Author: RR

FDA Approves Fruquintinib in Refractory Metastatic Colorectal Cancer

RR

SUMMARY: The FDA on November 8, 2023, approved Fruquintinib (FRUZAQLA®) for adult patients with metastatic Colorectal Cancer (mCRC) who received prior Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC will be diagnosed in the United States in 2023 and about 52,550 patients are expected to die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Approximately 15-25% of the patients with CRC present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with CRC will develop metastatic disease during the course of their illness. First line treatment of metastatic CRC includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab. Patients with Stage IV CRC are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). Regorafenib has limited efficacy and its adverse effects, particularly hepatotoxicity and fatigue, may be difficult to manage. Treatment options are limited for those who progress on these therapies and there is therefore a strong unmet clinical need.

The VEGF pathway plays a very important role in the neoangiogenesis associated with tumor proliferation. Antiangiogenic agents targeting the VEGF pathway inhibit new blood vessel growth and lead to vascular regression, tumor vessel normalization and constriction, in addition to offsetting the ability of chemotherapy to induce VEGF. This benefit was noted in the SUNLIGHT trial which demonstrated longer Overall Survival and Progression Free Survival among patients with refractory metastatic CRC, treated with LONSURF® plus Bevacizumab, compared to LONSURF® alone (N Engl J Med 2023; 388:1657-1667).

Fruquintinib is a highly selective and potent, oral small molecule inhibitor of VEGFR1/2/3. Fruquintinib was designed to have enhanced selectivity that limits off-target kinase activity, allowing for high drug exposure, sustained target inhibition, and flexibility for the potential use as part of combination therapy.

The present FDA approved was based on two Phase III trials, FRESCO and FRESCO-2. FRESCO is a randomized, double-blind, placebo-controlled, multicenter Phase III clinical trial conducted in China to evaluate the efficacy and safety of oral Fruquintinib, as third-line or later therapy in patients with metastatic CRC. It should be noted that unlike treatment patterns in North America and Europe, VEGF inhibitors such as Bevacizumab and Aflibercept are not routinely integrated into first- or second-line therapy in China. In this study 416 eligible patients (N=416) who had tumor progression following treatment regimens that included Fluoropyrimidine, Oxaliplatin, and Irinotecan were randomly assigned to receive Fruquintinib 5 mg (N=278) or placebo (N=138), both in combination with best supportive care, given orally once daily for 21 days, followed by 7 days off in 28-day cycles, until disease progression or intolerable toxicity. Randomization was stratified by prior use of VEGF inhibitor treatment (yes versus no) and K-ras mutational status (wild type versus mutated). The mean age was 55 years and most baseline demographics, disease characteristics, and prior treatments were similar between the treatment groups. Over 65% of patients had liver metastases. The Primary end point was Overall Survival (OS). Secondary efficacy endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate, Duration of Response and Safety.

The median Overall Survival was significantly prolonged with Fruquintinib compared with placebo (9.3 months versus 6.6 months; HR for death=0.65; P<0.001). The median PFS was also significantly increased with Fruquintinib (3.7 months versus 1.8 months; HR for progression or death=0.26; P<0.001).

The FRESCO-2 study is a global, multi-regional, randomized, placebo-controlled, Phase III trial conducted separately in the U.S., Europe, Japan and Australia among patients with heavily pretreated metastatic colorectal cancer. The reason for this trial was that practice patterns are different in these countries compared to China, with VEGF inhibitors such as Bevacizumab routinely integrated into first- or second-line therapy in these countries. In this study, 691 eligible patients (N=691) were randomly assigned (2:1) to receive Fruquintinib 5 mg (N=461) or matched placebo (N=230) orally once daily on days 1–21 in 28-day cycles, plus best supportive care. Patients received therapy until disease progression or unacceptable toxicity. This study included histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to LONSURF® or Regorafenib, or both. Patients had received a median of 4 lines of previous systemic therapy for metastatic disease, and 73% of the eligible patients had received more than 3 lines of therapy for metastatic disease. Patients were stratified based on previous therapy with LONSURF® or Regorafenib, or both, RAS mutation status, and duration of metastatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS) and Duration of Response.

