PharmaShots Interview: Janssen’s Mark Wildgust Shares Insights on Imbruvica for Chronic Lymphocytic Leukemia and Darzalex for Multiple Myeloma

In an interview with PharmaShots, Mark Wildgust, Vice President, Global Medical Affairs, Oncology at Janssen shared his views on the data of Imbruvica in P-III (GLOW) and P-II (CAPTIVATE) studies for the treatment of CLL or SLL and also highlighted the results of Darzalex in the P-II (GRIFFIN) & P-III (MAIA) study for multiple myeloma

The P-III (GLOW) and P-II (CAPTIVATE) studies evaluating Imbruvica + venetoclax (I+V) as a potential fixed-duration treatment in patients with prior untreated CLL or SLL including those with high-risk disease
In the P-III (GLOW) study, I+V showed uMRD responses compared to Clb+O and an additional analysis showed that uMRD responses were better sustained during 1yr. post-treatment
In P-II (CAPTIVATE) study, the results showed a sustained uMRD & DFS with a median of 38mos. of follow-up, no new MRD relapses, clinical progressions, or deaths in patients with confirmed uMRD following 12 cycles of combined I+V who were randomized to PBO or continued Imbruvica

Tuba: Give a summary of Janssen’s oral presentations in a non-scientific way.

Mark Wildgust: In December, Janssen had 11 oral presentations featured at the American Society of Hematology (ASH) Annual Meeting and Exhibition. The latest research presented to the oncology community represents our commitment to advancing science and the treatment of blood cancer.

The oral presentations highlight the depth and breadth of Janssen’s portfolio and pipeline, featuring studies of blood cancer treatments including, DARZALEX (daratumumab), DARZALEX FASPRO (daratumumab and hyaluronidase-fihj), and IMBRUVICA (ibrutinib), among others. Our latest data in multiple myeloma represents a multipronged approach to treating the disease in both the frontline and relapsed or refractory settings through the development of cell and biologic therapies. Our data on chronic lymphocytic leukemia highlights our approach to meeting the needs of patients with options that have the potential to provide treatment-free remissions.

Tuba: Can you please share data supporting the use of I+V as a 1L treatment for CLL?

Mark Wildgust: At ASH 2021, two key studies for IMBRUVICA plus venetoclax were presented; the Phase 3 GLOW and Phase 2 CAPTIVATE studies, which are evaluating the potential of time-limited IMBRUVICA-based therapy in patients with previously untreated CLL or SLL, including those with high-risk disease.

The Phase 3 GLOW study showed that fixed-duration treatment with I+V resulted in undetectable minimal residual disease (uMRD) responses that were deeper in comparison to patients treated with chlorambucil plus obinutuzumab (Clb+O), and an additional analysis showed that uMRD responses with I+V were better sustained during the first-year post-treatment.

Data from the MRD-guided cohort of the Phase 2 CAPTIVATE study demonstrated sustained uMRD and disease-free survival (DFS) with a median of 38 months of follow-up. There were no new MRD relapses, clinical progressions, or deaths with an additional year of study follow-up in patients with confirmed uMRD following 12 cycles of combined I+V who were randomized to placebo. The same was seen in patients who were randomized to continue IMBRUVICA.

We are pleased that the results from these two studies show that patients can achieve deep and durable responses with the IMBRUVICA plus venetoclax all-oral, once-daily combination, fixed duration regimen.

Tuba: What are the key points of the P-III GLOW study?

Mark Wildgust: The Phase 3 GLOW study is a randomized, open-label trial evaluating the efficacy and safety of first-line, fixed-duration I+V vs. Clb+O in CLL/SLL patients who were elderly (≥65 years of age) or 18-64 years of age with a cumulative illness rating scale (CIRS) score > 6 or creatinine clearance < 70 mL/min. Patients with del(17p) or known TP53 mutations were excluded. The primary analysis showed that the combination of IMBRUVICA plus venetoclax reduced the risk of progression or death by 78% compared to Clb+O. Additional analyses presented at ASH demonstrated that treatment with all-oral, once-daily, fixed duration I+V led to deeper responses at end of treatment and better sustained uMRD responses during the first year post-treatment versus the chemoimmunotherapy comparator.MRD responses were proportionally deeper in the I+V arm vs. Clb+O arm in bone marrow, and deep responses were seen in patients with unmutated IGHV.

Tuba: Can we have a glance at the P-II CAPTIVATE data presented at ASH?

Mark Wildgust: The MRD-guided cohort from the Phase 2 CAPTIVATE trial evaluated all-oral, once-daily I+V in adult patients younger than 70 years, including patients with high-risk disease (e.g., del(17p) or TP53 mutation). The primary endpoint was disease-free survival post-randomization in patients with confirmed uMRD following 12 cycles of combined I+V who were randomized to placebo or continued IMBRUVICA. Now with a median of 38 months of study follow-up, the DFS rate was maintained at 95 percent for patients randomized to placebo. There were no new MRD relapses, disease progressions, or deaths in patients with one additional year of follow-up since the last presentation.

