Author: RR

FDA Grants Accelerated Approval to SCEMBLIX® for Newly Diagnosed Chronic Myeloid Leukemia

RR

SUMMARY: The FDA on October 29, 2024, granted accelerated approval to Asciminib (SCEMBLIX®), for adult patients with newly diagnosed Philadelphia Chromosome-positive Chronic Myeloid Leukemia (CML) in chronic phase. The American Cancer Society estimates that about 9,280 new CML cases will be diagnosed in the United States in 2024 and about 1,280 patients will die of the disease. Chronic Myeloid Leukemia constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The Tyrosine Kinase Inhibitors (TKIs) approved for newly diagnosed chronic phase CML in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. They include first-generation TKI Imatinib (GLEEVEC®) or second-generation TKIs Nilotinib (TASIGNA®), Dasatinib (SPRYCEL®), or Bosutinib (BOSULIF®). Imatinib is associated with lower patient response and a higher incidence of disease progression than those with second-generation TKIs, whereas treatment with second-generation TKIs can result in faster, deeper molecular responses than Imatinib in frontline therapy, but are associated with more adverse events, necessitating dose modifications and switching treatments. Further, close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore, resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except Ponatinib (ICLUSIG®). There is therefore an unmet need for safe and effective frontline therapy for patients with newly diagnosed chronic phase CML

Asciminib (SCEMBLIX®) is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom Ponatinib had failed, and those with a T315I mutation.

Asciminib was previously approved by the FDA in the US for the treatment of adults with Philadelphia Chromosome positive chronic phase CML who have previously been treated with two or more TKIs. It is also approved in patients with Philadelphia Chromosome positive chronic phase CML with the T315I mutation.

The ASC4FIRST study is a pivotal Phase III, multi-center, open-label, randomized trial aimed at evaluating the efficacy and safety of Asciminib compared to investigator-selected Tyrosine Kinase Inhibitors (TKIs) in adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myeloid Leukemia in chronic phase (CML-CP). A total of 405 patients were enrolled and were randomly assigned in a 1:1 ratio to receive either Asciminib 80 mg orally once daily (N=201) or investigator-selected TKIs which included Imatinib and second generation TKIs such as Bosutinib, Dasatinib or Nilotinib given at approved doses (N=204). Before randomization, investigators, after discussing with patients, selected a TKI (either Imatinib or one of the second-generation TKIs a patient would take, if randomly assigned to the comparator group-prerandomization selected TKI), considering treatment goals, disease and patient characteristics, and coexisting conditions. Randomization was stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk), and by TKI selected by investigators before randomization. The two Primary objectives of this study were to compare the efficacy of Asciminib with that of investigator-selected TKIs (all members of this class considered together as a group), and to compare the efficacy of Asciminib with that of Imatinib. Asciminib was not compared with second-generation TKIs as a primary objective. The Primary end point for both objectives was Major Molecular Response (defined as BCR/ABL1 transcript levels 0.1% or less on the International Scale at week 48 that did not meet any treatment failure criteria). The Secondary objective of this study was assessment of Major Molecular Response (MMR) at week 48 with Asciminib, as compared with investigator-selected TKIs among patients with second-generation TKIs as their prerandomization-selected TKI. The median follow-up was 16.3 months in the Asciminib group and 15.7 months in the investigator-selected TKI group.

At the 48-week mark, Asciminib demonstrated a significantly higher MMR rate compared to investigator-selected TKIs (67.7% versus 49.0%; P<0.001). Deep molecular response rates (BCR/ABL1 transcript levels 0.01% or less, were also superior in the Asciminib group compared to investigator-selected TKIs (38.8% versus 20.6%). Patients preselected for Imatinib who were randomized to Asciminib achieved an MMR rate of 69.3% compared to 40.2% in the Imatinib group (P<0.001). Among those preselected for second-generation TKIs, the MMR rate was 66.0% for Asciminib versus 57.8% for the second-generation TKI group.

Asciminib exhibited a favorable safety profile with fewer Grade 3 or higher Adverse Events and lower rates of treatment discontinuation due to Adverse Events. Grade 3 or higher Adverse Events for Asciminib was 38%, for Imatinib was 44.4% and for second-generation TKIs was 54.9%. Discontinuation due to Adverse Events for Asciminib was 4.5%, for Imatinib was 11.1% and for Second-generation TKIs was 9.8%.

It was concluded that Asciminib is the only agent to demonstrate superiority over investigator selected standard-of-care TKIs in achieving higher MMR rates at 48 weeks in newly diagnosed chronic phase CML patients, alongside a better safety and tolerability profile. These findings indicate that Asciminib could significantly improve the treatment landscape for this group of patients, offering hope for better disease control and quality of life, thereby addressing key unmet needs in CML management.

Asciminib in Newly Diagnosed Chronic Myeloid Leukemia. Hochhaus A, Wang J, Kim DD, et al. for the ASC4FIRST Investigators. N Engl J Med 2024;391:885-898.

Adjuvant TAFINLAR® plus MEKINIST® in Stage III Melanoma – 10 Year Follow up

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SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 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. Surgical resection with a curative intent is the standard of care for patients with early-stage melanoma.

Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm, and 4 mm or less in thickness, with ulceration (T3b), or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with Stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.

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 demonstrated 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 result in constitutive activation of the MAPK pathway.

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. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

COMBI-AD, an international, multi-center, randomized, double-blind, placebo-controlled, Phase III trial, in which 870 patients with completely resected Stage III melanoma, and with BRAF V600E or V600K mutations were enrolled. Patients were randomly assigned in a 1:1 to receive TAFINLAR® 150 mg orally twice daily in combination with MEKINIST® 2 mg orally once daily (N=438) or two matched placebos (N=432). Treatment was given for 12 months. Eligible patients had undergone completion lymphadenectomy, with no clinical or radiographic evidence of residual regional node disease. None of the patients had received previous systemic anticancer treatment or radiotherapy for melanoma. BRAF V600 mutation status was confirmed in primary tumor tissue or lymph node tissue by a central reference laboratory. The median age was 50 years. Both treatment groups were well balanced and 18% had Stage IIIA disease, 41% had Stage IIIB disease, and 40% had Stage IIIC disease. Of the enrolled patients, 91% had a BRAF V600E mutation, and 9% had a BRAF V600K mutation. The Primary end point was Relapse Free Survival (RFS) and Secondary end points included Overall Survival (OS), Distant Metastasis-Free Survival, Freedom from relapse, and Safety.