This study met its Primary endpoint and the median OS was 7.4 months in the Fruquintinib group versus 4.8 months in the placebo group (HR=0.66; P<0.0001). This represented a 34% reduction in the risk of death in the Fruquintinib group. The median PFS in the Fruquintinib group was 3.7 months which was also statistically significant. The median Duration of Response was 10.7 months, the Disease Control Rate was 56%, and 41% of patients were alive at 9 months. The most common Grade 3 or worse adverse events in the Fruquintinib group included hypertension (14%)), asthenia (8%), and hand-foot syndrome (6%).

Both FRESCO and FRESCO-2 trials demonstrated a statistically significant and clinically meaningful improvement in Overall Survival, and Progression Free Survival in patients with refractory metastatic colorectal cancer, when treated with Fruquintinib. This innovative therapy fulfills an unmet need and provides a new treatment option for this heavily pretreated group of patients.

Effect of Fruquintinib vs Placebo on Overall Survival in Patients with Previously Treated Metastatic Colorectal Cancer-The FRESCO Randomized Clinical Trial. Li J, Qin S, Xu R_H, et al. JAMA. 2018;319:2486-2496.

Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Lancet. 2023;402:41-53. doi:10.1016/S0140-6736(23)00772-9.

Late Breaking Abstract – ESMO Congress 2023: Perioperative OPDIVO® Plus Chemotherapy Improves Survival in Resectable Non Small Cell Lung Cancer

RR

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 25% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor which is highly expressed on activated T cells, and blocks its interaction with PD-L1 or PD-L2 on tumor cells, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Combining cytotoxic chemotherapy with a PD 1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

In the CheckMate 816 Phase III trial, neoadjuvant Nivolumab plus platinum-doublet chemotherapy in earlier stage resectable NSCLC resulted in a marked improvement in pathologic Complete Response rate, with a statistically significant improvement in the Event Free Survival among those receiving Nivolumab plus chemotherapy group, compared to those receiving chemotherapy alone.

CheckMate 77T, a multicenter, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of perioperative Nivolumab + chemotherapy in patients with resectable NSCLC. In this study, 461 patients (N=461) with untreated, resectable Stage IIA (more than 4 cm)-IIIB (N2) NSCLC were randomly assigned 1:1 to receive Nivolumab 360 mg IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery, and adjuvant Nivolumab 480 mg IV every 4 weeks for 1 year (N=229), or placebo IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery and adjuvant placebo IV every 4 weeks for 1 year (N=232). Enrolled patients had no prior systemic anticancer treatment and no EGFR or ALK mutations. Patients were stratified according to histology, disease stage, and tumor PD-L1 expression (less than 1% versus 1% or more) and patients with brain metastasis were excluded. The median age was 66 years, and both treatment groups were well balanced. Approximately two-thirds had Stage III disease, more than 50% of patients had tumor PD-L1 expression of 1% or more, and about 40% of patients had PD-L1 expression less than 1%. Approximately 90% were current or former smokers and majority of patients (75%) received Carboplatin-based chemotherapy. Surgery was performed within 6 weeks following the last dose of neoadjuvant therapy and radiologic restaging. The Primary endpoint of this study was Event Free Survival (EFS) according to Blinded Independent Central Review. Secondary endpoints included Overall Survival, pathologic Complete Response, Major Pathologic Response (10% or less of viable tumor cells remaining at time of surgery), and Safety. The researchers presented the data from the first interim prespecified analysis of Event-Free Survival.

