Category: Hem/Onc Updates

Enfortumab Vedotin plus Pembrolizumab: A Breakthrough in Locally Advanced or Metastatic Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-302 is a landmark Phase III, global, open-label, randomized trial comparing the efficacy and safety of Enfortumab vedotin and Pembrolizumab with the efficacy and safety of platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma. A total of 886 eligible patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 and Pembrolizumab 200 mg IV on day 1 of every 3-week cycle (N=442) or chemotherapy consisting of Gemcitabine and either Cisplatin or Carboplatin (N=444), determined on the basis of eligibility to receive cisplatin, for a maximum of 6 cycles. The maximum number of Pembrolizumab cycles allowed was 35 and there was no maximum number of cycles set for Enfortumab vedotin. The treatment groups were well balanced. The median age was 69 yrs and randomization was stratified according to eligibility to receive Cisplatin (eligible or ineligible), PD-L1 expression status (High-CPS 10 or more versus Low-CPS less than 10), and liver metastases (present or absent). The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included Overall Response Rate (ORR) as assessed by BICR, Duration of Response, and Safety. As of the data cutoff date, the median duration of follow-up for survival was 17.2 months.

The PFS was significantly longer in the Enfortumab vedotin plus Pembrolizumab group compared to the chemotherapy group (median duration 12.5 months versus 6.3 months; HR=0.45; P<0.001), representing a 55% reduction in the risk of disease progression or death. Enfortumab vedotin plus Pembrolizumab also substantially improved median OS, and the median OS was 31.5 months compared to 16.1 months with chemotherapy (HR=0.47; P<0.001) representing a 53% reduction in the risk of death. These PFS and OS benefits were consistent between the intention-to-treat population and all the prespecified subgroups, including those defined according to Cisplatin eligibility status and PD-L1 expression status. The Overall Response Rate (ORR) in the Enfortumab vedotin plus Pembrolizumab group was 67.7%, significantly higher than the 44.4% ORR observed with chemotherapy alone (P<0.001), with a Complete Response rate of 29.1% versus 12.5% respectively. The median Duration of Response was Not Reached in the Enfortumab vedotin plus Pembrolizumab group and was 7.0 months in the chemotherapy group.

Treatment-related adverse events of Grade 3 or higher occurred in 55.9% of the patients in the Enfortumab vedotin plus Pembrolizumab group, and was 69.5% in the chemotherapy group. The most common treatment-related adverse events of any grade in the Enfortumab vedotin plus Pembrolizumab group were peripheral sensory neuropathy, pruritus and alopecia, whereas the most common such events in the chemotherapy group were anemia, neutropenia and nausea.

It was concluded that treatment with Enfortumab vedotin plus Pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, emerging as a potential new standard of care, irrespective of Cisplatin eligibility. The results from this study mark a significant paradigm shift in the management of locally advanced or metastatic urothelial carcinoma, offering new hope for patients and clinicians alike.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. Powles T, Valderrama BP, Gupta S, et al. for the EV-302 Trial Investigators. N Engl J Med 2024;390:875-888.

Novel Prognostic Factors for Treatment-Free Remission in Chronic Myeloid leukemia

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SUMMARY: Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia. 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. 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.

Chronic Myeloid Leukemia has long been a model for targeted cancer therapy, particularly through the development of Tyrosine Kinase Inhibitors (TKIs) targeting the BCR:ABL1 fusion gene. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including Imatinib, share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale-MR4) is a new molecular predictor of long term survival in CML patients, and this was achieved in a majority of patients treated with TKIs. Further, it has been shown from previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, precise criteria for stopping CML therapy have not been clearly defined.

Discontinuing TKI therapy after a Deep Molecular Response among patients with CML can potentially improve quality of life, minimize long term toxicities as well as drug-drug interactions, and reduce financial burden. Stopping TKI therapy among CML patients appears to be safe and feasible in over 50% of the patients, although about 20% of these patients experience TKI withdrawal syndrome manifesting as musculoskeletal symptoms. Discontinuation of TKI therapy should only be considered in consenting patients after a thorough discussion of the potential risks and benefits. TKIs have revolutionized the prognosis and quality of life for patients with CML, leading to a new treatment goal of achieving Treatment-Free Remission (TFR).

The European Stop Kinase Inhibitors (EURO-SKI) study is the largest clinical trial conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in stable Deep Molecular Response (DMR). The researchers presented the final analysis of the EURO-SKI trial after 3 years of follow up and highlighted the prognostic factors for short- and long-term molecular response maintenance. This comprehensive study evaluated the effects of stopping TKI treatment (Imatinib, Nilotinib or Dasatinib), in patients who had been on therapy for at least 3 years and had confirmed DMR, defined as BCR:ABL1-transcripts 0.01% or less on the International Scale for at least 12 months. The Primary outcomes of the study were the maintenance of Major Molecular Response (MMR), defined as BCR:ABL1 0.1% or less (MR3), at 6 and 36 months after stopping TKIs (Molecular Recurrence Free Survival).