The authors had previously reported the results for RFS and Distant Metastasis-Free Survival at 5 years of follow up. Overall survival was not analyzed as the data was not mature. The minimum duration of follow up was 59 months. The RFS at 5 years was 52% with TAFINLAR® plus MEKINIST® and 36% with placebo (HR for relapse or death=0.51). The Distant Metastasis-Free Survival at 5 years was 65% with TAFINLAR® plus MEKINIST® and 54% with placebo (HR for distant metastasis or death=0.55). As has been reported in previous studies, majority of relapses occurred within the first 3 years after surgery.

The researchers herein reported the final results of the COMBI-AD trial after a long-term follow-up of more than 8 years. The RFS continued to favor TAFINLAR® plus MEKINIST® over placebo. The median RFS was 93.1 months with TAFINLAR® plus MEKINIST® and 16.6 months with placebo (HR for relapse or death= 0.52). The estimated RFS at 10 years was 48% with TAFINLAR® plus MEKINIST® and 32% with placebo. A relapse with distant metastasis occurred in 28% of patients in the combination-therapy group and in 37% of patients in the placebo group (HR for distant metastasis or death=0.56). The estimated Distant Metastasis-Free Survival at 10 years was 63% and 48%, respectively. The estimated Overall Survival at 8 years was 71% with TAFINLAR® plus MEKINIST® and 65% with placebo (HR for death=0.80; P=0.06). However, this benefit was not statistically significant. A consistent survival benefit was seen across several prespecified subgroups, including those with BRAF V600E mutated tumors (HR for death=0.75). There was no new safety signals noted.

It was concluded that after nearly 10 years of follow-up, 12 months of adjuvant therapy with a combination of TAFINLAR® plus MEKINIST® resulted in longer Relapse Free and Distant metastasis-free Survival, compared to placebo, among patients with resected Stage III melanoma, with 25% reduction in the risk of death among those with BRAF V600E mutations.

Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. Long GV, Hauschild A, Santinami M, et al. N Engl J Med 2024;391:1709-1720.

Late Breaking Abstract – ESMO 2024: Addition of XTANDI® to XOFIGO® Significantly Improved Survival in Metastatic Castrate Resistant Prostate cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 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.

Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as Bicalutamide (CASODEX®), Nilutamide (NILANDRON®) and Flutamide (EULEXIN®) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPIs), which include Abiraterone (ZYTIGA®), Enzalutamide (XTANDI®), Apalutamide (ERLEADA®) and Darolutamide (NUBEQA®).

For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Pathway Inhibitors (ARPIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies.

Radium Ra 223 dichloride (XOFIGO®) is a bone seeking alpha particle emitter, and by virtue of its chemical similarity to calcium is preferentially taken up by the bone and forms complexes with bone mineral hydroxyapatite, in areas where there is increased bone turnover such as bone metastases. Ra-223 induces double stranded DNA breaks resulting in antitumor effects and has a very short range in tissues (around 2 and 10 cells), quickly losing energy, compared to beta or gamma radiation. The end result is less damage to the adjacent healthy tissues. Further, unlike its historical counterpart Ra-226 which was first isolated by Madame Curie, Ra-223 has a short half life of 11.4 days and rapidly decays, preventing significant radiation exposure. Ra-223 in a randomized, double-blind, Phase III trial (ALSYMPCA study) improved Overall Survival in patients with CRPC with bone metastases (mCRPC).

Enzalutamide is an orally administered, second-generation, anti-androgen, with no reported agonistic effects. It competitively inhibits androgens and AR binding to androgens as well as AR nuclear translocation and interaction with DNA. It thus inhibits several steps in the AR signaling pathway and was designed to overcome acquired resistance to first-generation nonsteroidal anti-androgens.

The PEACE-3 trial is a pivotal double-blind, randomized Phase III study exploring whether combining Enzalutamide with Ra-223 dichloride provides enhanced efficacy over Enzalutamide monotherapy in mCRPC with bone metastases. As a cooperative effort led by EORTC, CTI, CUOG, LACOG, and UNICANCER, the trial enrolled 426 mCRPC patients (N=426) from 12 countries between 2015 and 2023. Participants were required to have bone metastases, be asymptomatic or mildly symptomatic, and be naïve to prior treatments with Enzalutamide, Ra-223, or other specific anti-androgen therapies (Apalutamide or Darolutamide). Patients were randomized in a 1:1 to receive either Enzalutamide monotherapy (Standard of Care) at 160 mg taken orally once daily, or a combination of Enzalutamide 160 mg daily plus Ra-223 administered at 55 kBq/kg IV every four weeks, for six cycles. Patients were stratified by factors including country, baseline pain scores, prior use of Docetaxel, previous treatment with Abiraterone, and use of bone-protecting agents (which became mandatory after an early protocol amendment). The decision to require bone-protecting agents was driven by fracture rate concerns seen in the ERA-223 study, which had paired Ra-223 with Abiraterone and showed increased fracture risks without these bone-protecting agents. The median age of patients was 70 years and both treatment groups were well balanced. About 30% had received Docetaxel, with fewer than 5% previously treated with Abiraterone. About 42-44% of patients had ten or more bone lesions, and about 37% had elevated alkaline phosphatase levels, an indicator of high bone turnover. The Primary endpoint was radiological Progression-Free Survival (rPFS). Secondary endpoints include Overall Survival (OS), Time to subsequent systemic anti-neoplastic therapy, Time to pain progression, and Time to first symptomatic skeletal event. The median follow-up duration was 42.2 months.

