Category: Precision Oncology

TAGRISSO® after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC

RR

SUMMARY: The FDA on September 25, 2024, approved Osimertinib (TAGRISSO®) for adult patients with locally advanced, unresectable (Stage III) Non-Small Cell Lung Cancer (NSCLC) whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. 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 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. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.

Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.

In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. Lu S, Kato T, Dong X, et al. for the LAURA Trial Investigators. N Engl J Med. 2024;391:585-597.

FDA Grants Accelerated Approval to ZIIHERA®for Metastatic HER2-Positive Biliary Tract Cancer

RR

SUMMARY: The FDA on November 20, 2024, granted accelerated approval to Zanidatamab-hrii (ZIIHERA®), a bispecific HER2-directed antibody, for previously treated, unresectable or metastatic HER2-positive (IHC 3+) Biliary Tract Cancer (BTC), as detected by an FDA-approved test. The FDA simultaneously also approved VENTANA PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody as a companion diagnostic device to aid in identifying patients with BTC who may be eligible for treatment with Zanidatamab.

Biliary Tract Cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract Cancer and 174,000 patients will die of the disease each year globally. Biliary Tract Cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. BTCs consist of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and Ampulla of Vater cancer. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract Cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies. Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment.

BTCs are heterogenous and thus their pathogenesis and genomic drivers may vary. HER2 overexpression or gene amplification is one of the genomic drivers and HER2 overexpression rates vary depending on the anatomic origin of the Biliary Tract Cancer. Extrahepatic cholangiocarcinoma has a higher rate of HER2 overexpression (about 16-18%), compared to intrahepatic cholangiocarcinoma (about 5%), and about 10-16% for gallbladder cancers, making HER2 a potential therapeutic target in a vast majority of these patients.

Zanidatamab is a novel HER2-targeted, humanized, immunoglobulin G1 (IgG1), bispecific monoclonal antibody, that targets two distinct non-overlapping extracellular domains of HER2, ECD2 and ECD4 (biparatopic binding). This results in dual HER2 signal blockade, HER2 clustering, receptor internalization, and downregulation. This inhibits HER2 activation, HER2-mediated signaling and HER2-mediated tumor cell growth. The specific binding of Zanidatamab to tumor cells and HER2 aggregation also activates various immune-mediated responses, including Complement-Dependent Cytotoxicity (CDC), Antibody-Dependent Cellular Cytotoxicity (ADCC), and Antibody-Dependent Cellular Phagocytosis (ADCP) against tumor cells that overexpress HER2. Zanidatamab binds to HER2-expressing tumor cells with greater antibody saturation than Trastuzumab or Pertuzumab.

The present FDA approval was based on data from HERIZON-BTC-01 (NCT04466891), a pivotal Phase 2b, open-label, multicenter, single-arm trial, that evaluated the efficacy and safety of Zanidatamab in patients with HER2-positive BTC. This study included 87 patients with unresectable or metastatic HER2-positive BTC, and all patients received at least one prior Gemcitabine-containing regimen in the advanced disease setting. The median age was 64 years, 54% were women, 66% were Asian, 52% had gallbladder cancer, 30% had intrahepatic cholangiocarcinoma and 18% had extrahepatic cholangiocarcinoma. Patients received Zanidatamab at 20 mg/kg IV every two weeks in 28-day cycles.
Patients were assigned to one of two cohorts based on immunohistochemistry (IHC) status.
Cohort 1 (HER2-positive): Patients with IHC 3+ or IHC 2+ disease (N=80 total, including 62 with IHC 3+).
Cohort 2 (HER2-negative): Patients with IHC 0 or 1+ disease (N=7).
The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) as determined by an Independent Central Review.

Among the 62 patients with IHC3+ status per central assessment, the ORR was 52% and the median DOR was 14.9 months. The median Overall Survival was 18.1 months for IHC 3+ patients and 5.2 months for IHC 2+ patients. Common treatment related adverse events included diarrhea, infusion related reactions, nausea, vomiting, fatigue, and elevated liver enzymes. Treatment discontinuation rate was 2.3%.