In this study, 868 patients with Chronic Phase CML were screened, and 728 patients were included in the baseline analysis. The final analysis revealed that 61% of patients remained in MMR at 6 months, and 46% remained in MMR at 36 months after stopping TKI treatment. Several factors were identified as significant predictors of MMR maintenance. Longer duration of TKI treatment and DMR before stopping TKI treatment were associated with a higher likelihood of maintaining MMR at 6 months. Additionally, the type of BCR:ABL1 transcript emerged as a prognostic factor, with patients having transcript type e14a2 alone or in combination with e13a2 showing a significantly higher probability of maintaining MMR. For MMR maintenance between 6 and 36 months, the duration of TKI treatment (but not DMR duration) before stopping TKI treatment, and disease characteristics at diagnosis, including percentage of peripheral blood blast cells and platelet count at diagnosis, were significant factors influencing MMR maintenance. Among 315 patients evaluated at 36 months, the Molecular Recurrence Free Survival was 76%. Multivariate analysis over the entire 36-month trial period identified duration of TKI treatment, duration of DMR (Deep Molecular Response) while receiving TKI, percentage of peripheral blood blast cells at diagnosis, and transcript type (e14a2 plus e13a2 had a higher probability of maintaining MMR over 36 months than e13a2 alone) as independent factors for MMR maintenance.

The findings of the EURO-SKI trial have important implications and represent a significant milestone for the management of CML. They highlight the importance of considering not only the duration of TKI treatment but also disease characteristics and transcript type when predicting treatment-free remission. This study represents a significant step forward in understanding the factors influencing Treatment-Free Remission in CML patients, and may help guide clinical decision-making in the future.

European Stop Tyrosine Kinase Inhibitor Trial (EURO-SKI) in Chronic Myeloid Leukemia: Final Analysis and Novel Prognostic Factors for Treatment-Free Remission. Mahon F-X, Pfirrmann M, Dulucq S, et al. on behalf of the EURO-SKI Investigators. Journal of Clinical Oncology. March 12, 2024. https://doi.org/10.1200/JCO.23.01647.

Neoadjuvant KEYTRUDA® plus Chemotherapy Significantly Improves EFS in Early Stage High Risk Triple Negative 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.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival (OS) of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Neoadjuvant chemotherapy is the preferred treatment approach in this group of patients and can potentially increase the likelihood of tumor resectability and breast conservation. Further, a pathological Complete Response (pCR) after neoadjuvant chemotherapy can result in a longer Event-Free Survival and Overall Survival. Pathological Complete Response is therefore used as an end point for clinical testing of neoadjuvant treatment in patients with early triple-negative breast cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Pembrolizumab when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent Pembrolizumab in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, Pembrolizumab combination achieved pathological Complete Response rate of 65%, regardless of PD-L1 expression.

KEYNOTE-522 trial is a multicenter, randomized, double-blind, placebo-controlled Phase III trial, conducted to evaluate the efficacy and safety of neoadjuvant Pembrolizumab plus chemotherapy as compared with neoadjuvant placebo plus chemotherapy, followed by adjuvant Pembrolizumab or placebo in patients with early stage, high-risk, Triple Negative Breast Cancer. In this study, total of 1174 patients (N=1174) regardless of tumor PD⁠-⁠L1 expression, were randomly assigned 2:1 to receive Pembrolizumab plus chemotherapy (N=784) or placebo plus chemotherapy (N=390). Eligible patients had newly diagnosed, previously untreated, Triple Negative Breast Cancer, with tumor size more than 1 cm but 2 cm or less in diameter with nodal involvement, or tumor size more than 2 cm in diameter regardless of nodal involvement. Patients in the neoadjuvant phase received four cycles of Pembrolizumab 200 mg IV or placebo once every 3 weeks plus Paclitaxel 80 mg/m2 once weekly plus Carboplatin AUC 5 IV once every 3 weeks or Carboplatin AUC 1.5 IV once weekly in the first 12 weeks (first neoadjuvant treatment), followed by four cycles of Pembrolizumab or placebo along with Doxorubicin 60 mg/m2 IV or Epirubicin 90 mg/m2 IV plus Cyclophosphamide 600 mg/m2 IV once every 3 weeks in the subsequent 12 weeks (second neoadjuvant treatment). Patients then underwent definitive surgery (breast conservation or mastectomy with sentinel lymph-node evaluation or axillary dissection) 3-6 weeks after the last cycle of the neoadjuvant phase. In the adjuvant phase, patients received radiation therapy as indicated and Pembrolizumab or placebo once every 3 weeks for up to nine cycles. Adjuvant Capecitabine was not allowed. The median age was 49 yrs, 64% were white, 56% were premenopausal, and overall 75% had Stage II disease and 25% had Stage III disease. Both treatment groups were well balanced with regard to age, ECOG performance status, PD-L1-positivity, tumor size and nodal involvement. The Primary end points were a pathological Complete Response (pCR) at the time of definitive surgery and Event-Free Survival (EFS) in the intent-to-treat population. Pathological Complete Response was defined as absence of invasive cancer in the breast and lymph nodes (ypT0/Tis ypN0), and was assessed by the blinded local pathologist at the time of definitive surgery. EFS was defined as the time from randomization to the first occurrence of progression of disease that precludes definitive surgery, local or distant recurrence, second primary malignancy, or death due to any cause.