Additionally, the estimated 36-month PFS rates, calculated from the start of study treatment, were 95.3 percent with placebo and 100 percent with IMBRUVICA. The safety profile of the I+V regimen in CAPTIVATE was consistent with the known safety profiles of IMBRUVICA and venetoclax.

Tuba: Highlight the evidence that supports the front line use of Darzalex combo regimens in transplant-eligible or -ineligible myeloma patients.

Mark Wildgust: Among transplant-eligible patients, the GRIFFIN study shows the potential benefit of adding DARZALEX to VRd for the treatment of transplant-eligible patients. The data adds to existing evidence that quadruple combination regimens may be effective in achieving early, critical responses in this population. At 38.6 months of follow-up, the study showed improved stringent complete response, minimal residual disease negativity, and median progression-free survival rates compared to VRd.

Approximately half of the transplant-ineligible patients will not receive a second line of therapy, so first-line efficacy is crucial. The Phase 3 MAIA study supports the use of front line support the use of front line DARZALEX in this patient population with results showing overall survival and progression free survival benefits with DARZALEX-Rd compared to Rd alone. DARZALEX is the only CD-38 with a benefit in overall survival in patients with newly diagnosed, transplant-ineligible multiple myeloma. At ASH, a clinical sequencing scenario analysis was presented which used data from MAIA and real-world evidence from the Flatiron Health electronic health record-derived de-identified database. Researchers found that when DARZALEX was administered first in combination with lenalidomide and dexamethasone, results suggested the potential for a survival benefit compared to when VELCADE was administered first in combination with Rd.

Tuba: How does the P-ll GRIFFIN study justify the potential of an investigational DARZALEX quadruple combination regimen?

Mark Wildgust: The Phase II GRIFFIN data shows the potential benefit of adding DARZALEX to bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed, transplant-eligible patients with multiple myeloma. At 38.6 months of median follow-up, the study showed improved outcomes with the addition of DARZALEX, adding to the growing body of evidence for quadruple combination regimens in this population.

The rate of stringent complete response (sCR) favored DARZALEX-VRd compared to VRd alone (66 percent vs 47.4 percent). Additionally, minimal residual disease (MRD) negativity rates remained significantly higher in patients treated with DARZALEX-VRd compared to VRd alone (64.4 percent vs 30.1 percent). The study showed that at 38 months the progression-free survival (PFS) rate trended toward favoring DARZALEX-VRd compared to VRd alone (88.9 percent vs 81.2 percent).

Tuba: Discuss the key points of posthoc analysis of the Phase 3 MAIA study.

Mark Wildgust: The posthoc analysis of the Phase 3 MAIA study focused on patients with renal impairment and showed that approximately 20 to 50 percent of patients with multiple myeloma have baseline renal impairment that can impact their choice of treatment and efficacy. The findings showed that after a five-year follow-up, progression-free survival and overall survival benefits were observed in patients treated with D-Rd compared to Rd alone, regardless of the lenalidomide starting dose.

Tuba: Briefly summarize Janssen’s broader portfolio dealing with hematological diseases?

Mark Wildgust: We are continuously pushing boundaries to treat cancer and striving to deliver new therapeutic options for patients. The high unmet need in blood cancer drives our patient-centric approach to developing more complementary and combinable treatment regimens for a variety of hematologic malignancies. With our strong commitment and deep expertise in multiple myeloma, we believe we are uniquely positioned at Janssen to change the treatment paradigm of this blood cancer, through treatments such as our BCMA-targeting CAR-T therapy, cilta-cel; CD-38 targeting monoclonal antibody, DARZALEX; and bispecific therapies teclistamab and talquetamab.

For the treatment of chronic lymphocytic leukemia, IMBRUVICA is the only BTK inhibitor with a proven survival benefit and has the unique potential to be used in a continuous or fixed-duration regimen for patients.

We will continue to work with the oncology community to advance the understanding and use of newer and potential treatments to address unmet patient needs, with the ultimate goal of one-day developing curative therapies in blood cancer.

Source: UNC Lineberger

About Author:

Mark Wildgust, Vice President, Global Medical Affairs, Oncology at Janssen. He has spent more than 20 years in the pharmaceutical industry working primarily in oncology, hematology, and virology. He completed his undergraduate degree in Biological Sciences at the University of Plymouth, UK, and his Ph.D. in Trace Metal Toxicology at the University of Manchester, UK. He then spent a short time as a post-doctoral researcher at the University of Maryland in the United States.