The combination of Enzalutamide and Ra-223 showed a statistically significant improvement in rPFS. Patients in the combination arm had a median rPFS of 19.4 months, compared to 16.4 months for enzalutamide alone (HR=0.69; P=0.0009). Interim results demonstrated a 31% reduction in mortality risk in the combination arm, with median OS extending from 35 months with Enzalutamide alone to 42.3 months with the combination (HR=0.69; P=0.0031). Although nonproportional hazards were observed, necessitating a continued final OS analysis, these interim findings strongly suggest the potential survival benefit with this combination therapy.

Patients on the combination therapy had a significantly longer period before needing subsequent systemic treatments, with a 43% lower risk of starting a new therapy compared to those on Enzalutamide alone (HR=0.57; P< 0.0001). At the two-year mark, 51% of patients in the Enzalutamide-only group required additional treatments, compared to 30% in the combination group. There were no significant differences between the groups in time to pain progression or the onset of Symptomatic Skeletal Events (SSEs), which include fractures and spinal cord compression.

The combination of Enzalutamide plus Ra-223 was well tolerated, although it led to a slight increase in Grade 3 or higher adverse events (28%) compared to 19% in the Enzalutamide monotherapy group. Approximately 30% of patients in both groups experienced hypertension, though severe cases were more frequent in the combination arm. Other common side effects included fatigue and cytopenias. The safety protocol of the study was adjusted to include mandatory bone-protecting agents such as Denosumab or Zoledronate and baseline DEXA scans, contributing to fewer symptomatic skeletal events. Over 80% of patients received these agents during the trial, likely mitigating the risk of fractures and other bone-related adverse effects seen in similar trials.

It was concluded from the PEACE-3 trial that adding 6 cycles of Ra223 to Enzalutamide as first-line therapy for mCRPC patients, significantly improved radiological Progression-Free Survival. A preplanned interim analysis showed a statistically significant Overall Survival benefit favoring the Enzalutamide plus Ra-223 combination, although further analysis will address long-term survival and Quality of Life outcomes.

A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Gillessen S, Choudhury A, Saad F, et al. Annals of Oncology, Volume 35, S1254. September 2024.

SARCLISA® with VRd Regimen for Transplant Ineligible Newly Diagnosed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024, and 12,540 patients are expected to 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 CD38 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 2024 remains an incurable disease.

Newly diagnosed multiple myeloma patients are often treated with Bortezomib, Lenalidomide, and Dexamethasone (VRd), after the SWOG S0777 trial established this regimen as a standard first-line treatment, regardless of their transplantation eligibility. With the introduction of CD38 targeted therapies, new treatment combinations are being explored to increase the depth of response and attain long-term disease control.

Isatuximab-irfc (SARCLISA®) is a CD38-targeting IgG1monoclonal antibody, similar to Daratumumab (DARZALEX®), but unlike Daratumumab, is not associated with complement activation, and can therefore be more readily given to patients with asthma or Chronic Obstructive Pulmonary Disease. Further, Isatuximab targets a specific epitope on the CD38 receptor, and this distinction from Daratumumab allows use of Isatuximab in cases when Daratumumab fails. Additionally, Isatuximab infusions are less cumbersome.

The FDA in September 2024, approved Isatuximab with Bortezomib, Lenalidomide, and Dexamethasone for adults with newly diagnosed multiple myeloma who are not eligible for Autologous Stem Cell Transplant (ASCT). This approval was based on the IMROZ trial (NCT03319667), which was an international, multicenter, open-label, Phase 3, randomized, controlled trial, designed to evaluate the efficacy and safety of Isatuximab in combination with the established regimen of Bortezomib, Lenalidomide, and Dexamethasone (VRd) compared to VRd alone. This study aimed to address a critical gap in treatment options for patients with newly diagnosed multiple myeloma who are ineligible for ASCT, a situation often faced by older patients or those with significant comorbidities. A total of 446 patients, aged 18 to 80 years, with symptomatic, previously untreated multiple myeloma were randomly assigned in a 3:2 ratio to receive either the Isatuximab-VRd regimen (N=263) or the standard VRd regimen alone (N=181). The Induction phase of the treatment consisted of 4 cycles, with each cycle lasting 6 weeks. Patients in the Isatuximab-VRd Group received Isatuximab 10 mg/kg IV weekly during Cycle 1, then every 2 weeks for subsequent cycles. Patients received subcutaneous Bortezomib (1.3 mg/m²) on specified days, along with oral Lenalidomide (25 mg daily for 14 days) and Dexamethasone (20 mg on specified days). The VRd group received the same VRd regimen without Isatuximab. Following the induction phase, both groups continued treatment with a regimen consisting of Lenalidomide and Dexamethasone. For the Isatuximab-VRd group, Isatuximab was given every 2 weeks, transitioning to monthly administration starting at Cycle 18. The median patient age was 72 years and treatment groups were well balanced. The Primary endpoint of the trial was Progression-Free Survival (PFS), assessed by an Independent Review Committee in accordance with International Myeloma Working Group criteria. Secondary endpoints included Complete Response (CR) or better, Minimal Residual Disease (MRD) negativity in patients achieving a Complete Response, assessed at a sensitivity level of 10⁻⁵ using Next-Generation Sequencing, Overall Survival (OS) and Quality of Life measures.

The results from the interim analysis at a median follow-up of 59.7 months demonstrated a significant improvement in PFS for the Isatuximab-VRd group compared to the VRd group. The 60-month PFS was estimated at 63.2% in the Isatuximab-VRd group versus 45.2% in the VRd group (HR=0.60; P<0.001), indicating a 40% reduction in the risk of disease progression or death for the Isatuximab group. Approximately 75% of patients in the Isatuximab-VRd group achieved a Complete Response or better compared to 64.1% in the VRd group (P=0.01). Higher rates of MRD negativity (55.5% vs. 40.9%; P=0.003) were also observed in the Isatuximab group. The safety profile of the Isatuximab-VRd combination mirrored that of established regimens, with no new safety signals identified. Incidences of serious adverse events were comparable between the two groups, though a slight increase in infections and neutropenia was noted with the addition of Isatuximab.