The pathological Complete Response rate was 63% in the Pembrolizumab plus chemotherapy group and 55.6% in the placebo plus chemotherapy group, and this difference were statistically significant. The EFS after median follow up of 63.1 months showed a 5-year EFS rate of 81.3% with Pembrolizumab plus chemotherapy and 72.3% with placebo plus chemotherapy (HR=0.63). The median EFS had not been reached in either group. The EFS benefit appeared consistent across subgroups, including those assessed by nodal status, disease stage, PD-L1 expression, menopausal status and Carboplatin schedule. A prespecified, exploratory analysis showed higher 5-year EFS rates with Pembrolizumab among patients who achieved pathologic Complete Response (92.2% versus 88.2%) and among those who did not achieve pathologic Complete Response (62.6% versus 52.3%).

It was concluded that the addition of Pembrolizumab with neoadjuvant chemotherapy followed by Pembrolizumab monotherapy in the adjuvant setting resulted in a durable Event Free Survival benefit, for patients with early stage Triple Negative Breast Cancer, and this benefit was noted across key subgroups, as well as among patients who did or did not achieve pathologic Complete Response.

Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for early-stage triple-negative breast cancer: updated event-free survival results from the phase 3 KEYNOTE-522 study. Schmid P, Cortés J, Dent R, et al. Presented at the 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX; abstract LBO1-01.

Metformin May Reduce the Risk of Cancers, Especially GI Malignancies

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SUMMARY: The American Cancer Society estimates that in 2024, 2,001,140 new cancer cases will be diagnosed, and 611,720 cancer deaths are projected to occur in the United States. The Center for Disease Control and Prevention recommends healthy eating habits, limiting alcohol consumption and skin protection for cancer prevention, screening tests for breast, cervical, colorectal and lung cancer for early detection, as well as HPV and Hepatitis B vaccination to lower the risk of cervical and liver cancer respectively.

Metformin is one of the most commonly prescribed agents for Type 2 diabetes worldwide. Metformin is a synthetic guanidine derived compound. Numerous epidemiological studies have shown that Type 2 diabetes patients receiving Metformin had a decreased risk of the occurrence of various types of cancers, compared to those taking other antidiabetic agents. Numerous meta-analyses have also confirmed that Metformin reduces cancer incidence by 30-50%. These findings in addition to the safety and cost-effectiveness of Metformin have generated a lot of interest in the research community. Metformin exhibited promising anticancer effects in preclinical studies by inducing cell cycle arrest at different stages of cell division depending on the cancer type, promoting cell death, suppressing cancer cell migration, invasion and metastasis, as well as deregulating cancer metabolism. Further Metformin enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy.

There has been renewed interest in the anticancer mechanisms of Metformin and it has been reported to mimic significant metabolic effects of caloric restriction at both cellular and systemic levels. It has been postulated that Metformin induces a direct effect on cancer cells, independent of blood glucose and insulin levels, and indirect effect thru systemic metabolic changes depending on blood glucose and insulin levels. The primary site at which Metformin exerts its anticancer activity is the mitochondria. Metformin inhibits mitochondrial complex I and triggers energy depletion, which activates AMPK (Adenosine Monophosphate-activated Protein Kinase ) and inhibits mTOR, limiting cancer growth. Additionally, metformin also exerts anticancer effects that are independent of AMPK but rather dependent on Rag GTPases or REDD1.

To date, there has been no comprehensive review of the literature assessing the relationship between Metformin and cancer risk. The researchers therefore conducted a comprehensive systematic review of literature and meta-analysis, to investigate the association between Metformin or any of its analogs use, and cancer risk, and specific cancer type when possible. From an initial pool of more than 6,000 articles, identified in PubMed/MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from inception through March 7, 2023, 166 studies with cancer incidence information were included in the meta-analysis. Majority of these studies took place in populations with Type 2 diabetes. This analysis was then stratified by cancer type and study type. The authors decided not to provide a summary analysis for specific cancer types because of the heterogeneity between studies due to different study designs, as this analysis included many case-control studies, some prospective cohort studies and some retrospective cohort studies.