At a median follow-up of 25.4 months, approximately 78% in the Nivolumab/chemotherapy group and 77% in the placebo/chemotherapy group were able to undergo definitive surgery. Lobectomy was the most common type of surgery performed and about 90% of patients had a complete resection. Nivolumab plus chemotherapy significantly improved Event-Free Survival, compared to placebo plus chemotherapy (median Not Reached versus 18.4 months respectively; HR=0.58; P=00025). This represented a 42% improvement in Event-Free Survival among those treated with Nivolumab plus chemotherapy. The 12-month Event-Free Survival rate was 73% versus 59%, respectively and the 18-month Event-Free Survival rate was 70% versus 50%. The pathologic Complete Response rates as well as Major Pathologic Response rates were significantly higher with Nivolumab plus chemotherapy, compared to placebo plus chemotherapy (25.3% versus 4.7% and 35.4% versus 12.1% repectively). Surgery related adverse events were similar in both treatment groups at 12%.

The researchers concluded that CheckMate 77T met its primary endpoint and is the first Phase III perioperative study that builds on the current standard of care, neoadjuvant Nivolumab plus chemotherapy. Patient with early stage resectable NSCLC now have three different treatment options: 1) Neoadjuvant therapy followed by surgery 2) Surgery followed by adjuvant therapy, and 3) Now perioperative therapy, which includes neoadjuvant therapy, surgery, and adjuvant therapy. Circulating tumor DNA and other biomarkers may identify patients who are cured with chemoimmunotherapy and in whom adjuvant therapy can be avoided.

CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Cascone T, Awad M, Spicer J, et al. ESMO Congress 2023. Abstract LBA1. Presented on October 21, 2023.

First Line REBLOZYL® Superior to Epoetin Alfa in Lower Risk Myelodysplastic Syndromes

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

Patients with Lower-risk MDS (Revised IPSS-Very Low, Low, or Intermediate risk ) often present with symptomatic anemia and these patients are in chronic need for RBC transfusions which in turn can result in iron overload and can have a negative impact on quality of life and Overall Survival. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200 U per liter are less likely to respond to ESAs. Additionally, patients with MDS with ring sideroblasts have a shorter median duration of response to ESAs, than those who do not have ring sideroblasts. Patients with Lower-risk MDS with chromosome 5q deletion (del 5q) who are transfusion dependent are treated with Lenalidomide, regardless of previous treatment with ESAs. In contrast, only 39% of patients with non-del(5q) Lower-risk MDS receive second line therapy besides RBC transfusions, and there are few treatment options for patients who are refractory to, unresponsive to, or ineligible for ESAs. There is therefore an unmet clinical need for safe and effective treatment options, to reduce the RBC transfusion burden in these patients.

Signaling by the SMAD2 and SMAD3 pathway exerts an inhibitory effect on red cell maturation. This pathway is constitutively activated in the bone marrow cells of patients with MDS and diseases associated with ineffective erythropoiesis such as β-thalassemia. Luspatercept (REBLOZYL®) is a recombinant soluble fusion protein and is first-in-class erythroid maturation agent that enhances erythropoiesis by promoting late-stage Red Blood Cell precursor differentiation and maturation. It targets select Transforming Growth Factor (TGF)-β superfamily ligands such as GDF11, that regulate late-stage erythropoiesis. This results in a reduction in aberrant SMAD2 and SMAD3 signaling, thereby promoting late-stage RBC precursor differentiation and maturation. In the MEDALIST trial, Luspatercept significantly reduced the severity of anemia in patients with Lower-risk MDS with Ring Sideroblasts, who had been RBC transfusion-dependent, and who had disease that was refractory to, or unlikely to respond to ESAs.

COMMANDS trial is a global, randomized, controlled, open-label Phase III study, conducted to evaluate the efficacy and safety of Luspatercept in ESA-naive patients with Low Risk-MDS. This study included 354 eligible patients with lower-risk MDS as defined by the revised International Prognostic Scoring System (IPSS-R) criteria, with or without Ringed Sideroblasts. These patients had less than 5% bone marrow blasts and serum EPO levels less than 500 U/L and required red blood cell transfusions (defined as 2–6 RBC units/8 weeks for at least 8 weeks immediately prior to randomization). Patients were randomized 1:1 to receive Luspatercept (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) subcutaneous, once every 3 weeks for at least 24 weeks (N=178) or Epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg, with a maximum permitted total dose of 80 000 IU)) weekly for at least 24 weeks (N=176). The median patient age was 74 years and both treatment groups were well balanced. Patients were stratified by baseline RBC transfusion burden (less than 4 units per 8 weeks versus 4 or more units per 8 weeks), endogenous serum EPO concentration (200 U/L or less versus more than 200 to less than 500 U/L), and Ring Sideroblast status (positive versus negative). The Primary endpoint was RBC independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks.

