FDA Approves LIBTAYO® in Combination with Chemotherapy for Non-Small Cell Lung Cancer

SUMMARY: The FDA on November 8, 2022, approved LIBTAYO® (Cemiplimab-rwlc) in combination with platinum-based chemotherapy for adult patients with advanced Non-Small Cell Lung Cancer (NSCLC) with no EGFR, ALK, or ROS1 aberrations. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immuno-Oncology (IO) therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation, and a therapeutic response. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced NSCLC. It is now standard therapy for patients with lung cancer.

KEYTRUDA® (Pembrolizumab; anti PD-1) and TECENTRIQ® (Atezolizumab; anti PD-L1) are both approved in combination with platinum-based chemotherapy for the first-line treatment of patients with metastatic NSCLC. The FDA approval of TECENTRIQ® with platinum-doublet chemotherapy is however limited to non-squamous histology.

LIBTAYO® is a fully human monoclonal antibody targeting the immune checkpoint receptor PD-1. LIBTAYO® monotherapy was approved by the FDA in 2021 after it demonstrated significantly improved Overall Survival and Progression Free Survival compared with chemotherapy, in patients with advanced Non-Small Cell Lung Cancer with PD-L1 of at least 50%. The researchers in EMPOWER-Lung 3 evaluated the efficacy of first line LIBTAYO® in combination with investigator’s choice of platinum-doublet chemotherapy, among patients with advanced NSCLC, with either squamous or non-squamous histology, and any level of PD-L1 expression.

EMPOWER-Lung 3 is a randomized, multicenter, multinational, double-blind, active-controlled Phase III trial in which 466 patients with advanced NSCLC who had not received prior systemic treatment were randomized (2:1) to receive either Cemiplimab 350 mg IV once every 3 weeks (N=312) or placebo (N=154) every 3 weeks, in combination with four cycles of chemotherapy. Investigators’ choice of histology-specific chemotherapy options included Paclitaxel plus Carboplatin, Paclitaxel plus Cisplatin, Pemetrexed plus Carboplatin and Pemetrexed plus Cisplatin. Patients were treated for a maximum of 108 weeks, or until disease progression or unacceptable toxicity. For patients with non-squamous histology assigned to a Pemetrexed-containing regimen, maintenance Pemetrexed was mandatory. Patients were enrolled irrespective of PD-L1 expression or tumor histology and had advanced or metastatic NSCLC, with no ALK, EGFR or ROS1 aberrations. Among those enrolled, 43% had tumors with squamous histology, 67% had tumors with less than 50% PD-L1 expression, 15% had inoperable locally advanced disease not eligible for definitive chemoradiation, and 7% had pretreated and clinically stable brain metastases. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR).

The trial was stopped early upon recommendation by the Independent Data Monitoring Committee (IDMC) after the LIBTAYO® combination demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, compared to placebo plus chemotherapy. The median OS was 21.9 months in the LIBTAYO® plus chemotherapy group and 13.0 months in the placebo plus chemotherapy group (HR=0.71; P=0.0140). This represented a 21% relative reduction in the risk of death in the LIBTAYO® plus chemotherapy group. The 12-month probability of survival was 66% for the LIBTAYO® combination versus 56% for chemotherapy.

The median PFS per BICR was 8.2 months in the LIBTAYO® plus chemotherapy group and 5.0 months in the placebo plus chemotherapy group (HR=0.56; p<0.0001). This represented a 44% reduction in the risk of disease progression in the LIBTAYO® plus chemotherapy group. The 12-month probability of PFS for the LIBTAYO® combination was 38%, versus 16% for chemotherapy. The confirmed ORR per BICR was 43% and 23% in the respective treatment groups and the median Duration of Response was 16 months versus 7 months respectively. The most common (15% or more) adverse reactions were alopecia, musculoskeletal pain, nausea, fatigue, peripheral neuropathy, and decreased appetite.

It was concluded that LIBTAYO® is only the second anti-PD-1/PD-L1 agent to show efficacy in advanced Non-Small Cell Lung Cancer either as monotherapy in those with PD-L1 expression 50% or more, or in combination with chemotherapy, irrespective of PD-L1 expression or tumor histology.

Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Gogishvili M, Melkadze T, Makharadze T, et al. Nature Medicine 2022;(28):2374-2380.

TAFINLAR® and MEKINIST® versus OPDIVO® plus YERVOY® for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial

SUMMARY: The American Cancer Society estimates that for 2022, about 99,780 new cases of melanoma of the skin will be diagnosed in the United States and 7,650 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age.

The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules. BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. BRAF mutations have been detected in 6-8% of all malignancies. The most common BRAF mutation in melanoma is at the V600E/K site and is detected in approximately 50% of melanomas, and results in constitutive activation of the MAPK pathway.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate (ORR) and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years.

TAFINLAR® (Dabrafenib), is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. TAFINLAR® plus MEKINIST® led to long-term survival benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, from two randomized Phase III COMBI-d and COMBI-v trials.

A combination of OPDIVO® (Nivolumab) plus YERVOY® (Ipilimumab) showed durable improved outcomes among patients with unresectable or metastatic melanoma and approximately 50% of patients were alive at 6.5 years (J Clin Oncol 39, 2021. suppl 15; abstr 9506). The FDA granted approval for this combination in 2015 for the treatment of patients with metastatic melanoma, regardless of tumor BRAF mutation status.

It has been noted that BRAF/MEK inhibitor therapy tends to produce high tumor response rates and prolonged median Progression Free Survival (PFS), whereas OPDIVO® /YERVOY® tends to have its major impact on Duration of Response. However, the optimal treatment sequence for patients with treatment-naive BRAFV600-mutant metastatic melanoma, between combination OPDIVO®/YERVOY® checkpoint inhibitor immunotherapy and combination TAFINLAR® plus MEKINIST® molecularly targeted therapy, has remained unclear. Recently published tumor biology studies have suggested that resistance to BRAF/MEK-inhibitor therapy results in an immunosuppressive tumor microenvironment that is void of functional CD103+ dendritic cells, preventing effective antigen presentation to the immune system, and that immunotherapy may enhance BRAF-mutated melanoma responsiveness to targeted therapy.