This analysis showed a reduced risk for overall cancer in case-control studies (RR=0.55) and in prospective cohort studies (RR = 0.65). Metformin use was associated with reduced risk of gastrointestinal cancer (RR = 0.79), urologic cancer (RR = 0.88) and hematologic malignancies (RR = 0.87). The most striking association was observed for gastrointestinal cancer risk, which showed a risk reduction of 21%.

It was concluded that Metformin may be associated with a decreased risk of many cancer types, and there appears a striking association between Metformin and reduced risk for gastrointestinal cancers. The researchers added that additional studies in populations without diabetes are needed to better understand the utility of Metformin in cancer prevention.

Association of metformin use and cancer incidence: a systematic review and meta-analysis. O’Connor L, Bailey-Whyte M, Bhattacharya M, et al. JNCI:Journal of the National Cancer Institute, djae021, https://doi.org/10.1093/jnci/djae021. 30 January 2024.

FDA Approves BREYANZI®, First CAR-T Cell Therapy for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

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SUMMARY: The FDA on March 14, 2024 granted accelerated approval to BREYANZI® (Lisocabtagene maraleucel, Liso-cel), a CD19-directed Chimeric Antigen Receptor (CAR) T-cell therapy, for the treatment of adults with relapsed or refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) who have received at least two prior lines of therapy (including a Brutons Tyrosine Kinase-BTK inhibitor and a B-Cell Lymphoma 2-BCL2 inhibitor).

The American Cancer Society estimates that for 2024, about 20,700 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4440 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 CLL is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors such as Ibrutinib (IMBRUVICA®) Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), time limited therapy with BCL2 inhibitor Venetoclax, given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy. Patients have few options and poor outcomes upon progression on these therapies, and there is an unmet need for novel therapies.

Chimeric Antigen Receptor (CAR) T-cell therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure, and genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR). These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patients body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen.

BREYANZI® is a CD19-directed genetically modified autologous T cell immunotherapy, that seeks out cancer cells expressing the antigen CD19, which is found uniquely on B cells and destroy them. BREYANZI® was previously approved by the FDA for treatment of adults with relapsed or refractory Large B-cell lymphoma, who received at least one prior therapy. Patients, following treatment with CAR T-cells, develop B-cell aplasia (absence of CD19 positive cells) due to B-cell destruction and may need immunoglobin replacement. Hence, B-cell aplasia can be a useful therapeutic marker, as continued B-cell aplasia has been seen in all patients who had sustained remission, following CAR T-cell therapy. Cytokine Release Syndrome, an inflammatory process, is the most common and serious side effect of CAR T-cell therapy and is associated with marked elevation of Interleukin-6. Cytokine release is important for T-cell activation and can result in high fevers and myalgias. This is usually self limiting although if severe can be associated with hypotension and respiratory insufficiency. Tocilizumab (ACTEMRA®), an Interleukin-6 receptor blocking antibody, produces a rapid improvement in symptoms. This is however not recommended unless the symptoms are severe and life threatening, as blunting the cytokine response can in turn negate T-cell proliferation. Elevated serum ferritin and C-reactive protein levels are surrogate markers for severe Cytokine Release Syndrome. The CAR T-cells have been shown to also access sanctuary sites such as the CNS and eradicate cancer cells. CD19 antigen is expressed by majority of the B-cell malignancies and therefore most studies using CAR T-cell therapy have focused on the treatment of advanced B-cell malignancies.

TRANSCEND CLL 004 is an open-label, single-arm, multicenter Phase1/2 study, conducted in the United States, to evaluate the efficacy and safety of BREYANZI® in adult patients with relapsed or refractory CLL/SLL. This study included 117 eligible patients who underwent leukapheresis between January 2018 and June 2022, at 27 sites in the United States. Patients received a single intravenous infusion of BREYANZI® at one of two target dose levels: 50×10⁶ (Dose Level 1) or 100×10⁶ (Dose Level 2) Chimeric Antigen Receptor-positive T cells. The median age was 65 years, 68% were men, 44% had bulky lymphadenopathy, and 83% had high-risk cytogenetics. All patients had previously received and failed treatment with a BTK inhibitor and 80% had received prior Venetoclax. Among these patients, 60% had progressed on BTK inhibitors and had Venetoclax failure. Patients had a median of five prior lines of therapy. The Primary endpoint was Complete Response or Remission (including with incomplete marrow recovery), assessed by Independent Review in efficacy-evaluable patients with previous BTK inhibitor progression and Venetoclax failure at Dose Level 2 (100×10⁶). The total efficacy analysis included 89 patients treated at a dose level of 100×10⁶ CAR-positive T cells, with 49 patients evaluable.

In the Primary efficacy analysis set treated at a dose level of 100×10⁶ (N=49), the Complete Response or Remission rate (including with incomplete marrow recovery) was statistically significant at 18% (P=0.0006). The Overall Response Rate was 45%, and the median Duration of Response was 35.3 months. The median Duration of Response in the Complete Responders was Not Reached at the time of data cutoff and Minimal Residual Disease negativity rates were 100% in blood and 92.3% in bone marrow among Complete Responders. The median time to first response was 1.2 months, and for Complete Response or Remission was 3.0 months, respectively.