In conclusion, the results from the IMROZ trial clearly indicate that the addition of Isatuximab to the VRd regimen provides significant benefits in terms of Progression-Free Survival and Response Rates in patients with newly diagnosed multiple myeloma who are ineligible for transplantation, addressing an important unmet need. Further follow-up and analyses will continue to elucidate the long-term benefits and safety of this promising therapeutic strategy.

Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. Facon T, Dimopoulos M-A, Leleu XP, et al. for the IMROZ Study Group. N Engl J Med 2024;391:1597-1609.

IMFINZI® after Chemoradiotherapy in Limited-Stage Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2024 about 234,580 new cases of lung cancer will be diagnosed and about 125,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) accounts for approximately 13-15% of all lung cancers and is aggressive. Limited Stage-Small Cell Lung Cancer – LS-SCLC (Stage I-III) accounts for approximately 30% of SCLC diagnoses and the disease is confined to one hemithorax. These patients are often treated with a combination of Carboplatin or Cisplatin with Etoposide and radiotherapy. Despite initial response, LS-SCLC typically recurs and progresses rapidly, and only 15-30% of patients are alive, five years after diagnosis.

Based on the premise that SCLC has a high mutation rate, it was hypothesized that these tumors may be immunogenic, and more recently immunotherapy with checkpoint inhibitors has demonstrated clinical activity in SCLC. Durvalumab (IMFINZI®) is a selective, high-affinity, human IgG1 monoclonal antibody, that blocks the binding of Programmed Death Ligand 1 (PD-L1) to Programmed Death 1 (PD-1) receptor and CD80, thereby unleashing the T cells to recognize and kill tumor cells. Tremelimumab (IMJUDO®) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses.

The rationale for the ADRIATIC trial was supported by findings from the pivotal Phase III PACIFIC and CASPIAN trial. In the PACIFIC trial, Durvalumab after concurrent chemoradiotherapy for Stage III Non-Small Cell Lung Cancer, improved both Overall Survival (OS) and Progression Free Survival (PFS), whereas in the CASPIAN trial, Durvalumab with Platinum and Etoposide chemotherapy significantly improved OS, compared to chemotherapy alone, in newly diagnosed patients with extensive-stage SCLC.

The ADRIATIC trial is a Phase III, randomized, double-blind, placebo-controlled, multicenter, global study that assessed the efficacy and safety of Durvalumab as consolidation therapy in patients with Limited-Stage Small Cell Lung Cancer (LS-SCLC) who had not progressed after concurrent platinum-based chemoradiotherapy. This trial randomized 730 patients with Stage I to III LS-SCLC, including those with inoperable Stage I/II disease. Eligible patients had a WHO Performance Status of 0 or 1 and had not experienced disease progression after completing concurrent chemoradiotherapy. Chemotherapy consisted of a combination of Platinum plus Etoposide for up to 4 cycles, and the radiation therapy could either be once daily up to 66 Gy, or twice a day up to 45 Gy. Prophylactic Cranial Irradiation (PCI) was allowed before randomization. Patients were randomized within 6 weeks after completing concurrent chemoradiotherapy to experimental arms Durvalumab monotherapy 1500 mg IV every 4 weeks with or without Tremelimumab 75 mg IV every 4 weeks for up to 4 cycles each, followed by Durvalumab every four weeks for up to 24 months or Placebo every 4 weeks. There was a protocol amendment in November 2020, and patients were randomly assigned in a 1:1 ratio to the Durvalumab group or placebo group only. Baseline characteristics and prior treatment were well balanced between groups. The median age was 62 years and 87% of patients had Stage III disease at diagnosis. This analysis compared the outcomes in patients assigned to receive Durvalumab monotherapy (N=264) with patients who received placebo (N=266). The dual Primary endpoints were Progression Free Survival (PFS) and Overall Survival (OS) for Durvalumab monotherapy versus placebo. Key Secondary endpoints included OS and PFS for Durvalumab plus Tremelimumab versus placebo, Safety, and Quality of Life measures. The median duration of follow-up for OS and PFS in censored patients at this first planned interim analysis was 37.2 and 27.6 months, respectively.

Durvalumab demonstrated a statistically significant improvement in OS compared to placebo (HR=0.73; P=0.01), translating to a 27% reduction in the risk of death. The estimated median OS with Durvalumab was 55.9 months, compared to 33.4 months with placebo. The 24-month OS rate was 68% with Durvalumab versus 58.5% with placebo, and the 36-month OS rate was 56.5% versus 47.6%, respectively. The median PFS was 16.6 months with Durvalumab versus 9.2 months with placebo, representing a 24% reduction in the risk of disease progression or death (HR=0.76; P=0.02). The 18-month PFS rate was 48.8% with Durvalumab versus 36.1% with placebo, and the 24-month PFS rate was 46.2% with Durvalumab versus 34.2% with placebo. Treatment benefit was generally consistent across predefined patient subgroups for both OS and PFS. Grade 3/4 Adverse Events (AEs) were similar in both treatment groups at 24.3%, but treatment discontinuation due to AEs was slightly higher in the Durvalumab arm (16.3% versus 10.6% in the placebo arm). Any grade pneumonitis was reported in 38.0% of patients in the Durvalumab arm compared to 30.2% in the placebo arm.

The results of the ADRIATIC trial represent a significant advancement in the treatment of Limited Stage-Small Cell Lung Cancer (LS-SCLC). Durvalumab consolidation therapy demonstrated a statistically significant and clinically meaningful improvement in both OS and PFS compared to placebo. These findings support Durvalumab as a new standard of care for patients with LS-SCLC following concurrent chemoradiotherapy, potentially changing the treatment landscape for this aggressive disease.

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer. Cheng Y, Spigel DR, Cho BC, et al. for the ADRIATIC Investigators. N Engl J Med 2024;391:1313-1327.