DREAMseq (EA6134) is a two-arm, two-step, open-label, randomized Phase III trial, which investigated the anti PD-1/CLTA-4 immunotherapy combination of OPDIVO® plus YERVOY® followed by the anti-BRAF/MEK targeted therapy combination of TAFINLAR® plus MEKINIST®, versus the reverse sequence, in patients with advanced BRAF V600-mutant melanoma. This study was conducted to determine which treatment sequence produced the best efficacy.

In this study, 265 patients with treatment-naive BRAF V600-mutant metastatic melanoma were randomly assigned to receive either combination OPDIVO® plus YERVOY® (arm A=133) or TAFINLAR® plus MEKINIST® (arm B=132) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, TAFINLAR® plus MEKINIST® (arm C=27) or OPDIVO® plus YERVOY® (arm D=46). The two initial treatment arms were balanced and more patients on arm B had BRAF V600K-mutant tumors than those on arm A (25.2% versus 12.1%). The median patient age was 61 years and eligible patients had histologically confirmed, BRAF V600-mutant unresectable Stage III or IV melanoma with measurable disease. The Primary end point was 2-year Overall Survival (OS). Secondary end points included 3-year OS, Objective Response Rate (ORR), Duration of Response, Progression Free Survival (PFS), crossover feasibility, and Safety.

The study was stopped early by the Independent Data Safety Monitoring Committee because statistical significance was achieved for the Primary endpoint. The 2-year OS for those starting on arm A was 71.8% and arm B was 51.5% (P=0.01). Step 1 Progression Free Survival favored arm A (P=0.054). The Objective Response Rates were arm A: 46%, arm B: 43%, arm C: 47.8%, and arm D: 29.6%. The median Duration of Response was not reached for arm A, and 12.7 months for arm B (P<0.001). Crossover occurred in 52% of patients following documented disease progression. Grade 3 or more toxicities occurred with similar frequency between treatment groups and adverse events related to regimens were as expected.

It was concluded from this study that for patients with advanced BRAF V600-mutant metastatic melanoma, the treatment sequence beginning with the immune checkpoint inhibitor combination of OPDIVO® plus YERVOY® resulted in superior Overall Survival and longer Duration of Response, compared with the treatment sequence beginning with TAFINLAR® plus MEKINIST®, and should therefore be the preferred treatment sequence for most of these patients.

Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients with Advanced BRAF-Mutant Melanoma: The DREAMseq Trial—ECOG-ACRIN EA6134. Atkins MB, Lee SJ, Chmielowski B, et al. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763

Association of Gut Microbiome with Immune Checkpoint Inhibitor Response in Advanced Melanoma

SUMMARY: The American Cancer Society estimates that in 2022, there will be an estimated 1.92 million new cancer cases diagnosed and 609,360 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Over 50% of patients treated with a combination of PD-1 and CTLA-4 inhibitors are alive after five years. Nonetheless, less than 50% of the patients respond to single-agent ICI and a higher response to targeting both PD-1 and CTLA-4 is associated with significant immune-related Adverse Events.

Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD-L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL- Interferon-gamma, Neutrophil-to-ratio, and peripheral cytokines, have also been proposed as predictors of response. It has been postulated that concomitant medications during therapy with ICIs such as baseline steroid use as well as treatment with antibiotics may negate or lessen the efficacy of ICIs.

Preclinical studies have suggested that immune-based therapies for cancer may have a very complex interplay with the host’s microbiome and there may be a relationship between gut bacteria and immune response to cancer. The gut microbiome is unique in each individual, including identical twins. The crosstalk between microbiota in the gut and the immune system allows for the tolerance of commensal bacteria (normal microflora) and oral food antigens and at the same time enables the immune system to recognize and attack opportunistic bacteria. Immune Checkpoint Inhibitors strongly rely on the influence of the host’s microbiome, and the gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation. Broad-spectrum antibiotics can potentially alter the bacterial composition and diversity of our gut microbiota, by killing the good bacteria. It has been postulated that this may negate the benefits of immunotherapy and influence treatment outcomes. It should be noted however that the relationship between gut bacteria and immune response is influenced by several factors and may be partially cancer type specific and it is unlikely that the same microbiome features can reflect the uniqueness of the genetic and immune characteristics of each tumor.

Even though the composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, there is a lack of consistency of results between the published studies, and there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. The Predicting Response to Immunotherapy for Melanona with Gut Microbiome and Metabolomics (PRIMM) studies are two separate prospective observational cohort studies that has been recruiting patients in the UK (PRIMM-UK) and the Netherlands (PRIMM-NL) since 2018. These cohorts of previously ICI-naive patients with advanced melanoma have provided extensive biosamples, including stool, serum and peripheral blood mononuclear cells, before and during ICI treatment, with detailed clinical and dietary data collected at regular intervals longitudinally.

The authors therefore performed a meta-analysis on existing publicly available datasets to produce the largest study to date. In order to study the role of the gut microbiome in ICI response, the researchers recruited ICI-naive patients with advanced cutaneous melanoma from the PRIMM cohorts, as well as three additional cohorts of ICI-naive patients with advanced cutaneous melanoma, originating from Barcelona, Leeds and Manchester (N = 165), and performed shotgun metagenomic sequencing on a total of 165 stool microbiome samples collected before initiating ICI treatment. Shotgun sequencing is a laboratory technique for determining the DNA sequence of an organism’s genome. This dataset was integrated with 147 metagenomic samples from smaller publicly available datasets. This methodology provided the largest assessment of the potential of the gut microbiome as a biomarker of response to ICI, in addition to allowing for investigation of specific microbial species or functions associated with response. Patient demographics including age, gender, BMI, previous non-immunotherapy treatments, previous drug therapies such as antibiotics, Proton Pump Inhibitors (PPIs) and steroids, as well as dietary patterns, were collected in these cohorts for the majority of patients, and were considered in the multivariate analysis.