Among 89 patients in the study treated with BREYANZI®, Cytokine Release Syndrome (CRS) and neurologic events were mostly low-grade. CRS of any grade occurred in 83% of patients, with grade 3 CRS reported in 9% of patients, and with no grade 4 or 5 events reported. Any-grade neurologic events were reported in 46% of patients, with grade 3 neurologic events reported in 20% of patients, and one grade 4 neurologic event reported. No deaths due to either toxicity were reported.

It was concluded that a single infusion of BREYANZI® induced Complete Response or Remission in patients with relapsed or refractory CLL/SLL, including those with previous treatment failure on both BTK inhibitors and Venetoclax. It is the first CAR T-cell therapy approved in this setting and the safety profile was deemed manageable, offering a potential breakthrough in the treatment paradigm for these challenging diseases. Further confirmatory trials will be required to validate these findings and support continued approval of BREYANZI® for this indication.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Siddiqi T, Maloney DG, Kenderian SS, et al. The Lancet. 2023;402:641-654.

FDA Approves TEVIMBRA® for Advanced Esophageal Squamous Cell Carcinoma

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SUMMARY: The FDA on March 14, 2024 approved TEVIMBRA® (Tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. The American Cancer Society estimates that in 2024, about 22,370 new cases of esophageal cancer will be diagnosed in the US and about 16,130 individuals will die of the disease. It is the sixth most common cause of global cancer death. Squamous Cell Carcinoma is the most common type of cancer of the esophagus among African Americans, while Adenocarcinoma is more common in Caucasians. Squamous Cell Carcinoma accounts for approximately 85% of cases. Majority of esophageal cancers are unresectable at diagnosis, and most patients treated with curative intent eventually will relapse, and only about 20% of patients will survive at least 5 years following diagnosis. Patients with advanced esophageal cancer have a median survival of less than a year when treated with the standard Fluoropyrimidine plus Platinum based chemotherapy. For those patients progressing on first line chemotherapy, treatment options are limited, with a 5-year relative survival rate of 8% or less.

Tislelizumab is a humanized immunoglobulin G4 (IgG4) anti-Programmed cell Death protein- 1 (PD-1) monoclonal antibody with high affinity and binding specificity against PD-1. It is uniquely designed to minimize binding to Fc-gamma receptors on macrophages, helping to aid the body’s immune cells to detect and fight tumors, while minimizing off-target effects.

The present approval was based on RATIONALE 302 study, which is a global, randomized, open-label, Phase III trial, designed to investigate the efficacy and safety of TEVIMBRA® when compared with investigators choice of chemotherapy as a second-line treatment, for patients with unresectable, locally advanced or metastatic ESCC. In this study, 512 patients (N=512) with advanced or metastatic ESCC who had progressed during or after first-line systemic treatment were randomly assigned 1:1 to receive either Tislelizumab 200 mg IV every 3 weeks or investigator’s choice of chemotherapy. Those in the chemotherapy group received one of the following regimens: Paclitaxel 135-175 mg/m2 IV every 3 weeks or 80-100 mg/m2 IV weekly, Docetaxel 75 mg/m2 IV every 3 weeks or Irinotecan 125 mg/m2 IV Day 1 and Day 8 every 3 weeks. Stratification factors included ECOG PS and choice of chemotherapy. The Primary end point of this trial was Overall Survival (OS) in the Intention-to-Treat (ITT) population. Secondary end points included Progression Free Survival (PFS), Overall Response Rate (ORR), Duration of Response (DOR), and Safety.

The trial met its Primary endpoint with a statistically significant and clinically meaningful survival benefit for TEVIMBRA® compared with chemotherapy. The median OS in the TEVIMBRA® group was 8.6 months compared to 6.3 months in the chemotherapy group (HR=0.70; P=0.0001). This survival benefit was noted across the predefined subgroups, including PD-L1 status, race, and region. In the subset of patients with a PD-L1 CPS of at least 10%, the median OS with Tislelizumab was 10.3 months versus 6.8 months with chemotherapy (HR=0.54; P=0.0006). The 6-month PFS rates in the Tislelizumab and chemotherapy groups were 21.7% and 14.9% respectively, 12-month PFS rates were 12.7% and 1.9%. The Overall Response Rate was higher in the Tislelizumab group versus chemotherapy group (20.3% versus 9.8%) and the median Duration of Response was 7.1 months versus 4.0 months, respectively. The safety profile of Tislelizumab was also favorable over chemotherapy.

It was concluded that Tislelizumab significantly improved Overall Survival compared with chemotherapy as second-line therapy in patients with advanced or metastatic Esophageal Squamous Cell Carcinoma, with a tolerable safety profile. This survival benefit was even more in patients with PD-L1 CPS of 10% or more. Studies are underway, evaluating Tislelizumab in combination with chemotherapy in treatment naïve patients with advanced esophageal carcinoma.