In conclusion, the approval of Zanidatamab represents a significant advancement in the management of HER2-positive BTC and a critical unmet need. A Phase 3 trial is planned to evaluate Zanidatamab in the first-line setting for metastatic BTC.

Zanidatamab in previously-treated HER2-positive (HER2+) biliary tract cancer (BTC): Overall survival (OS) and longer follow-up from the phase 2b HERIZON-BTC-01 study. Pant S, Fan J, Oh D-Y, et al. J Clin Oncol. 2024;42(suppl 16):4091. doi:10.1200/JCO.2024.42.16_suppl.4091.

FDA Approves REVUFORJ® for Acute Leukemia with KMT2A Translocation

RR

SUMMARY: The FDA on November 15, 2024, approved Revumenib (REVUFORJ®), a menin inhibitor, for Relapsed or Refractory acute leukemia with a lysine methyltransferase 2A gene (KMT2A) translocation in adult and pediatric patients 1 year and older. The American Cancer Society estimates that in 2024, 20,800 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,220 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium. Over 50% of AML cases lack targetable mutations, relying instead on toxic chemotherapy.

Rearrangements of KMT2A gene previously known as MLL are found in 80% of infant Acute Lymphoblastic Leukemia (ALL) and in 5-15% of acute leukemia cases in children and adults, including myeloid, lymphoid, or mixed phenotypes. NPM1 mutations are the most common genetic alteration in adult Acute Myeloid Leukemia (AML), occurring in up to 30% of cases. Acute leukemias with KMT2A rearrangements have a poor prognosis, with a 5-year overall survival rate of less than 25%. There are no targeted therapies currently approved specifically for acute leukemia with KMT2A gene rearrangements or NPM1 mutations. Both KMT2A gene rearrangements and NPM1 mutations cause blood cells to regress to a stem-cell-like state, leading to the formation of leukemia cells. For leukemias driven by KMT2A gene rearrangements and NPM1 mutations, menin is a critical oncogenic cofactor. Menin interacts with the protein MLL1 (produced by KMT2A), forming a menin–MLL1 complex. This complex binds to chromatin and activates aberrant gene pathways, specifically HOX genes and their cofactor MEIS1, critical for leukemia development.

Revumenib is a potent, oral, small molecule menin inhibitor. It blocks the menin–MLL1 interaction, preventing the formation of the menin–MLL1 complex. By disrupting this complex, Revumenib stops the aberrant activation of HOX and MEIS1 gene expression and allows leukemia cells to either die or differentiate back into normal blood cells. Unlike other targeted therapies that block dysfunctional proteins, Revumenib prevents aberrant gene expression at its source. Its ability to target a common mechanism in AML makes it broadly applicable. Preclinical Studies demonstrated that menin inhibition reverses leukemia progression by downregulating HOX and MEIS1 transcription disrupting oncogenic complexes formed by either option for patients with KMT2A gene arrangements or NPM1-mutated AML. Revumenib showed dramatic antileukemic activity, making this agent promising.

AUGMENT-101 is a single-arm cohort of an open-label, multicenter trial which included 104 adult and pediatric patients (at least 30 days old) with Relapsed or Refractory (R/R) acute leukemia with a KMT2A translocation. Eligible patients had a corrected QT interval of less than 450 milliseconds and those with an11q23 partial tandem duplication were excluded. Revumenib was administered at a dose that was approximately equivalent to 160 mg in adults orally twice daily. Treatment was continued until progressive disease, unacceptable toxicity, failure to achieve a morphological leukemia-free state by 4 cycles of treatment, or Hematopoietic Stem Cell Transplantation (HSCT). The median patient age was 37 years, 83% of patients had AML, 15% had Acute Lymphoblastic Leukemia, and 2% had mixed phenotype acute leukemia. Approximately 59% had relapsed/refractory disease, 21% had primary refractory disease, 20% of patients had untreated relapsed disease and 44% of patients underwent prior HSCT. The main efficacy outcome measures were Complete Remission (CR) plus CR with partial hematologic recovery (CRh), the duration of CR plus CRh, and conversion from transfusion dependence to independence.