The researchers used machine learning analysis to understand the association between gut microbiome and response to ICIs. This analysis confirmed the link between the microbiome and Overall Response Rates (ORRs), as well as Progression Free Survival (PFS) with ICIs. This analysis also revealed limited reproducibility of microbiome-based signatures across cohorts. A panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansiamuciniphila were associated with responders, but no single species could be regarded as a fully reliable biomarker across studies. Based on these findings from this large set of real-world cohorts, the authors noted that the relationship between human gut microbiome and response to ICIs is more complex than previously understood, and extends beyond the presence or absence of different microbial species in responders and nonresponders.

It was concluded that future studies should include large samples and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course. Until then, the authors recommend high-quality, diverse, whole-foods diet to optimize gut health, rather than consumption of commercial probiotics.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Lee KA, Thomas AM, Bolte LA, et al. Nat Med. 2022;28:535-544.

NUBEQA® Combination Improves Overall Survival in Metastatic Hormone Sensitive Prostate Cancer

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with Prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of Prostate cancer will be diagnosed in 2022 and 34,500 men will die of the disease. The development and progression of Prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced Prostate cancer and is the first treatment intervention.

The first-generation NonSteroidal Anti-Androgen (NSAA) agents such as EULEXIN® (Flutamide), CASODEX® (Bicalutamide) and NILANDRON® (Nilutamide) act by binding to the Androgen Receptor (AR) and prevent the activation of the AR and subsequent up-regulation of androgen responsive genes. They may also accelerate the degradation of the AR. These agents have a range of pharmacologic activity from being pure anti-androgens to androgen agonists. CASODEX® is often prescribed along with GnRH (Gonadotropin-Releasing Hormone) agonists for metastatic disease, or as a single agent second line hormonal therapy for those who had progressed on LHRH agonists.

NUBEQA® (Darolutamide) is a potent second-generation Androgen Receptor (AR) inhibitor with a new chemical structure and has a high affinity to the AR. NUBEQA® does not cross the blood-brain barrier and for this reason has a favorable safety and tolerability profile in prespecified adverse events such as seizures, when compared with other second-generation AR inhibitors such as ERLEADA® (Apalutamide) and XTANDI® (Enzalutamide). It has been associated with increased Overall Survival (OS) among patients with non-metastatic Castration-Resistant Prostate Cancer (CRPC) and has been approved by the FDA for this indication. Whether a combination of NUBEQA®, in combination with Androgen Deprivation Therapy (ADT), and Docetaxel would increase survival among patients with metastatic Hormone-Sensitive Prostate Cancer, is unknown.

ARASENS is an international, randomized, double-blind, placebo-controlled, Phase III trial, which evaluated the efficacy and safety of NUBEQA® (Darolutamide) added to Androgen Deprivation Therapy (ADT) and Docetaxel in patients with metastatic Hormone Sensitive Prostate Cancer. In this study, a total of 1306 patients were randomly assigned 1:1 to receive NUBEQA® (N=651) or placebo (N=655), both in combination with ADT and Docetaxel. All the patients received ADT (either a Luteinizing Hormone Releasing Hormone (LHRH} agonist or antagonist) or underwent Orchiectomy within 12 weeks before randomization and received six cycles of Docetaxel 75 mg/m2 IV given on Day 1 every 21 days, with Prednisone or Prednisolone. Patients received LHRH agonists along with a first-generation anti-androgen agent for at least 4 weeks before randomization to help prevent a tumor flare, and the anti-androgen agent was discontinued before randomization. Patients were then randomly assigned to receive either NUBEQA® 600 mg orally twice daily or matched placebo, and treatment was continued until disease progression or unacceptable toxicities.

Eligible patients had biopsy proven prostate cancer with bone metastases and had to be candidates for ADT and Docetaxel. Patients with regional lymph node involvement only (N1, below the aortic bifurcation) or if they had received ADT more than 12 weeks before randomization, second-generation Androgen Receptor pathway inhibitors, chemotherapy, or immunotherapy for prostate cancer before randomization, or radiotherapy within 2 weeks before randomization, were excluded. The median age was 67 years and both treatment groups were well balanced. All patients had metastatic disease at baseline, 78% of the patients had a Gleason score of 8 or greater, about 80% had bone metastases (Stage M1b) and 18% had visceral metastases (Stage M1c). The Primary end point was Overall Survival (OS) and Secondary end points included were time to Castration-Resistant Prostate Cancer, time to pain progression, symptomatic Skeletal Event-Free Survival and time to initiation of subsequent systemic antineoplastic therapy, as well as Safety. The median follow up for Overall Survival was 43 months.

The median Overall Survival was not estimable in the NUBEQA® group versus 48.9 months in the placebo group. The addition of NUBEQA® to the combination with ADT and Docetaxel reduced the risk of death by 32%, compared to the placebo group (HR=0.68; P<0.001). This OS benefit was noted across most subgroups. Further, the significant OS benefit with the addition of NUBEQA® was observed, despite receipt of subsequent life-prolonging systemic therapies such as different Androgen-Receptor pathway inhibitors by 75.6% of patients in the placebo control group. The OS at 4 years was 62.7% in the NUBEQA® group and 50.4% in the placebo group.

With regard to Secondary endpoints, the addition of NUBEQA® to ADT and Docetaxel demonstrated consistent benefits. The time to development of Castration-Resistant Prostate Cancer was significantly longer in the NUBEQA® group (HR=0.36; P<0.001), the time to pain progression was also significantly longer in the NUBEQA® group (HR=0.79; P=0.01), as well as symptomatic Skeletal Event-Free Survival (HR=0.61; P<0.001). Further, the time to the initiation of subsequent systemic antineoplastic therapy was also significantly longer in the NUBEQA® group (HR=0.39; P<0.001). Adverse events were similar in the two groups.

The authors concluded that among patients with metastatic Hormone Sensitive Prostate Cancer, the addition of NUBEQA® to Androgen Deprivation Therapy and Docetaxel resulted in significantly longer Overall Survival, as well as improvement in key Secondary end points, with no increase in adverse events.

Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. Smith MR, Hussain Saad F, et al. for the ARASENS Trial Investigators. N Engl J Med 2022;386:1132-1142.

XPOVIO® (selinexor): A Treatment Approved for Multiple Myeloma as Early as First Relapse

Author: Cristina Gasparetto, MD
Sponsored by: Karyopharm Therapeutics, Inc.
Dr. Gasparetto is a paid consultant for Karyopharm Therapeutics, Inc. and has been compensated.

