaceutical companies announced the latest progress on their respective anticancer drugs.

1. AstraZeneca's BTK Inhibitor Calquence

At this conference, AstraZeneca announced the full results of the ELEVATE TN Phase III clinical study of the BTK inhibitor Calquence. The study was conducted in previously untreated (treatment-naïve) patients with chronic lymphocytic leukemia (CLL) and evaluated the efficacy and safety of Calquence monotherapy, Calquence in combination with obinutuzumab, and chlorambucil plus obinutuzumab (a standard chemoimmunotherapy regimen).

Results showed that, with a median follow-up of 28.3 months: (1) Compared with the chlorambucil plus obinutuzumab combination regimen, the Calquence plus obinutuzumab combination regimen reduced the risk of disease progression or death by 90% (HR=0.10 [95% CI: 0.06–0.17], p<0.0001), significantly prolonged progression-free survival (PFS) (median PFS: not reached vs. 22.6 months), and substantially improved the 24-month progression-free or death-free survival rate (93% vs. 47%). (2) Compared with the chlorambucil plus obinutuzumab combination regimen, Calquence monotherapy significantly reduced the risk of disease progression or death by 80% (HR=0.20 [95% CI: 0.13–0.30], p<0.0001), significantly prolonged PFS (median PFS: not reached vs. 22.6 months), and substantially improved the 24-month PFS rate (87% vs. 47%). (3) Exploratory analyses demonstrated consistent PFS benefits with both Calquence combination therapy and monotherapy across most prespecified subgroups of patients with high-risk disease features, including unmutated immunoglobulin heavy chain variable region genes (IGHV), del(11q), and complex karyotype. (4) The safety and tolerability profile of Calquence observed in this study was consistent with its known profile.

2. Roche’s Two Bispecific Antibodies

At this conference, Roche presented new data on two novel CD20-CD3 T-cell-engaging bispecific antibodies, mosunetuzumab and CD20-TCB, for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (R/R NHL). These two agents differ structurally and can simultaneously bind to CD3 on T cells and CD20 on B cells. This dual targeting activates and redirects the patient’s T cells to kill target B cells by releasing cytotoxic proteins into them.

GO29781 is a dose-escalation study evaluating mosunetuzumab in patients with relapsed or refractory non-Hodgkin lymphoma (R/R NHL), including those who experienced relapse after or were refractory to CAR-T cell therapy, a population with very limited treatment options. The results demonstrated encouraging efficacy of mosunetuzumab: (1) The objective response rate (ORR) was 62.7% (n=42/67) in indolent NHL and 37.1% (n=46/124) in aggressive NHL. (2) The complete response (CR) rate was 43.3% (n=29/67) in indolent NHL and 19.4% (n=24/124) in aggressive NHL. (3) CR responses were durable, with 82.8% (n=24/29) of indolent NHL patients remaining in remission at 26 months after initial treatment, and 70.8% (n=17/24) of aggressive NHL patients remaining in remission at 16 months after initial treatment. (4) In patients previously treated with CAR-T cell therapy, the ORR was 38.9% (n=7/18) and the CR rate was 22.2% (n=4/18). (5) Regarding adverse events, cytokine release syndrome (CRS) occurred in 28.9% of patients, with 20.0% being Grade 1 and 1.1% being Grade 3; the incidence of Grade 3 neurological adverse events was 3.7%.

NP30179 is a dose-escalation Phase I/Ib study evaluating CD20-TCB (dose range 0.6 mg–16 mg) in combination with Gazyva/Gazyvaro (obinutuzumab, an anti-CD20 monoclonal antibody) for the treatment of patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL). The results showed: (1) The overall response rate (ORR) was 54% (n=15/28), and the complete response (CR) rate was 46% (n=13/28). (2) In follicular lymphoma (FL), both ORR and CR were 66.7% (n=4/6); in aggressive NHL, the ORR was 50.0% (n=11/22) and the CR rate was 40.9% (n=9/22). (3) The most common adverse event observed across all treatment doses was cytokine release syndrome (CRS), with an incidence of 67.9% (n=19/28), with most events being low-grade (Grade 1–2).

3. Johnson & Johnson’s BCMA CAR-T Therapy JNJ-4528

At this conference, Johnson & Johnson announced the preliminary results of the Phase Ib/II CARTITUDE-1 study evaluating JNJ-4528, a BCMA CAR-T therapy, for the treatment of relapsed or refractory multiple myeloma (R/R MM). The study enrolled patients who had previously received at least three prior therapies, were double-refractory to proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), or had been treated with PIs, IMiDs, and an anti-CD38 antibody and experienced disease progression during or within 12 months after their last line of therapy.

Results from the Phase Ib cohort demonstrated that JNJ-4528 (median dose of 0.73×10⁶ CAR+ viable T cells/kg) induced early and deep responses in patients with relapsed/refractory multiple myeloma (R/R MM; n=29) who had received a median of 5 prior lines of therapy (range: 3–18). With a median follow-up of 6 months, 100% of patients achieved a response, yielding an overall response rate (ORR) of 100%. Among these, 69% of patients achieved a complete response (CR) or better (with 66% achieving stringent CR), 86% achieved a very good partial response (VGPR) or better, and 14% achieved a partial response (PR). Furthermore, 100% of evaluable patients attained early minimal residual disease (MRD) negativity by Day 28 post-infusion. During the 6-month follow-up period, 27 out of 29 patients remained progression-free. Based on the Phase Ib results, the recommended Phase II dose was determined to be 0.75×10⁶ CAR+ viable T cells/kg.