At the planned interim analysis of 301 patients, 147 patients in the Luspatercept group and 154 patients in the Epoetin alfa group completed 24 weeks of treatment or discontinued earlier and the median treatment duration was 41.6 weeks for Luspatercept and 27.0 weeks for Epoetin alfa. Luspatercept was superior in efficacy compared to Epoetin alfa. Among patients receiving Luspatercept at the planned interim analysis, 58.5% achieved RBC transfusion independence for at least a 12-week consecutive period within the first 24 weeks, along with an increase in hemoglobin of at least 1.5 g/dL compared to 31.2% of patients receiving Epoetin alpha (P<0.0001). Luspatercept was effective regardless of baseline serum EPO, red blood cell transfusion burden, SF3B1 mutation status, or Ring Sideroblast status. These results were similar when comparisons of baseline serum erythropoietin and baseline RBC transfusion burden in subgroups were made. However, responses were different based on ring sideroblast status. Approximately 65% of Ringed Sideroblast positive patients on Luspatercept achieved the Primary endpoint compared to 26% on Epoetin alfa. Among Ringed Sideroblast negative patients, slightly more met this end point on Epoetin alfa (46% versus 41% respectively). The Secondary endpoints in the study included Hematologic Improvement-Erythroid Response of 8 weeks or more and RBC transfusion independence at 24 weeks or more and at 12 weeks or more. Similar to the Primary endpoint, Luspatercept was more effective than Epoetin alfa across these Secondary endpoints.

It was concluded from this interim analysis that compared with Epoetin alfa, Luspatercept significantly improved RBC transfusion independence, and erythroid response, as well as duration of response, with no new toxiciites. The authors added that this innovative therapy with Luspatercept could represent a new standard of care for patients with RBC transfusion dependent Low Risk Myelodysplastic Syndromes. Long-term follow up will be needed to confirm these results and further refine findings in patients with Lower-Risk Myelodysplastic Syndromes, including non-mutated SF3B1 or Ring Sideroblast-negative subgroups.

Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Platzbecker U, Della Porta MG, Santini V, et al. The Lancet. 2023; 402:373-385

FDA Approves Nivolumab for Adjuvant Treatment of Stage IIB/C Melanoma

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SUMMARY: The FDA on October 13, 2023, approved Nivolumab (OPDIVO®) for the adjuvant treatment of completely resected Stage IIB/C melanoma in patients 12 years and older. The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 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.

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk, resected, Stage III melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab was 55.4% versus 38.3% with placebo, in patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab among patients with resected Stage IIIB/C and IV melanoma.

CHECKMATE-76K is an ongoing, randomized, double-blind, Phase III study conducted to evaluate the efficacy of Nivolumab versus placebo as adjuvant treatment for patients with resected Stage IIB/C melanoma. In this study, 790 eligible patients were randomized (2:1) to Nivolumab 480 mg (N=526) or placebo (N=264) by IV infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Patient characteristics at baseline were well balanced between treatment groups and 50.5% had nodular melanoma, 39% had Stage IIC disease and patients were stratified by tumor category. The Primary endpoint was investigator-assessed Recurrence-Free Survival (RFS). Secondary endpoints included Distant Metastasis-Free Survival (DMFS) and Safety.