Multiple myeloma (MM) remains an incurable hematologic cancer due to the clonal nature of the disease.1 With each relapse, cancer cells undergo clonal evolution and acquire new mutations that render them resistant to certain treatments.1 Triplet therapies combining proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (CD38-mAbs) have improved patient outcomes and their use has steadily increased over the past decade.2,3 When patients relapse after exposure to daratumumab (a CD38-mAb), the prognosis becomes unfavorable; even if patients previously responded to PIs or IMiDs, median survival may not reach one year.3 A significant unmet need therefore remains for providing durable disease control for patients with MM.1

For patients with previously-treated MM, the National Comprehensive Cancer Network® (NCCN®) recommends a new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months.4 For patients with MM who are triple class exposed, a selective inhibitor of nuclear export (SINE) may be a potential treatment class to consider in early relapsed (1-3 prior therapies) MM.4 Once-weekly XPOVIO® (selinexor), is a first-in-class, oral SINE compound approved as early as first relapse in MM that reversibly inhibits exportin 1 (XPO1).5 This action leads to accumulation of tumor suppressor proteins in the nucleus and reductions in several oncoproteins, such as c-myc and cyclin D1, cell cycle arrest, and apoptosis of cancer cells.5 Oral, once weekly selinexor (XPOVIO®) in combination with bortezomib and dexamethasone (XVd) is recommended by the NCCN as a Category 1 therapeutic option in early relapsed (1 to 3 prior therapies) MM.4

The efficacy and safety of XPOVIO was assessed in a phase 3, randomized, open-label trial comparing XPOVIO (100 mg once weekly) in combination with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) with Vd alone in patients exposed to one to three prior lines of therapy.6 Patient disease characteristics were well balanced in both treatment groups and the primary endpoint was progression-free survival (PFS).5,6 Patients in the XVd group demonstrated a median PFS of 13.9 months (95% CI: 11.73-NE) compared with 9.5 months (95% CI: 8.11-10.78) in the Vd group (HR 0.70 [95% CI: 0.53-0.93], P=0.0075).6 In patients treated with XVd, a greater median PFS was consistently observed in certain subgroups compared with patients treated with Vd (Figure 1).6,7 When comparing patients 65 years of age and older to younger patients, older patients had a higher incidence of discontinuation due to an adverse reaction (28% vs 13%) and a higher incidence of serious adverse reactions (56% vs 47%).5

XPOVIO-Combination-Demonstrated-Sustained-PFSFigure 1. Median PFS in the XVd and Vd treatment groups (primary endpoint) and in select patient subgroups in the XVd trial.

Oral, once-weekly XPOVIO dosage may be adjusted to help mitigate potential adverse reactions (ARs).5 The indicated starting dose of XPOVIO is 100 mg once weekly and the dose may be reduced to 80 mg, 60 mg, or 40 mg based on ARs.5 Dose reductions were permitted in the XVd trial to help mitigate ARs – 65% of patients in the XVd group had a dose reduction and the median dose of XPOVIO in that group was 80 mg once weekly.5,7 Patients in my clinical practice typically get reduced from 100 mg to 60 mg once weekly and experience minimal tolerability issues at 60 mg. In an exploratory post-hoc analysis of the XVd trial, efficacy was maintained with XPOVIO dose reductions (Figure 2).7

Efficacy-Maintained-Even-With-XPOVIO-Dose-ReductionFigure 2. Median PFS in XPOVIO dose-reduced patients in the XVd trial.

XVd was not associated with serious organ toxicities of the cardiac, pulmonary, renal, or hepatic systems.6,7 Warnings and precautions include life-threatening thrombocytopenia and neutropenia, gastrointestinal toxicities, severe life-threatening hyponatremia, serious infection, and life-threatening neurological toxicities.5 The most common adverse reactions (≥20% with a difference between arms of >5% compared to Vd) were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting (Figure 3).5 The XVd trial protocol required a prophylactic 5-HT3 antagonist to address nausea but allowed for other interventions as required.7 Nausea events were reported in 50% of patients, however, treatment-related nausea associated with XPOVIO diminished over time; 92% of nausea cases were resolved/resolving in the first month of treatment.7 Patients should be counseled on what to expect with XPOVIO therapy and monitored throughout treatment, with more frequent monitoring during the first three months of treatment.5

Figure 3. Adverse reactions reported in the XVd trial.

Below we consider 2 hypothetical patients where XPOVIO may be considered.

Patient A is a 66-year-old woman with relapsed/refractory MM. She was started on lenalidomide, bortezomib, and dexamethasone, and received autologous stem cell transplant (ASCT) followed by lenalidomide maintenance, which she did well on for 16 months. Upon relapsing, she was given daratumumab, pomalidomide with dexamethasone, and after 7 months, imaging confirmed that her MM progressed again. Given her DPd exposure, Patient A (RVd → ASCT → R → DPd) may be a candidate for a class switch to XVd.

Patient B is a 74-year-old man with a history of hypertension and was diagnosed with MM 2 years ago. Because of his hypertension, he was unable to start a PI due to risk of cardiotoxicity and he is ASCT ineligible. His healthcare provider started him on daratumumab, lenalidomide, and dexamethasone (DRd), but after 2 years, he has relapsed. A class switch to XPOVIO could be considered for Patient B as his second-line therapy.

Healthcare providers should consider patients’ individual clinical characteristics when making treatment decisions. Consider switching class with XPOVIO® (selinexor) for patients at relapse, including those who have been exposed to a CD38-mAb–based regimen.5 Based on the results of the XVd trial and considering the clonal nature of MM, switching patients to XPOVIO may be an option to consider.

XPOVIO® (selinexor) is a prescription medicine approved:
• in combination with bortezomib and dexamethasone to treat adult patients with multiple myeloma who have received at least one prior therapy.
• in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti‐CD38 monoclonal antibody.


XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma.
Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of bleeding. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection.
Monitor more frequently during the first 3 months of treatment. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients.

Provide prophylactic antiemetics or treatment as needed.

Anorexia/Weight Loss:
Monitor weight, nutritional status, and volume status at baseline and throughout treatment and provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

XPOVIO can cause severe or life-threatening hyponatremia.
Monitor sodium level at baseline and throughout treatment.