The CR plus CRh rate was 21.2%, and the median CR plus CRh duration was 6.4 months. Of the 22 patients achieving CR or CRh, the median time to CR or CRh was 1.9 months. Among the 83 patients dependent on RBC and/or platelet transfusions at baseline, 14% became independent of RBC and platelet transfusions during any 56-day post-baseline period. Of the 21 patients independent of both RBC and platelet transfusions at baseline, 48% remained transfusion independent during any 56-day post-baseline period. The most common adverse reactions noted in this study were hemorrhage, nausea, increased phosphate, musculoskeletal pain, neutropenia, infection, elevated liver enzymes, differentiation syndrome, QT prolongation and fatigue.

It was concluded that Revumenib is the first menin inhibitor and its efficacy represents a substantial improvement over previously available therapies, and represents a major breakthrough for patients with Relapsed or Refractory acute leukemia with a KMT2A translocation.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-revumenib-relapsed-or-refractory-acute-leukemia-kmt2a-translocation

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

RR

SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early-stage melanoma.

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

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

TAFINLAR® (Dabrafenib) is a selective oral BRAF inhibitor and MEKINIST® (Trametinib) is a potent and selective inhibitor of MEK gene, which is downstream from RAF in the MAPK pathway. In patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, a combination of TAFINLAR® and MEKINIST® resulted in a median Overall Survival (OS) of more than 2 years, with approximately 20% of the patients remaining progression free at 3 years. These encouraging results led to the study of this combination in patients with Stage III melanoma, with BRAF V600E or V600K mutations, after complete surgical resection.

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

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

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

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

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

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

RR

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

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

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

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

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

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

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

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

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

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

ENHERTU® Effective Against Brain Metastases in Patients with HER2+ Breast Cancer

RR

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. It is estimated 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Patients with high levels of HER2 expression (IHC 3+ or 2+/FISH positive) are classified as HER2-positive. Patients with HER2-positive metastatic breast cancer are often treated with anti-HER2 targeted therapy along with chemotherapy, irrespective of hormone receptor status, and this has resulted in significantly improved treatment outcomes.

With advances in systemic therapies for this patient population, the incidence of brain metastases as a sanctuary site has increased. Approximately 50% of patients with HER2-positive metastatic breast cancer develop brain metastases which result in a significantly worse prognosis compared to those without brain metastases. Local therapeutic interventions for brain metastases include neurosurgical resection and Stereotactic or Whole-Brain Radiation Therapy. However, CNS progression usually occurs within 6-12 months post-treatment. Furthermore, Whole-Brain Radiation Therapy, while commonly used for multiple brain metastases, is linked with cognitive decline, which is a particular concern for HER2+ breast cancer patients who can live several years after their diagnosis.

With regards to systemic treatment options for brain metastases, various other HER2-directed therapies have been explored including Tucatinib (TUKYSA®), which can cross the blood brain barrier. Tucatinib combined with Trastuzumab and Capecitabine is currently the preferred systemic treatment for HER2+ metastatic breast cancer patients with active brain metastases. The HER2CLIMB study investigated this combination in patients who had been previously treated. In patients with measurable brain metastasis at baseline, those receiving Tucatinib combined with Capecitabine, and Trastuzumab showed a confirmed intracranial Objective Response Rate (ORR) of 47.3%. CNS Progression-Free Survival (PFS) was 9.9 months for all patients and 9.6 months for those with active brain metastases.

Trastuzumab Deruxtecan-T-DXd (ENHERTU®) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). T-DXd has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike ado-Trastuzumab emtansine (KADCYLA®), another ADC targeting HER2, T-DXd has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, thus minimizing systemic exposure.

T-DXd has also shown promising intracranial activity in several studies, such as DESTINY-Breast01, 02, and 03, as well as the ongoing DESTINY-Breast07 and the DEBBRAH study, among others. These studies reported encouraging responses in patients with active brain metastases, suggesting potential efficacy in this difficult-to-treat population.