Superior Outcomes with First Line OPDIVO® versus ADCETRIS® in Advanced Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 8570 new cases of Hodgkin Lymphoma will be diagnosed and about 910 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

For patients with Hodgkin Lymphoma, the goal of first-line chemotherapy is cure. A positive PET scan following first-line chemotherapy is indicative of incomplete response with residual disease and warrants subsequent chemotherapy or radiation. Advanced stage (Stage III-IV) Classical Hodgkin lymphoma has a cure rate of approximately 70-80% when treated in the first-line setting with a combination of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine (ABVD). This regimen which was developed more than 40 years ago is less expensive, easy to administer, is generally well tolerated and is often used in first line setting. Nonetheless, this regimen which contains Bleomycin can cause pulmonary toxicity, the incidence of which is higher in older patients and in those who receive consolidation radiotherapy to the thorax.

Brentuximab Vedotin (ADCETRIS®) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death. In the ECHELON-1 study, frontline treatment with Brentuximab Vedotin (BV) in combination with Doxorubicin, Vinblastine and Dacarbazine (AVD) resulted in a significant improvement both in Progression Free Survival as well as Overall Survival, after a median follow up of 6 years. However, frontline BV adds toxicity, and 7-20% of patients still develop Relapsed/Refractory Hodgkin Lymphoma.

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells.

SWOG S1826 was an open-label, randomized Phase III trial conducted to compare the combination of Nivolumab plus AVD to Brentuximab Vedotin plus AVD, in patients with advanced-stage classical Hodgkin Lymphoma (cHL). In this study, 976 newly diagnosed Stage III or IV cHL patients (N=976) were randomly assigned 1:1 to receive either 6 cycles of Nivolumab at 240 mg IV on days 1 and 15 (N=489) or Brentuximab Vedotin 1.2 mg/kg IV on days 1 and 15 (N=487). Both treatment groups also received AVD IV (Doxorubicin, Vinblastine, Dacarbazine ) on days 1 and 15, and treatment was repeated every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Granulocyte-Colony Stimulating Factor (G-CSF) Pegfilgrastim SC on days 2 and 16, or Filgrastim SC on days 6-10 and 21-25 was optional in the Nivolumab group (N-AVD) but was required in the Brentuximab Vedotin group (BV-AVD). Approximately 54% in the N-AVD group received G-CSF compared to 95% in the BV-AVD group. After completion of cycle 6, patients could receive radiation therapy at the discretion of the treating physician, to metabolically active residual lesions noted on the end of treatment PET. Less than 1% of patients had received radiotherapy. Patients were stratified by age, International Prognostic Score (IPS) and intent to use radiation therapy. The median age was 27 years, 76% were Caucasian, 55% were men, 64% had Stage IV disease and 32% had IPS of 4-7. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Event-Free Survival (EFS), Patient-Reported Outcomes (PROs), and Safety.

At the planned 2nd interim analysis, upon recommendation from the SWOG Data and Safety Monitoring Committee, the primary results were reported. With a median follow up of 12.1 months, PFS was superior in the N-AVD group compared to the BV-AVD group (HR=0.48; P=0.001). The 1 year PFS was 94% in the N-AVD group compared with 86% among patients treated with BV-AVD.

The researchers repeated the analysis after an additional one year of follow up, to assess the durability of PFS benefit. At a median follow-up of 2.1 years, the 2-year PFS was 92% with N-AVD compared to 83% with BV-AVD (HR=0.45). The PFS benefit was consistent across prespecified treatment subgroups, including subgroups according to age, disease stage and IPS score. The 2-year EFS was 90% with N-AVD versus 81% with BV-AVD (HR for death=0.50). More importantly, N-AVD was associated with favorable side-effect profile with a lower frequency of neurotoxicities. Further, there was a dramatic reduction in the use of radiation in adolescent patients.

The rate of Grade 3 or more hematologic AEs were 48.4% after N-AVD, compared to 30.5% after BV-AVD. There was however no increase in infectious complications even though there was a higher rate of neutropenia in the N-AVD group. It should be noted that the frequency of neutropenia with BV-AVD was ameliorated by the required use of G-CSF, as compared with the optional use of G-CSF with N-AVD. Hypo/Hyperthyroidism was more frequent after N-AVD whereas peripheral neuropathy was more common after BV-AVD.

The researchers concluded that in this largest Hodgkin Lymphoma study in National Clinical Trials Network (NCTN) history, Nivolumab in combination with AVD significantly improved Progression Free Survival with fewer toxicities, compared to Brentuximab Vedotin in combination with AVD, in patients with advanced stage Hodgkin Lymphoma. Nivolumab in combination with AVD may be the new standard therapy for this group of patients. Follow-up is ongoing to confirm the durability of PFS benefit, and to assess Overall Survival and Patient Reported Outcomes.

Nivolumab+AVD in Advanced-Stage Classic Hodgkin’s Lymphoma. Herrera AF, LeBlanc M, Castellino SM, et al. N Engl J Med 2024;391:1379-1389.

Neoadjuvant Immunotherapy in Early Breast cancer

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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. The American Cancer Society estimates that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence.

Neoadjuvant chemotherapy is commonly used for patients with locally advanced Triple-Negative Breast Cancer (TNBC) and HER2-positive breast cancer. Alongside this standard treatment, there has been a push to develop new strategies aimed at increasing pathologic Complete Response (pCR) rates and improving survival outcomes. The introduction of Immune Checkpoint Inhibitors (ICIs) marked a major shift in cancer treatment, initially proving effective in melanoma and later showing promise in metastatic TNBC. This success led researchers to test ICIs in early-stage breast cancer as well.

Multiple randomized clinical trials have studied the impact of combining ICIs with chemotherapy in the neoadjuvant setting, some continuing ICI therapy as adjuvant treatment. These trials have gone beyond TNBC, exploring their use in other breast cancer subtypes like HER2-positive and Hormone Receptor-positive (HR-positive)/HER2-negative cancers. While some trials achieved their goals, the best way to integrate ICIs into early treatment remains debated, with concerns about cost and safety still under discussion.