Serious Infection:
XPOVIO can cause serious and fatal infections. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Neurological Toxicity:
XPOVIO can cause life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.
Advise patients to refrain from driving and engaging in hazardous occupations or activities until the neurological toxicity fully resolves. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity:
XPOVIO can cause fetal harm when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

Cataracts: New onset or exacerbation of cataract has occurred during treatment with XPOVIO. The incidence of new onset or worsening cataract requiring clinical intervention was reported.


The most common adverse reactions (ARs) (≥20%) in patients with multiple myeloma who received XVd were fatigue, nausea, decreased appetite, diarrhea, peripheral neuropathy, upper respiratory tract infection, decreased weight, cataract, and vomiting.

Grade 3-4 laboratory abnormalities (≥10%) were thrombocytopenia, lymphopenia, hypophosphatemia, anemia, hyponatremia and neutropenia.

Fatal ARs occurred in 6% of patients within 30 days of last treatment. Serious ARs occurred in 52% of patients. Treatment discontinuation rate due to ARs was 19%. The most frequent ARs requiring permanent discontinuation in >2% of patients included fatigue, nausea, thrombocytopenia, decreased appetite, peripheral neuropathy and vomiting. Adverse reactions led to XPOVIO dose interruption in 83% of patients and dose reduction in 64% of patients.


No overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥65 years old had a higher incidence of discontinuation due to an adverse reaction (AR) and a higher incidence of serious ARs than younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

Please see full Prescribing Information.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm Therapeutics Inc. at 1-888-209-9326 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

© 2022 Karyopharm Therapeutics Inc. US-XPOV-10/22-00003

1. Mikkilineni L, Kochenderfer JN. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol. 2021;18(2):71-84. doi:10.1038/s41571-020-0427-6
2. Braunlin M, Belani R, Buchanan J, Wheeling T, Kim C. Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011-2019 oncology clinic electronic health record data. Leuk Lymphoma. 2021;62(2):377-386. doi:10.1080/10428194.2020.1827253
3. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/s41375-019-0435-7
4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V.5.2022. © National Comprehensive Cancer Network, Inc. 2022. All rights reserved. Accessed October 18, 2022. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
5. XPOVIO (selinexor) [prescribing information]. Karyopharm Therapeutics Inc. https://www.karyopharm.com/wp-content/uploads/2019/07/NDA-212306-SN-0071-Prescribing-Information-01July2019.pdf
6. Grosicki S, Simonova M, Spicka I, et al. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. The Lancet. 2020;396(10262):1563-1573. doi:10.1016/S0140-6736(20)32292-3
7. Data on File. Karyopharm Therapeutics Inc. 2021. Published online 2021.

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. Approximately 20% of patients had a del(17p) and/or TP53 mutation and fewer than 15% of patients were on anticoagulants. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

BeiGene recently announced that BRUKINSA® achieved superior Progression Free Survival (PFS) when compared to IMBRUVICA® in the final analysis of this Phase III ALPINE trial, as assessed by an Independent Review Committee (IRC) and investigator. This data will be presented at future scientific meetings. The interim analysis conducted at a median follow-up was 15 months showed significantly higher Overall Response Rate with BRUKINSA®, compared with IMBRUVICA® (78.3% versus 62.5%; P =0.0006). The Overall Response Rate was higher in patients with del11q (83.6% versus 69.1%) and del17p (83.3% versus 53.8%) with BRUKINSA®, as well as the overall 12-month Progression Free Survival (94.9% versus 84.0%) and Overall Survival rates (97.0% versus 92.7%). Major bleeding rates as well as adverse events leading to treatment discontinuation, was lower with BRUKINSA®, compared to IMBRUVICA®. The rate of Atrial Fibrillation/Flutter, a pre-specified safety endpoint, was significantly lower with BRUKINSA®, compared to IMBRUVICA® (2.5% versus 10.1%; P=0.0014).

It was concluded from this randomized, Phase III study that, among patients with relapsed/refractory CLL/SLL, BRUKINSA® was superior to IMBRUVICA®, with a lower rate of Atrial Fibrillation/Flutter. The researchers added that BTK inhibition, with more complete and sustained BTK occupancy, results in improved efficacy and safety outcomes.

First interim analysis of ALPINE study: results of a phase 3 randomized study of zanubrutinib vs ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Brown JR, Hillmen P, Eichhorst B, et al. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster CLL-115.

RNF43 Mutations Predict Response to Anti-BRAF/EGFR Combination Therapy in BRAF V600E Metastatic Colorectal Cancer

SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 151,030 new cases of CRC will be diagnosed in the United States in 2022 and about 52,580 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. Advanced colon cancer is often incurable and standard chemotherapy when combined with anti EGFR (Epidermal Growth Factor Receptor) targeted monoclonal antibodies such as VECTIBIX® (Panitumumab) and ERBITUX® (Cetuximab) as well as anti VEGF agent AVASTIN® (Bevacizumab), have demonstrated improvement in Progression Free Survival (PFS) and Overall Survival (OS). The benefit with anti EGFR agents however is only demonstrable in patients with metastatic CRC (mCRC) whose tumors do not harbor KRAS mutations in codons 12 and 13 of exon 2 (KRAS Wild Type). It is now also clear that even among the KRAS Wild Type patient group about 15-20% have other rare mutations such as NRAS and BRAF mutations, which confer resistance to anti EGFR agents. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy.

Approximately 8-15% of all metastatic CRC tumors present with BRAF V600E mutations, which is recognized as a marker of poor prognosis in this patient group. These patients predominantly present with right-sided proximal tumors, tend to have aggressive disease with a higher rate of peritoneal metastasis, and do not respond well to standard treatment intervention. Approximately 30% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group. Further, in striking contrast to patients with melanoma harboring BRAF V600E mutations in whom there is a 70% Objective Response Rate with BRAF inhibitor monotherapy, there is little or no clinical benefit with the same treatment among BRAF V600E mutant CRC patients.