At a minimum follow up of 7.8 months, CheckMate 76K met its primary endpoint and Nivolumab significantly improved RFS versus placebo. Nivolumab demonstrated a 58% reduction in the risk of recurrence or death versus placebo in patients with resected stage IIB/C melanoma (HR = 0.42; P < 0.0001). The 12-month RFS was 89.0% for nivolumab and 79.4% for placebo. The benefit with nivolumab over placebo was observed across all pre-specified subgroups, including all disease Stages and T-category subgroups. Adjuvant Nivolumab demonstrated significant benefit in those with stage IIC disease, head and neck primaries or nodular disease, who are all considered to be at a higher absolute recurrence risk. Additionally, there was a clinically meaningful improvement in the Distant Metastasis-Free Survival with Nivolumab versus placebo (HR = 0.47). Further, a lower proportion of patients treated with nivolumab had multiple lesions detected at first recurrence versus those treated with placebo (3.4% versus 9.1%). Adverse events were similar to that observed in patients with resected stage III or stage IV disease and similar to the established anti-PD-1 monotherapy profile.

It was concluded that adjuvant Nivolumab significantly improved Relapse Free Survival as well as Distant Metastasis-Free Survival in patients with resected Stage IIB/C melanoma and this clinical benefit was observed across disease subgroups, including all T categories.

Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Kirkwood, J.M., Del Vecchio, M., Weber, J. et al. Nat Med (2023). https://doi.org/10.1038/s41591-023-02583-2

Amivantamab plus Chemotherapy with and without Lazertinib after Progression on Osimertinib in Advanced Lung Cancer

RR

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

Epidermal Growth Factor Receptor (EGFR) plays an important role in regulating cell proliferation, survival and differentiation, and is overexpressed in a variety of epithelial malignancies. EGFR targeted Tyrosine Kinase Inhibitors (TKIs) such as Gefitinib, Erlotinib, Afatinib, Dacomitinib and Osimertinib target the EGFR signaling cascade. However, patients eventually will develop drug resistance due to new EGFR mutations. Another important cause of drug resistance to TKIs is due to the activation of parallel RTK (Receptor Tyrosine Kinase) pathways such as Hepatocyte Growth Factor/Mesenchymal-Epithelial Transition factor (HGF/MET) pathway, thereby bypassing EGFR TKI inhibitors. These patients are often treated with platinum-based chemotherapy as the next line of therapy, resulting in a median Progression Free Survival of 5 months.

Amivantamab (RYBREVANT®) is a fully-human bispecific antibody directed against EGFR and MET receptors. 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. Amivantamab also engages effector cells such as Natural Killer cells, monocytes, and macrophages via its optimized Fc domain. Amivantamab demonstrated activity against a wide range of activating and resistance mutations in EGFR-mutated NSCLC, and in patients with MET exon 14 skip mutations, and is approved for the treatment of patients with EGFR exon 20 insertion mutations, whose disease progressed on or after platinum-based chemotherapy.

Lazertinib is a highly selective, third-generation TKI that penetrates the CNS, with demonstrated efficacy in activating EGFR mutations and acquired T790M “gatekeeper” point mutation. Combining Amivantamab with Lazertinib has been shown to provide a synergistic benefit by targeting the extracellular and catalytic EGFR domains. In early phase studies, Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy demonstrated an Objective Response Rate of 44% and 50% in advanced and refractory NSCLC, and in patients whose disease had progressed on prior TKIs, respectively.