In response to the need for clarity, a comprehensive systematic review and meta-analysis was conducted to assess the efficacy of neoadjuvant ICI therapy combined with chemotherapy in early-stage breast cancer. The analysis reviewed randomized controlled trials retrieved from the PubMed database up until December 2023. These trials focused on comparing ICIs plus chemotherapy versus chemotherapy alone in patients with early-stage breast cancer. The meta-analysis included 5114 patients from nine randomized controlled trials. These patients were subdivided into three major subgroups – TNBC (N=2097) patients, HR-positive/HER2-negative (N=1924) patients, and HER2-positive (N=1115) patients. The Primary outcomes evaluated were pathologic Complete Response (pCR) and Event-Free Survival (EFS) stratified by molecular phenotype and PD-L1 status. Secondary outcomes included incidence of Adverse Events (AEs), with a focus on immune-related toxicities.
The following are the Key Findings:
Pathologic Complete Response (pCR):
Triple-Negative Breast Cancer: Neoadjuvant ICIs improved the pCR rate significantly, with an increase from 46.6% to 59.9% (absolute improvement of 13.3%), regardless of PD-L1 status.
Hormone Receptor-Positive, HER2-Negative Tumors: There was a significant benefit of ICIs in PD-L1-positive tumors. The pCR rate increased from 14.8% to 24.6% in these cases (absolute improvement of 9.8%). However, there was no significant benefit in PD-L1-negative HR-positive/HER2-negative patients.
HER2-Positive Tumors: No significant pCR improvement was observed with the addition of ICIs in this subtype.

Event-Free Survival (EFS):
TNBC Patients with pCR: For those with TNBC who achieved a pCR, ICIs improved EFS (HR=0.65, 95% CI 0.42–1.00). The 5-year EFS was 92.0% for patients treated with ICIs compared to 88.0% without ICIs.
TNBC Patients with Residual Disease: ICIs also showed better EFS (HR=0.77, 95% CI 0.61–0.98) in patients who had residual disease after treatment, with a 5-year EFS of 63.3% compared to 56.1% without ICIs.
Adjuvant ICI in TNBC: No additional survival benefit was found with the use of adjuvant ICIs (after surgery) in TNBC patients, regardless of whether they achieved pCR or had residual disease.

Safety Profile:
Adverse Events (AEs): During neoadjuvant treatment, grade 3 or higher immune-related adverse events (AEs) were observed in 10.3% of patients treated with ICIs. The overall incidence of severe AEs (grade 3 or worse) was higher in ICI-treated patients (63.6%) compared to chemotherapy alone (54.1%). This reflects the toxicity costs associated with ICIs

Implications:
Neoadjuvant vs. Adjuvant ICI: The findings suggest that ICIs have greater efficacy when used in the neoadjuvant setting compared to adjuvant treatment. This is likely due to the tumor presence during neoadjuvant therapy, which allows for immune system priming through exposure to tumor antigens.
PD-L1 as a Biomarker: PD-L1 expression appears to be a more reliable biomarker of response to ICIs in HR-positive/HER2-negative tumors than in TNBC, where ICI benefit seems independent of PD-L1 status.
TNBC and Residual Disease: In patients with residual disease after neoadjuvant therapy, the benefit of continuing ICIs in the adjuvant setting is limited. This raises the question of whether continuing ICIs postoperatively is necessary or whether alternative strategies, like the use of other novel therapies, may be more effective.

In conclusion, Neoadjuvant Immune Checkpoint Inhibitors improve pathologic Complete Response rates and Event-Free Survival in early-stage breast cancer, especially in TNBC and PD-L1-positive HR-positive/HER2-negative tumors. However, their use in the adjuvant setting does not appear to provide added benefit. Ongoing trials, like the OptimICE-PCR trial, are designed to answer this question definitively by randomizing patients who achieve pCR to either continued ICI therapy or observation. For patients with residual disease post-neoadjuvant therapy, novel treatment approaches like Antibody-Drug Conjugates such as Sacituzumab Govitecan combined with ICIs are being investigated, offering potential new treatment paradigms.

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer: A Systematic Review and Meta-Analysis. Villacampa G, Navarro V, Matikas A, et al. JAMA Oncol. 2024;10(10):1331-1341. doi:10.1001/jamaoncol.2024.3456.

FDA Approves VYLOY® with Chemotherapy for Biomarker Positive Gastric or GEJ Adenocarcinoma

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SUMMARY: The FDA on October 18, 2024, approved Zolbetuximab-clzb (VYLOY®), a claudin 18.2 (CLDN18.2)-directed cytolytic antibody, with fluoropyrimidine and platinum-containing chemotherapy, for the first-line treatment of adults with locally advanced unresectable or metastatic Human Epidermal growth factor Receptor 2 (HER2)-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. The FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with Gastric or GEJ adenocarcinoma who may be eligible for treatment with Zolbetuximab.

The American Cancer Society estimates that in the US about 26,890 new gastric cancer cases will be diagnosed in 2024 and about 10,880 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction (GEJ) adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients with metastatic disease is approximately 6%. These patients frequently are treated with platinum containing chemotherapy along with a fluoropyrimidine such as modified FOLFOX6 or CAPOX. Patients with HER2-positive disease are usually treated with chemotherapy plus Trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor, or checkpoint inhibitor alone, if the tumors express PD-L1.

CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed on the surface of the cancer cells and accessible to targeted therapies with antibodies. CLDN18.2 is expressed in 30-40% of Gastric adenocarcinomas.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. This study met the Primary endpoint and the median Progression Free Survival (PFS) was 10.6 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The Overall Survival (OS) was also significantly improved (18.23 versus 15.54 months, HR=0.75; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population.