Preclinical studies have shown that inhibiting BRAF in colorectal tumors can transiently reduce Mitogen-Activated Protein (MAP) kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR. In the Phase III BEACON Colorectal Cancer study, a combination of BRAF inhibitor BRAFTOVI® (Encorafenib) and EGFR antagonist ERBITUX® (Cetuximab), with or without concomitant MEK inhibition improved Response Rates, Overall Survival and Progression Free Survival in patients with metastatic CRC with a BRAF V600E mutation. The FDA approved this doublet therapy in 2020 for this patient group. Despite this improved efficacy, a significant percentage of patients do not respond this therapy and among those who respond, the responses noted in CRC are still not as robust as has been in BRAF-mutant metastatic melanomas treated with anti-BRAF therapy. This suggests that there may be other factors modulating treatment response, including molecular determinants, that need to be identified, to optimize clinical management of these patients.

BRAF V600E mutated tumors in CRC are also associated with specific molecular features, including a low frequency of APC mutations and a high rate of mutations in the tumor suppressor gene RNF43 (Ring Finger Protein 43). RNF43 is a E3 ubiquitin ligase which negatively regulates Wnt signaling by inducing degradation of the Wnt receptors. It has been postulated that the a cross-talk between the MAPK and WNT signaling pathways may modulate the antitumor activity of anti-BRAF/EGFR therapy.

The researchers in this study sought to explore which genes were enriched for somatic mutations in responder and non-responder groups, among patients with BRAF V600E mutant CRC, treated with anti-BRAF/EGFR combination therapy. This study included 166 patients (N=166) with BRAF V600E mutant CRC of whom 98 patients received treatment with anti-BRAF/EGFR combination therapy (N=46 in the Discovery cohort and N=52 in the Validation cohort). The Control cohort (N=68) consisted of BRAF V600E mutant CRC patients treated with chemotherapy with or without antiangiogenic therapy, and were not exposed to anti-BRAF therapy. Whole-Exome Sequencing (WES) and/or targeted gene sequencing was performed on baseline tumor and/or plasma cell-free DNA (cfDNA) samples of all included patients, and over 20,000 genes were analyzed.

It was noted that RNF43 mutations were identified in 29% of BRAF V600E-mutated MicroSatellite-Stable (MSS) metastatic CRC tumors, and this finding was strongly associated with a clinical response to anti-BRAF/EGFR-based combination therapy. When compared to BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC patients without the RNF43 mutation (RNF43 wild-type), patients with BRAF V600E-mutated, MicroSatellite-Stable metastatic CRC carrying a RNF43 mutation had a Response Rate of 72.7% versus 30.8% (P=0.03), longer median Progression Free Survival (10.1 months versus 4.1 months, HR=0.30; P=0.01) and longer median Overall Survival (13.6 months versus 7 months, HR=0.26; P=0.008). Conversely, the predictive value of RNF43 mutations seen in MicroSatellite-Stable tumors was not observed in MicroSatellite Instability (MSI)-High tumors.

The researchers concluded that these findings suggest that RNF43 may be a potential stratification biomarker that could help with decision making, in patients with MicroSatellite-Stable, BRAF V600E–mutant metastatic Colorectal cancer. They added that RNF43 gene may be a predictive biomarker of a response to treatment with anti-BRAF/EGFR combination therapy in this patient group.

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF V600E metastatic colorectal cancer. Elez, E, Ros J, Fernandez J, et al. Nature Medicine 2022;28:2162–2170.

FDA Approves TECVAYLI® for Relapsed or Refractory Multiple Myeloma

SUMMARY: The FDA on October 25, 2022, granted accelerated approval to TECVAYLI® (Teclistamab-cqyv), the first bispecific B-Cell Maturation Antigen (BCMA)-directed CD3 T-cell engager, for adult patients with Relapsed or Refractory multiple myeloma who have received at least four prior lines of therapy, including a Proteasome Inhibitor, an Immunomodulatory agent, and an anti-CD38 monoclonal antibody. Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,470 new cases will be diagnosed in 2022 and 12,640 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2022 remains an incurable disease.

B-Cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma. At the time of writing, there are three BCMA-targeted therapies approved by the FDAfor patients with Relapsed or Refractory multiple myeloma with triple-class exposure. They include CARVYKTI® (Ciltacabtageneautoleucel) and ABECMA® (Idecabtagenevicleucel),which are B-Cell Maturation Antigen (BCMA)-directed genetically modified autologous T cell immunotherapies (CART-Cell therapies), and BLENREP® (Belantamabmafodotin-blmf), which is a B-Cell Maturation Antigen (BCMA)-directed antibody and microtubule inhibitor drug conjugate (Antibody Drug Conjugate). Even though CAR T-cell therapies have resulted in remarkable clinical responses, logistic challenges include at least 2 weeks of hospital stay, long manufacturing times, need for bridging therapy, and high cost of treatment.

TECVAYLI® is a bispecific antibody with dual binding sites, that targets both CD3 expressed on the surface of T cells and BCMA expressed on the surface of myeloma cells, and thereby mediates T-cell activation and lysis of BCMA-expressing myeloma cells. This effect occurs regardless of T-cell–receptor specificity or Major Histocompatibility Complex class I molecules on the surface of myeloma cells. This mechanism of action of TECVAYLI® is distinct from that of other available therapies for this patient group.

The present FDA approval was based on the efficacy and safety results from the pivotal, single-arm, multi-cohort, open-label, multi-center Phase 1/2 portion of MajesTEC-1 study, which enrolled 165 patients, who had Relapsed or Refractory myeloma after at least three therapy lines, including triple-class exposure to an Immunomodulatory drug, a Proteasome Inhibitor, and an anti-CD38 antibody. Patients received TECVAYLI® 1.5 mg/kg subcutaneously once weekly, after receiving step-up doses of 0.06 and 0.3 mg/kg separated by 2- 4 days and completed 2-4 days before the administration of the first full TECVAYLI® dose. Patients were hospitalized and premedicated with Dexamethasone, Acetaminophen, and Diphenhydramine for each step-up dose and for the first full dose of TECVAYLI®. Treatment was continued until disease progression, unacceptable toxicity, or the end of the study. The median age was 64 years, the median time between diagnosis and the first treatment dose was 6 years, 26% had at least one high-risk cytogenetic abnormality defined as del(17p), t(4;14), or t(14;16) among those with available cytogenetic data (N=148), 77.6% had triple-class refractory disease, and patients had received a median of 5 previous lines of therapy. The Primary end point was the Overall Response Rate (ORR), which was defined as a Partial Response or better according to the International Myeloma Working Group criteria, as assessed by an Independent Review Committee. Secondary end points included Duration of Response, Very Good Partial Response (VGPR) or better, Progression Free and Overall Survival, Minimal Residual Disease (MRD) status and Safety.