DESTINY-Breast12 is an open-label, multicentre, Phase IIIb/IV 2-cohort, non-comparative clinical trial designed to evaluate the efficacy and safety of T-DXd 5.4 mg/kg in patients with previously treated advanced/metastatic HER2-positive breast cancer. This study included two cohorts – patients without brain metastases (Cohort 1) and patients with brain metastases (Cohort 2), who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline. A total of 504 eligible patients (N=504) were enrolled across multiple sites of whom 263 patients had baseline brain metastases, and 241 patients had no baseline brain metastases. All patients received T-DXd 5.4 mg per kg every three weeks until disease progression or unacceptable toxicity occurred. Notably, patients with leptomeningeal metastases were excluded, as well as those who had received Tucatinib in prior treatments, to avoid confounding effects from a drug known to affect CNS lesions. The study allowed the inclusion of patients with stable or active brain metastases (previously treated and progressing), though it excluded those with no clinical indication for immediate retreatment of their brain metastases. Tumor assessments were performed regularly using MRI or CT scans. The Primary endpoint of Cohort 1 (non-brain metastases cohort) was Objective Response Rate (ORR) as assessed by Independent Review and the Primary endpoint of Cohort 2 (brain metastases cohort) was Progression-Free Survival (PFS). Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and Safety.

Results showed a 12-month PFS rate of 61.6% for patients with brain metastases, with CNS-specific PFS of 58.9%. Those with stable brain metastases had a 12-month PFS of 62.9%, while patients with active brain metastases had a 12-month CNS PFS of 60.1%. For patients without brain metastases at baseline, the ORR was 62.7%, with a significant proportion achieving Partial or Complete Responses. A post-hoc analysis revealed a CNS ORR of 82.6% in patients with active brain metastases who had not undergone prior local CNS therapy and 50% in those who had progressed after prior local CNS treatments. Importantly, the safety profile of T-DXd was consistent with prior studies, though Interstitial Lung Disease (ILD) or pneumonitis occurred in approximately 13-16% of patients, with a small percentage experiencing Grade 5 (fatal) events.

In summary, the DESTINY-Breast12 study highlights the efficacy of Trastuzumab deruxtecan in treating HER2+ metastatic breast cancer, particularly in patients with brain metastases. These findings provide valuable insights into managing a challenging subset of breast cancer patients who often experience poor outcomes due to CNS progression. Further research is warranted to refine treatment strategies, especially for patients with ILD risk factors, and to explore potential combinatory regimens for long-term CNS control.

Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Harbeck, N., Ciruelos, E., Jerusalem, G. et al .for the the DESTINY-Breast12 study group. Nat Med (2024). https://doi.org/10.1038/s41591-024-03261-7

FDA Approves RYBREVANT® plus Chemotherapy for EGFR-Mutated NSCLC

RR

SUMMARY: The FDA on September 19, 2024 approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for adult patients with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor. 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 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.

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.

The efficacy of Amivantamab was assessed in the Phase 3 MARIPOSA-2 trial, a multicenter, open-label study involving 657 patients. These participants, all with EGFR-mutant NSCLC, who had progressed on Osimertinib treatment, were randomly assigned in a 1:2:2 ratio to receive either Amivantamab with Carboplatin and Pemetrexed (referred to as Amivantamab plus chemotherapy-N=131), Carboplatin and Pemetrexed alone (chemotherapy alone-N=263), or Amivantamab combined with other regimens (N=263). Eligible patients had documented presence of EGFR exon 19 deletion or exon 21 L858R mutation and experienced disease progression after receiving Osimertinib as their most recent line of therapy. 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. Chemotherapy consisted of Carboplatin AUC 5 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 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), and race (Asian or non-Asian). All three treatment groups were well balanced. The Primary endpoint of the study was Progression-Free Survival (PFS), assessed by Blinded Independent Central Review (BICR). Key Secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), Time to Treatment Discontinuation (TTD), Time to Subsequent Therapy (TTST), Progression-Free Survival after first subsequent therapy (PFS2) and Time to Symptomatic Progression (TTSP).