GLOW trial is a global, multi-center, double-blind, randomized Phase III study, conducted to assess the efficacy and safety of Zolbetuximab plus CAPOX (N=254) versus placebo plus CAPOX (N=253) as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. In this trial, 507 eligible patients were randomly assigned 1:1 to receive Zolbetuximab 800 mg/m2 IV as a loading dose on cycle 1, day 1, of the first 21-day cycle, followed by 600 mg/m2 IV on day 1 of subsequent cycles, along with CAPOX regimen consisting of Capecitabine 1000 mg/m2 orally twice daily on days 1-14 of each cycle and Oxaliplatin 130 mg/m2 IV on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both treatment groups and patients could continue beyond 8 cycles with Zolbetuximab or placebo plus Capecitabine at investigator’s decision, and treatment continued until disease progression or unacceptable toxicities. CLDN18.2 positive was defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining and patients were stratified by region (Asia versus non-Asia), number of organs with metastases, and prior gastrectomy (yes versus no). The median patient age was 60 years, majority of patients were male from Asia, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1. Basline characteristics were similar in both treatment groups. The Primary end point was Progression Free Survival (PFS) and Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

At a median follow up of 12.6 months, the combination of Zolbetuximab plus CAPOX significantly improved PFS, and the median PFS was 8.2 months, compared with 6.8 months for those given placebo plus CAPOX (HR=0.68; P=0.0007). The median OS was 14.4 months versus 12.2 months respectively (HR=0.77; P=0.01). The PFS and OS benefits were sustained at 24 months, and the benefits were observed across most subgroups. The most common side effects were nausea and vomiting and the authors recommended increasing the infusion duration time, or splitting the dose over a 2 day period, in addition to the administration of prophylactic antiemetics.

The researchers concluded that the addition of first-line Zolbetuximab to CAPOX significantly improved PFS and OS in patients with CLDN18.2-positive, HER2-negative, unresectable, locally advanced or metastatic Gastric or GEJ cancer. The authors added that Zolbetuximab plus CAPOX represents a potential new first-line therapy for this patient group. Taken together, both GLOW and SPOTLIGHT trials showed a similar reduction in the risk of disease progression or death and a similar reduction in the risk of death with the addition of Zolbetuximab to chemotherapy, when compared with placebo plus chemotherapy.

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Shah MA, Shitara K, Ajani JA, et al. Nature Medicine 2023; 29:2133–2141

Liquid Biopsy May Predict Survival in Metastatic Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 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.

Metastatic prostate cancer remains a significant concern in the United States, being the second leading cause of cancer-related deaths among men. Over recent years, the incidence of metastatic prostate cancer has notably increased. For men diagnosed with metastatic Hormone-Sensitive Prostate Cancer (mHSPC), survival rates have improved with the introduction of Androgen Receptor Signaling Inhibitors (ARSIs) and chemotherapy. These therapeutic advancements, used in conjunction with androgen suppression, have demonstrated survival benefits, though patient outcomes remain highly variable. In previous studies, treatment intensification has been deemed justified based on tumor histology and radiographic disease burden, but these criteria have not consistently predicted outcomes, underscoring the urgent need for robust new, noninvasive, prognostic biomarkers.

Liquid biopsy, a noninvasive method of analyzing blood-based biomarkers, has emerged as a promising tool for early cancer detection, prognosis, personalized treatment decisions, and disease monitoring. In particular, Circulating Tumor Cells (CTCs)-cancer cells shed from primary or metastatic tumors into the bloodstream-offer a dynamic snapshot of disease status and have shown promise as biomarkers for prognosis, disease monitoring, and personalized treatment decisions. While CTCs have been extensively studied in metastatic Castration-Resistant Prostate Cancer (mCRPC), their role in mHSPC remains underexplored.

The S1216 trial is a prospective, multicenter, Phase 3, randomized clinical trial, conducted by SWOG in collaboration with the National Cancer Institute (NCI) and other research groups, to determine whether incorporating baseline CTC enumeration could serve as a reliable biomarker for predicting long-term outcomes, aiding in the identification of patients who may benefit from treatment intensification or novel therapeutic regimens. The primary goal of this study is to evaluate the prognostic value of Circulating Tumor Cell (CTC) counts in men with mHSPC, particularly their association with Overall Survival (OS).

The S1216 trial included 1313 men with newly diagnosed mHSPC, randomized in a 1:1 ratio to receive Androgen Deprivation Therapy (ADT) combined with either Orteronel, a CYP17 inhibitor that blocks androgen biosynthesis, or Bicalutamide, a nonsteroidal anti-androgen. ADT was administered using a Luteinizing Hormone-Releasing Hormone agonist, and Bicalutamide was given at a dose of 50 mg once daily, while Orteronel was administered at 300 mg twice daily. Treatment allocation was stratified based on disease severity, timing of ADT initiation prior to or after enrollment, and Zubrod Performance Status.

A key component of the trial was the collection and analysis of liquid biopsy samples, particularly CTC enumeration, at baseline and at disease progression to mCRPC. These blood samples were processed using the CellSearch platform, the only FDA-cleared system for CTC enumeration. The platform employs immunomagnetic beads that bind to epithelial cell adhesion molecules (EpCAM) on the surface of CTCs, enriching the sample for CTCs. After isolation, the CTCs were stained with specific markers to distinguish them from non-tumor cells: Cytokeratins (CK) markers for epithelial cells, CD45, a leukocyte antigen, used to exclude non-cancerous white blood cells, and DAPI, a nuclear stain to identify cells with intact nuclei. CTC counts were categorized into three groups: 0, 1-4, and 5 or more CTCs per 7.5 mL of blood. This categorization was based on findings from prior research in mCRPC, where higher CTC counts were associated with worse clinical outcomes. The goal was to determine whether a similar association could be observed in men with mHSPC. The Primary outcome of the study was Overall Survival (OS), with secondary outcomes including Progression-Free Survival (PFS) and Prostate-Specific Antigen (PSA) levels at 7 months.

Of the 1313 trial participants, 503 men had evaluable blood samples for CTC analysis at baseline. The results of the study showed that higher baseline CTC counts were strongly associated with worse clinical outcomes. Patients with 5 or more CTCs had a median OS of 27.9 months, compared with 56.2 months for men with 1-4 CTCs, and median OS of more than 78 months for men with 0 CTCs (median not reached). A similar trend was observed for PFS, with men who had 5 or more CTCs showing a significantly higher risk of disease progression. After adjusting for baseline clinical covariates, men with 5 or more CTCs were 3.22 times more likely to die during the study period and 2.46 times more likely to have their cancer progress, and had a lower odds of achieving a complete PSA response, compared to men with 0 CTCs at baseline.