At a median follow-up of 14.1 months, the Overall Response Rate was 63%, with 39.4% having a Complete Response or better. Close to 60% of patients had a Very Good Partial Response or better. Approximately, 27% of patients had negative results for Minimal Residual Disease in bone marrow (<1 myeloma cell in 100,000 cells), and the MRD-negativity rate among the patients with a Complete Response or better was 46%. The median Duration of Response was 18.4 months, and the median duration of Progression Free Survival was 11.3 months. Common adverse events included Cytokine Release Syndrome (CRS) noted in 72% and were mostly Grade 1 or 2 and fully resolved. None of the patients discontinued TECVAYLI® due to CRS. Other common adverse events included neutropenia, anemia, and thrombocytopenia, as well as immune effector cell–associated neurotoxicity syndrome, but none of the patients discontinued therapy because of neurotoxic events.

It was concluded from this study that TECVAYLI® had substantial clinical activity, with a high rate of deep and durable response in patients with triple-class-exposed Relapsed or Refractory multiple myeloma. Toxic effects were common but were mainly of low grade and reversible. The researchers added that the efficacy of TECVAYLI® compared favorably with other FDA approved treatments that are currently available for later lines in multiple myeloma, including BLENREP® (Belantamabmafodotin-blmf), XPOVIO® (Selinexor), and CAR T-cell therapies.

Teclistamab in Relapsed or Refractory Multiple Myeloma. Moreau P, Garfall AL,van de DonkNW,et al. N Engl J Med 2022; 387:495-505

FDA Approves IMJUDO® plus IMFINZI® for Patients with Advanced Hepatocellular Carcinoma

SUMMARY: The FDA on October 21, 2022, approved IMJUDO® (Tremelimumab) in combination with IMFINZI® (Durvalumab), for adult patients with unresectable HepatoCellular Carcinoma (HCC). The American Cancer Society estimates that for 2022, about 41,260 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the US and 30,520 patients will die of their disease. Liver cancer is seen more often in men than in women and the incidence has more than tripled since 1980. This increase has been attributed to the higher rate of Hepatitis C Virus (HCV) infection among baby boomers (born between 1945 through 1965). Obesity and Type II diabetes have also likely contributed to the increasing trend. Other risk factors include alcohol, which increases liver cancer risk by about 10% per drink per day, and tobacco use, which increases liver cancer risk by approximately 50%. HepatoCellular Carcinoma (HCC) is also a leading cause of cancer deaths worldwide, accounting for more than 700,000 deaths each year, and majority of patients typically present at an advanced stage. The prognosis for unresectable HCC remains poor and one year survival rate is less than 50% following diagnosis and only 7% of patients with advanced disease survive five years. NEXAVAR® was approved by the FDA in 2007 for the first line treatment of unresectable HepatoCellular Carcinoma (HCC) and the median Overall Survival was 10.7 months in the NEXAVAR® group and 7.9 months in the placebo group.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMJUDO® is a human monoclonal antibody that targets and blocks the activity of CTLA-4, contributing to T-cell activation, priming the immune response to cancer and fostering cancer cell death. In a Phase II study, a single priming dose of IMJUDO® added to IMFINZI® (STRIDE regimen), showed encouraging clinical activity and limited toxicity in patients with unresectable HepatoCellular Carcinoma (HCC), suggesting that a single exposure to IMJUDO® may be sufficient to improve upon activity of IMFINZI®.

HIMALAYA trial is a randomized, open-label, multicenter, global, Phase III study conducted in 190 centres across 16 countries, including in the US, Canada, Europe, South America and Asia. In this study, 1,171 patients with Stage III or IV unresectable HepatoCellular Carcinoma who had received no prior systemic therapy and were not eligible for locoregional therapy (treatment localized to the liver and surrounding tissue), were randomly assigned to receive either the STRIDE regimen which consisted of a single priming dose of IMJUDO® 300 mg IV added to IMFINZI® (Durvalumab) 1500 mg IV, followed IMFINZI® 1500 mg IV by every 4 weeks (N= 393), IMFINZI® monotherapy given at the same dose and schedule (N = 389) or NEXAVAR® (Sorafenib) 400 mg orally BID (N=389). Enrolled patients had ECOG performance status of 0 or 1 and Child-Pugh A disease and could not have main portal vein thrombosis. Patients were stratified based on macrovascular invasion (Yes versus No), etiology of liver disease (Hepatitis B virus versus Hepatitis C virus versus others), and ECOG Performance Status (0 versus 1). The Primary endpoint was Overall Survival (OS) for STRIDE regimen versus NEXAVAR® and key Secondary endpoints included OS for IMFINZI® monotherapy versus NEXAVAR®, Objective Response Rate and Progression Free Survival (PFS) for STRIDE and IMFINZI® monotherapy. The present FDA approval was based on a comparison of the 782 patients randomized to IMJUDO® plus IMFINZI® (STRIDE regimen) to NEXAVAR®.

The Primary objective of this study was met at the time of data cutoff. At a median follow up of 16.1 months of treatment with the STRIDE regimen, there was a 22% reduction in the risk of death for patients who received the STRIDE regimen compared to NEXAVAR® alone (HR=0.78; P=0.0035). The median OS with the STRIDE regimen was 16.4 months, compared with 13.8 months with NEXAVAR®, and the 3 year OS rate was 30.7% versus 20.2 % respectively. The Overall Response Rate for the combination STRIDE regimen was 20.1% compared to 5.1% for NEXAVAR®.