JNJ-4528, also known as LCAR-B38M, is a structurally differentiated innovative CAR-T therapy co-developed by Legend Biotech and Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, containing two BCMA-targeting single-domain antibodies. JNJ-4528 is defined as the investigational drug developed in the United States or European Union countries, while LCAR-B38M is defined as the investigational drug developed in China.

At this conference, Legend Biotech announced the long-term efficacy and safety results of the LEGEND-2 study. The results showed an overall response rate of 88%, with 46% of all treated patients and 64% of MRD-negative CR patients remaining progression-free. Among all treated patients, the median progression-free survival (PFS) was 20 months (range: 10–28), while the median PFS for MRD-negative CR patients was 28 months (range: 20–31).

4. Gilead's CD19 CAR-T Therapy Yescarta

At this conference, Gilead Sciences presented new data from the pivotal Phase II ZUMA-1 clinical trial evaluating Yescarta, a CD19 CAR-T therapy, in adult patients with refractory large B-cell lymphoma, including updated overall survival (OS) data three years after a single infusion. The results showed that three years after a single infusion of Yescarta (median follow-up: 39.1 months), 47% of patients (n=47/100) remained alive, with a median OS of 25.8 months.

Updated results from a separate ZUMA-1 safety management study (Cohort 4) were also presented at the conference. In this analysis, patients with relapsed or refractory large B-cell lymphoma treated with Yescarta received early steroid intervention to reduce the incidence of severe cytokine release syndrome (CRS) and neurologic events. A total of 41 patients received Yescarta in this analysis, with a median follow-up of 8.7 months; 73% of patients received steroids, and 76% received the anti-inflammatory drug Actemra (tocilizumab). The results showed that early steroid intervention reduced the percentage of patients experiencing Grade ≥3 CRS (2%) and neurologic events (17%), both of which were lower than the percentages observed in the ZUMA-1 registration cohort (13% for CRS and 31% for neurologic events). No Grade 4 or 5 CRS or neurologic events occurred in Cohort 4, and there were no Grade 5 adverse events related to Yescarta.

The objective response rate (ORR) in Cohort 4 was 73%, with a complete response (CR) rate of 51% and a median duration of response (DOR) of 8.9 months. With at least 6 months of follow-up after Yescarta infusion, 54% of patients maintained their response, and the median overall survival (OS) had not been reached. Data from this cohort confirm that early steroid intervention can further improve the benefit-risk profile of CAR-T therapy.

5. Johnson & Johnson/AbbVie BTK Inhibitor Imbruvica

At this conference, Johnson & Johnson and AbbVie announced the latest data on Imbruvica for the treatment of chronic lymphocytic leukemia (CLL).

Follow-up data from the Phase III E1912 study evaluated Imbruvica in combination with rituximab versus the chemoimmunotherapy regimen FCR (fludarabine + cyclophosphamide + rituximab) as first-line treatment for younger patients with chronic lymphocytic leukemia (CLL) (age ≥70 years). The results showed that, with a median follow-up of 48 months, the Imbruvica plus rituximab arm demonstrated significantly improved progression-free survival (PFS: HR=0.39 [95% CI: 0.26–0.57], p<0.0001) and overall survival (OS: HR=0.34; 95% CI: 0.15–0.79; p=0.009) compared with the FCR arm. Grade ≥3 treatment-related adverse events occurred in 70% of patients in the Imbruvica plus rituximab arm versus 80% in the FCR arm (odds ratio [OR]=0.56; 95% CI: 0.34–0.90; p=0.013).

A new pooled analysis of two Phase III studies (RESONATE and RESONATE-2) has confirmed the long-term efficacy of Imbruvica monotherapy for the early treatment of chronic lymphocytic leukemia (CLL) (n=136 treatment-naïve CLL patients, median age 73 years; n=135 relapsed or refractory CLL patients, median age 65 years). With up to 6 years of follow-up (first-line group: 59.8 months; 1–2 prior therapies group: 66.2 months; ≥3 prior therapies group: 65.1 months), the median progression-free survival (PFS) was not reached in the first-line and 1–2 prior therapies groups, while the median PFS was 40.1 months in the ≥3 prior therapies group.

Among patients treated in the early setting, a substantial proportion remained progression-free or alive at 60 months (first-line: 70%; 1–2 prior therapies: 60%; ≥3 prior therapies: 33%). Compared with the groups receiving 1–2 prior therapies and ≥3 prior therapies, first-line treatment reduced the risk of disease progression or death by 34% (HR=0.66, 95% CI: 0.40–1.09) and 68% (HR=0.32, 95% CI: 0.21–0.49), respectively. Furthermore, median overall survival (OS) had not been reached in the first-line or 1–2 prior therapy groups, whereas it was 67.4 months in the ≥3 prior therapy group. At 60 months, the overall response rates (ORR) were 92%, 96%, and 88% in the first-line, 1–2 prior therapy, and ≥3 prior therapy groups, respectively.

Source: Websites of various pharmaceutical companies