This study demonstrates that baseline CTC count is a powerful, independent prognostic biomarker for men with mHSPC. CTC enumeration at the start of therapy can help identify men at higher risk of poor survival, even before the disease progresses to mCRPC. This information is particularly valuable for selecting patients for clinical trials of more aggressive or novel therapies. By identifying high-risk patients early, clinicians can potentially intensify treatment upfront, before PSA levels or clinical symptoms worsen.

In summary, CTC count provides critical insights into the biological behavior of metastatic prostate cancer and offers a noninvasive method for stratifying patients based on their risk of poor outcomes. Future research may expand the role of liquid biopsy beyond CTC enumeration to include molecular profiling of CTCs and circulating tumor DNA (ctDNA), enabling even more precise and personalized treatment strategies.

Circulating Tumor Cell Count and Overall Survival in Patients With Metastatic Hormone-Sensitive Prostate Cancer. Goldkorn A, Tangen C, Plets M, et al. JAMA Netw Open. 2024;7(10):e2437871. doi:10.1001/jamanetworkopen.2024.37871

Measuring Lymphocyte Count May Predict Response to CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,780 new cases will be diagnosed in 2024 and 12,540 patients are expected to 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 CD38 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 2024 remains an incurable disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median Progression-Free Survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with relapsed or refractory myeloma often have disease that is refractory to multiple drugs.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase III studies involving patients with relapsed or refractory myeloma.

The researchers conducted an insightful study aimed at identifying predictive biomarkers to enhance the efficacy of CAR T-cell therapy for patients with relapsed or refractory multiple myeloma (MM). While CAR T-cell therapy has revolutionized treatment for B-cell malignancies and other blood cancers, the high cost of therapy and variability in patient response highlight the need for precise biomarkers that could guide clinicians in selecting the best candidates for this therapy. This research delves into the factors that affect patient response, specifically focusing on the role of the Absolute Lymphocyte Count (ALC) in predicting treatment success and disease progression.

The researchers analyzed data from 156 patients with relapsed or refractory multiple myeloma, treated with two BCMA-targeting CAR T-cell therapies: Ciltacabtagene autoleucel (CARVYKTI®) and Idecabtagene vicleucel (ABECMA®). These patients, who were treated between 2017 and 2023, had previously undergone several lines of therapy, rendering them refractory to conventional treatments. The research team collected and analyzed Absolute Lymphocyte Counts (ALC), a key immune marker, from 5 days before the CAR-T infusion for up to 15 days post-infusion, to determine if ALC could be used as a predictive biomarker for patient outcomes. The focus on this early post-infusion window was based on the hypothesis that the expansion of T cells, which is critical for the effectiveness of CAR T-cell therapy, would be reflected in the ALC levels. This study sought to correlate early ALC levels with long-term outcomes such as depth of response, Progression-Free Survival (PFS), and overall Duration of Response (DoR).

The findings demonstrated that ALC is a strong predictor of response to CAR T-cell therapy, with higher ALC values correlating with deeper responses and longer PFS. Specifically, patients who had an ALC maximum (ALCmax) above 1.0 x 103/µL during the first 15 days after infusion experienced a significant improvement in PFS, more than five times greater, compared to those with lower ALC counts. Patients with ALCmax above 1.0 x 103/µL had a median PFS of 33.1 months, while those with counts at or below 0.5 x 103/µL had a significantly shorter PFS of 6 months. The high-risk group, with an ALCmax of 0.5 or less x 103/µL, showed over three times the likelihood of early disease progression compared to their counterparts with higher ALC counts, making them a vulnerable population within the study cohort. The analysis also took into account a variety of potential confounding factors, such as patient age, previous therapies, high-risk cytogenetics, and the specific CAR T-cell product used. Even when these factors were considered, ALC remained an independent prognostic indicator, making it a reliable marker for predicting the depth and duration of response in this setting.

The researchers also explored the biological mechanisms underlying this phenomenon. CAR T-cell therapy relies heavily on the expansion of the infused T cells within the patient’s body. ALC, which includes a count of lymphocytes such as T cells, may serve as a surrogate marker for this expansion. Patients with higher ALC are likely to experience more robust CAR T-cell proliferation, leading to deeper and more durable anti-tumor responses. This aligns with previous findings that T-cell expansion after infusion is closely linked to treatment success. Additionally, the study noted that patients with higher ALC levels were also more likely to experience Cytokine Release Syndrome (CRS), a common side effect of CAR T-cell therapy that results from the rapid activation and expansion of T cells. While CRS can be a challenging complication to manage, its occurrence might also be a marker of effective CAR T-cell therapy.

The identification of ALC as a biomarker has significant implications for clinical practice. Physicians can now use ALC levels measured within the first 15 days post-infusion to guide treatment decisions. For patients with low ALC counts, this early biomarker could signal the need for alternative treatment approaches or additional therapeutic interventions to manage potential relapse. Given the limited options for patients who relapse after CAR T-cell therapy, having this early warning could be vital for planning the next steps in their treatment journey. Conversely, patients with high ALC levels can be reassured that they are more likely to achieve a deep and sustained response, allowing clinicians to optimize follow-up care and monitoring accordingly.

The researchers are further investigating the biological factors that influence ALC levels after CAR T-cell infusion. By analyzing patient samples and conducting deeper biological studies, they aim to uncover why some patients experience robust lymphocyte expansion while others do not. Understanding these underlying mechanisms could lead to new interventions that enhance CAR T-cell expansion, ultimately improving outcomes for a broader range of patients. Identifying potential pre-infusion markers that could predict whether a patient will have a favorable ALC response may be relevant. If such biomarkers can be identified, clinicians might be able to intervene even earlier, adjusting treatment plans before CAR T-cell therapy begins.

Absolute lymphocyte count after BCMA CAR-T therapy is a predictor of response and outcomes in relapsed multiple myeloma. Saldarriaga MM, Pan D, Unkenholz C, et al. Blood Adv (2024) 8 (15): 3859–3869. https://doi.org/10.1182/bloodadvances.2023012470