MARIPOSA-2 is a global, randomized, Phase 3 trial, conducted to assess the efficacy and safety of Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone, in patients with EGFR-mutated advanced NSCLC, whose disease had progressed on or after Osimertinib monotherapy. Amivantamab is a large molecule and was not expected to readily cross the blood-brain barrier. This was one of the main reasons for the addition of Lazertinib, a known CNS-active TKI, to Amivantamab plus chemotherapy. A total of 657 patients (N=657) with EGFR-mutated (exon 19 deletions or L858R substitution mutations) locally advanced or metastatic NSCLC, after disease progression on Osimertinib, were randomized 2:2:1 to receive either Amivantamab along with Lazertinib and chemotherapy (N=263), chemotherapy alone (N=263), or Amivantamab plus chemotherapy (N=131). Patients received Amivantamab 1400 mg IV (1750 mg for body weight 80 kg or greater) weekly for the first 4 weeks, then 1750 mg (2100 mg for body weight 80 kg or greater) every 3 weeks starting at cycle 3 (week 7). The first Amivantamab infusion was split over 2 days, with 350 mg IV on cycle 1, day 1 and the remainder on cycle 1, day 2. Lazertinib was administered at 240 mg orally daily. Chemotherapy consisted of Carboplatin AUC5 IV, starting on day 1 every 3 weeks for the first 4 cycles along with Pemetrexed 500 mg/m2 IV every 3 weeks until disease progression. The median age was 62 years, 48% of patients were Asian, about 45% of patients had a history of brain metastases, and approximately 70% of patients had Osimertinib as first line treatment and 30% had Osimertinib as second line treatment. Randomization was stratified by Osimertinib line of therapy (first or second), race (Asian or non-Asian), and history of brain metastasis (yes or no). All three treatment groups were well balanced. The dual Primary endpoints were Progression Free Survival (PFS) of Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy, versus chemotherapy alone. Secondary endpoints included Objective Response Rate (ORR), Duration of Response, Overall Survival (OS) and Safety.

At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (HR for disease progression or death=0.48 and 0.44, respectively; P<0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively). The Objective Response Rate was significantly higher for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (64% and 63% versus 36%, respectively; P<0.001 for both). The median intracranial PFS was 12.5 and 12.8 versus 8.3 months for Amivantamab plus chemotherapy and Amivantamab, Lazertinib plus chemotherapy versus chemotherapy alone (HR for intracranial disease progression or death=0.55 and 0.58, respectively). The researchers postulated that the mechanism by which Amivantamab improves intracranial PFS could either be through direct antitumor effects or indirectly through immune-based mechanisms. The most common adverse events with the Amivantamab combinations were cytopenias, infusion-related reactions and venous thromboembolism. The researchers recommend prophylactic anticoagulation.

It was concluded that Amivantamab plus chemotherapy, as well as Amivantamab, Lazertinib plus chemotherapy, significantly improved Progression Free Survival (PFS) and intracranial PFS, compared with chemotherapy alone, in patients with EGFR-mutated advanced NSCLC with disease progression on or after Osimertinib. The authors added that MARIPOSA-2 is the first study to demonstrate improved PFS versus chemotherapy, after disease progression on Osimertinib.

Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: Primary results from the phase 3 MARIPOSA-2 study. Passaro A, Wang J, Wang Y, et al. Annals of Oncology. 2023. DOI:https://doi.org/10.1016/j.annonc.2023.10.117

FDA Approves Ivosidenib for Myelodysplastic Syndromes

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SUMMARY: The FDA on October 24, 2023, approved Ivosidenib (TIBSOVO®) for adult patients with Relapsed or Refractory MyeloDysplastic Syndromes (MDS) with a susceptible Isocitrate DeHydrogenase-1 (IDH1) mutation, as detected by an FDA-approved test. The FDA also approved the Abbott RealTime IDH1 Assay as a companion diagnostic device to select patients for Ivosidenib.

It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as Azacitidine and Decitabine and these agents can favorably modify the natural history of the disease, and have been shown to improve survival. However, outcomes are poor and no therapies currently exist for patients with Isocitrate Dehydrogenase 1-mutant Relapsed or Refractory MDS, following failure on a hypomethylating agent.