Tislelizumab Versus Chemotherapy as Second-Line Treatment for Advanced or Metastatic Esophageal Squamous Cell Carcinoma (RATIONALE-302): A Randomized Phase III Study. Shen L, Kato K, Kim S-B, et al. J Clin Oncol.2022;40:3065-3076.

FDA Approves RYBREVANT® in Combination with Chemotherapy for Advanced NSCLC with EGFR Exon 20 Insertion Mutations

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SUMMARY: The FDA on March 1, 2024, approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for the first-line treatment of locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. The FDA also granted traditional approval to Amivantamab-vmjw for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. FDA previously granted accelerated approval for this indication based on Phase 1 CHRYSALIS study.

The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 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. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions and occur in about 2-3% patients with NSCLC and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5-year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available, and platinum-doublet chemotherapy remains the standard of care for these patients.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors, with immune cell-directing activity. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Additionally, Amivantamab has been shown to engage macrophages, monocytes, and Natural Killer cells through its Fc domain. Amivantamab in combination with Carboplatin and Pemetrexed demonstrated synergy, with improvement in Response Rates, in previously published studies.

PAPILLON trial is an international, randomized, Phase III study, conducted to assess the efficacy and safety of Amivantamab plus chemotherapy as compared with standard chemotherapy alone, as first-line treatment, in patients with advanced NSCLC with EGFR exon 20 insertions. In this study, 308 patients (N=308) were randomly assigned 1:1 to receive Amivantamab plus chemotherapy (N=153) or chemotherapy alone (N=155), given in 3 week cycles. Amivantamab was given at a dose of 1400 mg (1750 mg for a body weight of 80 kg or more) IV weekly for the first 4 weeks, with the first infusion split over 2 days (at a dose of 350 mg on cycle 1, day 1, and the remainder on cycle 1, day 2). Starting at cycle 3 (week 7), the dose of Amivantamab was increased to 1750 mg IV (2100 mg for a body weight of 80 kg or more) administered every 3 weeks until disease progression. Carboplatin was administered at AUC 5 IV every 3 weeks for up to 4 cycles. Pemetrexed was administered at a dose of 500 mg/m2 IV every 3 weeks until disease progression. Both treatment groups were well balanced and the patients mutational status was determined by local testing of tissue samples in 92% of cases, and plasma samples in 8% of cases. Patients with treated brain metastases were eligible if they were asymptomatic. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive Amivantamab monotherapy. The Primary end point was Progression Free Survival (PFS) as determined by Blinded Independent Central Review. Secondary end points included Objective Response Rate (ORR), Overall Survival (OS), Duration of Response and Safety.

At a median follow-up of 14.9 months, the median PFS was significantly longer in the Amivantamab plus Chemotherapy group and was 11.4 months, compared to 6.7 months in the chemotherapy alone group (HR=0.40; P<0.001). At 18 months, the PFS in the Amivantamab plus chemotherapy group was 31% and 3% in the chemotherapy group. The Objective Response was 73% in the Amivantamab plus chemotherapy group and 47% in the chemotherapy alone group (P<0.001). Overall Survival results were immature at the time of current analysis, with a trend toward improvement in Overall Survival despite a high rate of crossover for the control arm (42%).

The most common adverse events associated with Amivantamab plus chemotherapy were reversible hematologic and EGFR-related toxic effects and included rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, diarrhea, nausea and vomiting. Approximately 7% of patients discontinued Amivantamab due to adverse reactions.

It was concluded that Amivantamab in combination with chemotherapy resulted in superior efficacy as compared with chemotherapy alone, in previously untreated advanced NSCLC patients with EGFR exon 20 insertions.

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. Zhou C, Tang K-J, Cho BC, et al. for the PAPILLON Investigators. N Engl J Med 2023;389:2039-2051.

FDA Approves OPDIVO® in Combination with Chemotherapy for the First Line Treatment of Advanced Urothelial Carcinoma

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SUMMARY: The FDA on March 6, 2024, approved Nivolumab (OPDIVO®) in combination with Cisplatin and Gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of all urothelial cancers, and the latter can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Platinum-based chemotherapy remains the standard of care for the first line treatment of unresectable or metastatic urothelial carcinoma. Cisplatin-based chemotherapy is preferred over Carboplatin-based chemotherapy for eligible patients and has a response rate of over 40%, with a median Overall Survival (OS) of approximately 15 months. These responses, however, are not durable. To date, no novel agent has improved Overall Survival when added to platinum-based chemotherapy, for first-line treatment of metastatic urothelial carcinoma. There is an unmet need for more effective treatment.