IMFINZI® monotherapy met the objective of OS non-Inferiority to NEXAVAR® (HR=0.86), and the median OS after 16.5 months of median follow up was 16.6 months with IMFINZI® monotherapy versus 13.8 months with NEXAVAR®, and the 3 year OS rate was 24.7% versus 20.2 % respectively. The Overall Response Rate with IMFINZI® monotherapy was 17% compared to 5.1% for NEXAVAR®. The Secondary endpoint of PFS was not superior in either investigational study group relative to the NEXAVAR® control arm. The most common adverse reactions occurring in patients were rash, diarrhea, fatigue, pruritis, musculoskeletal pain and abdominal pain.

It was concluded that HIMALAYA is the first large Phase III trial to add a novel single priming dose of an anti-CTLA4 antibody IMJUDO®, to another checkpoint inhibitor, IMFINZI®. This combination regimen (STRIDE) demonstrated superior efficacy and a favorable benefit-risk profile when compared with NEXAVAR® and should be considered a novel , first-line standard of care systemic therapy, for patients with unresectable Hepatocellular Carcinoma.

Tremelimumab plus Durvalumab in Unresectable Hepatocellular Carcinoma. Abou-Alfa GK, Lau G, Kudo M, et al. Published June 6, 2022. NEJM Evid 2022; 1 (8) DOI:https://doi.org/10.1056/EVIDoa2100070.

Improved Outcomes with Early Switch to Fulvestrant Plus Palbociclib in ESR1 Mutated Advanced Breast Cancer

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in most of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay for the management of ER+/HER2- metastatic breast cancer as first-line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, including development of ESR1 (Estrogen Receptor gene alpha) mutations.

ESR1 is the most common acquired mutation noted in breast tumors as they progress from primary to metastatic setting. These mutations promote ligand independent Estrogen Receptor activation and have been shown to promote resistance to estrogen deprivation therapy. It appears that ESR1 mutations are harbored in metastatic ER+ breast cancers with prior Aromatase Inhibitor (AI) therapy, but not in primary breast cancers, suggesting that ESR1 mutations may be selected by prior therapy with an AI, in advanced breast cancer. In a recently published study (JAMA Oncol.2016;2:1310-1315), ESR1 mutations Y537S and D538G mutations detected in baseline plasma samples from ER+/HER- advanced breast cancer patients, was associated with shorter Overall Survival. In this study it was noted that there was a three-fold increase in the prevalence of these mutations in patients who had failed first line hormonal therapy for metastatic disease, compared with those who were initiating first line therapy for advanced breast cancer (33% versus 11%).

Fulvestrant (FASLODEX®) is an estrogen antagonist and like Tamoxifen binds to estrogen receptors (ERs) competitively, but unlike Tamoxifen causes rapid degradation and loss of ER protein (ER down regulator) and is devoid of ER agonist activity. Palbociclib (IBRANCE®) is a reversible, oral, selective, small molecule inhibitor of Cyclin Dependent Kinases, CDK4 and CDK6, and prevents RB1 phosphorylation. Palbociclib is the first CDK inhibitor approved by the FDA. It exhibits synergy when combined with endocrine therapies. The FDA in February 2016, approved Palbociclib in combination with Fulvestrant, for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, with disease progression following endocrine therapy.

Patients with ESR1 mutations on Fulvestrant had improved Progression Free Survival (PFS) compared with Exemestane (AROMASIN®) in the SoFEA trial. The combination of Palbociclib and Fulvestrant improved PFS compared with Fulvestrant plus placebo in both ESR1 mutant and ESR1 wild-type patients, in the PALOMA3 trial.

The PADA-1 study aimed to show the efficacy of an early change in therapy based on a rising ESR1 mutation in the peripheral blood, while assessing the global safety of the combination Fulvestrant and Palbociclib. PADA-1 is a prospective, randomized, open-label, multicentre, Phase III trial in which 1017 patients with ER-positive, HER2-negative advanced breast cancer were included. These patients were monitored for a rising ESR1 mutation in the peripheral blood, while on first-line treatment with an Aromatase Inhibitor (Letrazole 2.5 mg, Anastrozole 1 mg or Exemestane 25 mg orally once daily, taken continuously) and Palbociclib 125 mg orally once daily on days 1-21 of a 28-day treatment cycle, at enrollment and every 2 months thereafter. Blood samples were monitored for several ESR1 mutations which included E380, P535, L536, Y537, and D538. The median time from trial enrollment to detection of the ESR1 mutation was 14.2 months. Patients with newly present or rising ESR1 mutation in the peripheral blood circulating tumor DNA and no synchronous disease progression (N=172) were randomly assigned (1:1) to continue with the same therapy (N=84) or to switch to Fulvestrant 500 mg IM on day 1 of each 28-day cycle and on day 15 of cycle 1, along with Palbociclib as previously dosed (N=88). Baseline characteristics were similar in both treatment groups. The median patient age was 61 years, and one-third of patients had prior treatment with an Aromatase Inhibitor. Patients were stratified according to visceral involvement (present or absent) and the time from inclusion to detection of ESR1 mutation in the peripheral blood (<12 months or 12 months or more). The co-Primary endpoints were Progression Free Survival and Grade 3 or more hematologic adverse events in all patients.

At a median follow up of 26.0 months from randomization, switching patients from an Aromatase Inhibitor to Fulvestrant, upon detection of ESR1 mutation in the peripheral blood was associated with a 39% reduction in the risk of disease progression or death. The median Progression Free Survival was 11.9 months in the Fulvestrant and Palbociclib group versus 5.7 months in the Aromatase Inhibitor and Palbociclib group (HR=0.61; P=0·004). The co-Primary endpoint of Grade 3 or more hematologic adverse events found no safety signals associated with switching from an Aromatase inhibitor to Fulvestrant. The most frequent Grade 3 or more hematological adverse events were neutropenia. lymphopenia, and thrombocytopenia. Dose reductions were similar in both randomized treatment groups.

The authors concluded that PADA-1 is the first prospective randomized trial to demonstrate that early therapeutic targeting of ESR1 mutation in the peripheral blood results in significant clinical benefit. The researchers added that the original design explored in PADA-1 might help with addressing acquired resistance to new drugs in future trials.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial. Bidard FC, Hardy-Bessard AC, Dalenc F, et al. The Lancet Oncology. Published: September 29, 2022.DOI:https://doi.org/10.1016/S1470-2045(22)00555-1