Isocitrate DeHydrogenase (IDH) is a metabolic enzyme that helps generate energy from glucose and other metabolites, by catalyzing the conversion of Isocitrate to Alpha-Ketoglutarate. Alpha-ketoglutarate is required to properly regulate DNA and histone methylation, which in turn is important for gene expression and cellular differentiation. IDH mutations lead to aberrant DNA methylation and altered gene expression thereby preventing cellular differentiation, with resulting immature undifferentiated cells. IDH mutations can thus promote leukemogenesis in Acute Myeloid Leukemia and tumorigenesis in solid tumors and can result in inferior outcomes. There are three isoforms of IDH. IDH1 is mainly found in the cytoplasm, as well as in peroxisomes, whereas IDH2 and IDH3 are found in the mitochondria, and are a part of the Krebs cycle. Approximately 20% of patients with AML, 70% of patients with Low-grade Glioma and secondary Glioblastoma, 50% of patients with Chondrosarcoma, 20% of patients with Intrahepatic cholangiocarcinoma, 30% of patients with Angioimmunoblastic T-cell lymphoma and 8% of patients with Myelodysplastic syndromes/Myeloproliferative neoplasms, are associated with IDH mutations.

Ivosidenib is a first-in-class, oral, potent, targeted, small-molecule inhibitor of mutant IDH1. The FDA in 2018, approved Ivosidenib for adult patients with Relapsed or Refractory AML with a susceptible IDH1 mutation, and in 2019 approved Ivosidenib for newly diagnosed AML with a susceptible IDH1 (Isocitrate DeHydrogenase-1) mutation, in patients who are at least 75 years old or who have comorbidities that preclude the use of intensive induction.

The present FDA approval is supported by a pivotal Phase 1, open-label, multinational study, in which the safety, tolerability, and clinical activity of Ivosidenib was evaluated among patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. In this study 18 eligible patients (N=18) received Ivosidenib 500 mg orally daily, continuous for 28-day cycles, until disease progression, unacceptable toxicity, or Hematopoietic Stem Cell Transplantation. The median treatment duration was 9.3 months. One patient underwent a Stem Cell Transplantation following Ivosidenib. IDH1 mutations were detected in peripheral blood or bone marrow by a local or central diagnostic test and confirmed retrospectively by the Abbott RealTime IDH1 Assay. The median age was 73 years and majority of patients had intermediate or high IPSS-R score at the time of screening for the study. The Primary efficacy end point was the Complete Response (CR) plus Partial Response (PR) rate. Secondary endpoints included duration of CR plus PR, duration of transfusion independence, and time to transfusion independence.

All observed responses were Complete Responses. The CR rate was 38.9%. The median time to Complete Response was 1.9 months and at the time of data cutoff, the median duration of Complete Responses was not estimable and ranged from 1.9 to 80.8+ months. Additionally, of the 9 patients who were transfusion dependent with Red Blood Cells or platelets at baseline, 67% became RBC and platelet transfusion independent during any 56-day post-baseline period. Of the 9 patients independent of both RBC and platelet transfusions at baseline, 78% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions included GI toxicities such as mucositis, diarrhea, constipation and nausea, fatigue, arthralgia, myalgia, cough, and rash. Differentiation syndrome was rare and manageable. It should be noted that Ivosidenib can also cause QTc prolongation.

It was concluded from this study that Ivosidenib induced durable remissions including a substantial proportion of Complete Remissions with an acceptable safety profile, in patients with Relapsed or Refractory Myelodysplastic syndromes with an IDH1 mutation. Further, a significant proportion of patients became or remained transfusion independent. This is the first targeted therapy approved for this indication.

UPDATED SUBSTUDY RESULTS FOR IVOSIDENIB IN IDH1-MUTANT RELAPSED/REFRACTORY MYELODYSPLASTIC SYNDROME. Dinardo C, Roboz G, Watts JM, et al. Hemasphere. 2023 Aug; 7(Suppl): e75740ab. DOI: 10.1097/01.HS9.0000969800.75740.ab.

ROZLYTREK® (Entrectinib)

RR

The FDA on October 20, 2023, granted accelerated approval to ROZLYTREK® for pediatric patients older than 1 month with solid tumors that have a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed following treatment or have no satisfactory standard therapy. In August 2019, FDA granted accelerated approval to ROZLYTREK® for pediatric patients 12 years of age and older for this indication. ROZLYTREK® is a product of Genentech Inc.