OPDIVO® (Nivolumab) 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. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Nivolumab presently is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma after previous platinum-based chemotherapy, as well as for adjuvant treatment of high-risk muscle-invasive urothelial carcinoma after radical resection.

Based on the data from Phase II studies, CheckMate 901 clinical trial was conducted to evaluate the benefit of a combination of Nivolumab plus Gemcitabine and Cisplatin, as compared with Gemcitabine and Cisplatin alone, in patients with previously untreated advanced urothelial carcinoma. CheckMate 901 is an international, open-label, randomized, Phase III trial, consisting of 2 parts. In the first part which is summarized below, Nivolumab plus Gemcitabine and Cisplatin was compared with Gemcitabine and Cisplatin alone, in patients with previously untreated, unresectable or metastatic urothelial carcinoma. In the second part of this study, which is ongoing, patients were assigned to receive either Nivolumab plus Ipilimumab or platinum-based chemotherapy.

In the current trial, 608 patients (N=608) with previously untreated unresectable or metastatic urothelial carcinoma were randomized assigned 1:1 to receive either Nivolumab 360 mg IV in combination with Cisplatin and Gemcitabine every 3 weeks for up to six cycles, followed by Nivolumab 480 mg IV every 4 weeks until disease progression, unacceptable toxic effects, or up to a maximum of 2 years, or Gemcitabine and Cisplatin alone every 3 weeks for up to six cycles. Patients who discontinued Cisplatin alone could be switched to Gemcitabine and Carboplatin for the remainder of the platinum-doublet cycles up to six cycles in total. Randomization was stratified by tumor PD-L1 expression and presence of liver metastasis. Patient characteristics were well-balanced between the two study groups. The median patient age was 65 years. The primary tumor site was the bladder in 75% of patients. 37% of patients had a high tumor PD-L1 expression (1% or more) and 21% of patients had evidence of liver metastases. The dual Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Objective response rate (ORR) per BICR was an exploratory endpoint.

At a median follow up of 33.6 months, there was a statistically significant improvement in both Overall Survival and Progression Free Survival for Nivolumab in combination with Cisplatin and Gemcitabine followed by Nivolumab, compared to Cisplatin and Gemcitabine alone. The median OS was 21.7 months for patients who received Nivolumab in combination with Cisplatin and Gemcitabine and 18.9 months for those who received Cisplatin and Gemcitabine alone, (HR=0.78; P=0.02). Overall survival was 70.2% and 62.7%, respectively, at 12 months and 46.9% and 40.7%, respectively, at 24 months. The median PFS was 7.9 months and 7.6 months, respectively (HR=0.72; P=0.0012). The PFS was 34.2% and 21.8%, respectively, at 12 months and 23.5% and 9.6%, respectively, at 24 months.

The Objective Response Rate and Complete Response Rates were 57.6% and 21.7% respectively with Nivolumab combination therapy, versus 43.1% and 11.8% with Gemcitabine and Cisplatin alone. The median duration of Complete Response was 37.1 months with Nivolumab combination therapy and 13.2 months with Gemcitabine and Cisplatin alone. The most common treatment-related Adverse Events with the Nivolumab combination were anemia, nausea, and neutropenia.

It was concluded that a combination of Nivolumab with Gemcitabine and Cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma, compared to Gemcitabine and Cisplatin alone. The researchers added that this study provides evidence of the benefit of concurrent administration of an immune checkpoint inhibitor and chemotherapy in improving Overall Survival in this patient population.

Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. van der Heijden MS, Sonpavde G, Powles T, et al., for the CheckMate 901 Trial Investigators. N Engl J Med 2023; 389:1778-1789.

Stockholm3 Blood Test Identifies Aggressive 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.

PSA (Prostate Specific Antigen) is one of the most widely used prostate cancer biomarkers, and the widespread use of PSA testing in the recent years has resulted in a dramatic increase in the diagnosis and treatment of prostate cancer. The management of clinically localized prostate cancer that is detected based on PSA levels remains controversial, and management strategies for these patients have included Surgery, Radiotherapy or Active Monitoring. However, it has been proposed that given the indolent nature of prostate cancer in general, majority of the patients do not benefit from treatment intervention and many patients die of competing causes. PSA test CANNOT distinguish between aggressive and benign cancer. As a result, many men have to undergo unnecessary follow-ups with a biopsy of the prostate. Further, treatment intervention can result in adverse effects on sexual, urinary, or bowel function. PSA test is also difficult to interpret, and PSA elevation can be associated with several non-malignant conditions such as older age, infection, inflammation and Benign Prostatic Hypertrophy. The U.S. Preventive Services Task Force (USPSTF) has recommended that population screening for prostate cancer with PSA should not be adopted as a public health policy, because the risks appeared to outweigh benefits, from detecting and treating PSA-detected prostate cancer.

Stockholm3 is a blood test that combines 5 protein biomarkers, 101 genetic markers, and clinical data with an advanced algorithm, in order to detect almost 100% of aggressive prostate cancers at an early stage. The Stockholm3 test has been validated in over 75, 000 men and has been used in health systems in Sweden, Norway, Finland, Germany, Switzerland, UK and Turkey, and results have been published in international peer-reviewed journals. Evidence suggests that Stockholm3 is more effective at predicting risk than PSA testing alone, for men aged 45-74 with PSA of at least 1.5ng/ml. Several studies have shown that the application of this test can reduce the number of biopsies by 32%, without compromising the diagnostic capacity of intermediate grade prostate cancers (Gleason 7 or higher), in comparison with the use of the PSA value 3 ng/ mL as cut-off value for biopsy recommendation. However, none of the validation studies included ethnically diverse population.

SEPTA is a prospective trial conducted to validate Stockholm3 in an ethnically diverse population, for prostate cancer risk stratification, and determine whether it could achieve noninferior sensitivity and superior specificity in this diverse population. This trial included men who were referred for prostate biopsy at North American sites from 2019 to 2023. Study participants had no previous diagnosis of prostate cancer. This study also used bio-banked specimens from 2008 to 2020. The cohort comprised 912 enrolled men and 1,217 with bio-banked blood. The median age was 63 years, 46% were White, 24% Black, 16% Asian and 14% were Hispanic.

This trial had 2 prespecified Primary goals: 1) Demonstrate noninferiority of the test in detecting Clinically Significant Prostate Cancer (defined as Gleason Grade group 2 or more), compared to PSA testing. 2) Prove superior specificity of the test versus PSA testing, thereby reducing the number of biopsies in men with benign or Gleason Grade group 1 biopsies. A Secondary goal was to evaluate Stockholm3 and PSA across ethnic subgroups. The study assessed Stockholm3 performance using prespecified thresholds and compared it to PSA across different ethnic subgroups. Statistical analysis plans were established before data analysis.

It was noted that the median PSA and Stockholm3 values among the participants were 6.1 ng/mL and 17, respectively. A total of 16% underwent MRI-targeted biopsies, and 20% had a prior benign biopsy. On biopsy, 29% were diagnosed with Clinically Significant Prostate Cancer, 14% with Gleason Grade group 1 cancer, and 57% with benign findings. The detection rate for Clinically Significant Prostate Cancer varied across ethnic groups: African American/Black (37%), White/Caucasian (28%), Hispanic/Latino (29%), and Asian (21%).

Overall, Stockholm3 value 15 or higher demonstrated noninferiority to a PSA value of 4 ng/mL or higher and nearly three times superior specificity. These results were consistent across ethnic subgroups. The researchers noted that using a Stockholm3 value of 15 or higher would have reduced benign and Gleason Grade group 1 biopsies by 45% overall and between 42-52% across ethnic subgroups, compared to PSA of 4 ng/ml or higher.

The study concluded that in an ethnically diverse population, Stockholm3 could significantly reduce unnecessary biopsies and diagnoses of low-grade tumors, while maintaining similar sensitivity to PSA, for detecting Clinically Significant Prostate Cancer. The results suggest that
Stockholm3 could improve risk stratification and reduce harms associated with prostate cancer screening in diverse populations.

Stockholm3 validation in a multi-ethnic cohort for prostate cancer (SEPTA) detection: A multicentered, prospective trial. Vigneswaran HT, Eklund M, Discacciati A, et al. J Clin Oncol 42, 2024 (suppl 4; abstr 262). DOI 10.1200/JCO.2024.42.4_suppl.262. Abstract#262.

FDA Approves ONIVYDE® for First-Line Treatment of Metastatic Pancreatic Adenocarcinoma

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SUMMARY: The FDA on February 13, 2024, approved ONIVYDE® (Irinotecan liposome) with Oxaliplatin, Fluorouracil, and Leucovorin, for the first-line treatment of metastatic Pancreatic adenocarcinoma. The American Cancer Society estimates that in 2024, about 66,440 people will be diagnosed with Pancreatic cancer and 51,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced Pancreatic cancer has been dismal, with a 5-year survival rate for metastatic Pancreatic cancer of approximately 10%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States. Majority of patients with Pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic Pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic Pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic Pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Approximately 80% of patients had liver metastases. Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.83; P=0.04). The 12 months OS rate was 45.6% versus 39.5%, and 18 months OS rate was 26.2% versus 19.3% respectively. There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.69; P=0.0001). The 12 months PFS rate was 27.4% versus 13.9%, and 18 months PFS rate was 11.4% versus 3.6% respectively. This OS and PFS benefit was observed across subgroups.

The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and the median Duration of Response was 7.3 months versus 5.0 months respectively. A lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and included a higher incidence of diarrhea, nausea and hypokalemia.

It was concluded that first-line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic Pancreatic ductal adenocarcinoma.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Wainberg ZA, Melisi D, Macarulla T, et al. The Lancet. 2023;402: 1272-1281.