At a median follow-up of 8.7 months, the PFS was significantly longer for Amivantamab plus chemotherapy versus chemotherapy alone. The median PFS was 6.3 months in the Amivantamab plus chemotherapy group and 4.2 months in the chemotherapy alone group (HR for disease progression or death=0.48; P<0.0001), indicating a a 52% reduction in the risk of progression or death. The ORR was significantly higher in the Amivantamab plus chemotherapy group at 53%, compared to 29% in the chemotherapy alone group (P<0.0001).

In the prespecified second interim analysis, a numerical improvement in OS was noted for the Amivantamab plus chemotherapy group with a median OS of 17.7 months compared to 15.3 months for the chemotherapy alone group (HR=0.73; P=0.039). However, this did not meet the prespecified significance level.

With regards to Post-Progression Endpoints, the median TTD was significantly longer in the Amivantamab plus chemotherapy group versus chemotherapy alone group (10.4 months versus 4.5 months; HR=0.42; P<0.0001). The Median TTST was also prolonged in the Amivantamab plus chemotherapy group versus chemotherapy alone group (12.2 months compared to 6.6 months HR=0.51; P< 0.0001). The median PFS2 was significantly longer in the Amivantamab plus chemotherapy group compared to the chemotherapy alone group (16.0 months versus 11.6 months (HR= 0.64; P=0.002). Common adverse reactions observed in patients receiving Amivantamab plus chemotherapy included rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19 infection.

In conclusion, the results from the MARIPOSA-2 trial provide compelling evidence for the use of Amivantamab in combination with Carboplatin and Pemetrexed in the treatment of advanced EGFR-mutant NSCLC post-Osimertinib progression. While the PFS outcomes were significantly improved, the OS benefits, promising as they may be, require further follow-up for conclusive results. The final Overall Survival analysis will be eagerly awaited, as it will further illuminate the long-term efficacy of this treatment approach.

Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Popat S, Reckamp KL, Califano R, et al. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. LBA54.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

RR

SUMMARY: Colorectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 153,020 new cases of CRC were diagnosed in the United States in 2023 and about 52,550 patients died 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 colorectal cancer 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). These therapies however have shown limited efficacy.

The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.

Sotorasib (LUMAKRAS&reg;) is a small molecule that specifically and irreversibly inhibits KRAS G12C protein and traps KRAS G12C in the inactive GDP-bound state, thus blocking downstream proliferation and survival signaling. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation. In the CodeBreaK 101 Phase 1b trial involving patients with chemorefractory colorectal cancer with mutated KRAS G12C, the Response Rate was 30% with Sotorasib plus Panitumumab, as compared with 9.7% with Sotorasib monotherapy.

CodeBreaK 300 trial is an international, multicenter, open-label, randomized, active-controlled Phase III study, conducted to evaluate the efficacy and safety of two different doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab as compared with the investigator’s choice of standard-care therapy (Trifluridine-Tipiracil or Regorafenib) in patients with chemorefractory metastatic colorectal cancer with KRAS G12C mutation. A lower dose of Sotorasib 240 mg orally once daily was tested in this study because of the nonlinear pharmacokinetic properties of Sotorasib. A total of 160 patients were randomly assigned in a 1:1:1 ratio to receive Sotorasib 960 mg orally once daily plus Panitumumab 6 mg/kg IV every 2 weeks (the 960 mg Sotorasib/Panitumumab group; N=53), Sotorasib 240 mg orally once daily plus Panitumumab (the 240 mg Sotorasib/Panitumumab group; N=53), with each treatment cycle repeating every 28 days, or the investigator’s choice of standard of care therapy which could be either Trifluridine-Tipiracil 35 mg/m2 (up to a maximum of 80 mg per dose) orally twice daily on days 1-5 and days 8-12 every 28 days, or Regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle (N=54). Treatment continued until disease progression or unacceptable toxicities. The median age was 61 years and majority of patients had more than 2 or more lines of previous anti-cancer therapy. KRAS G12C mutation was confirmed by prospective central molecular testing. Randomization was stratified according to previous use of antiangiogenic therapy, the time from initial diagnosis of metastatic disease to randomization and ECOG-PS. The Primary end point was Progression Free Survival (PFS) as assessed by Blinded Independent Central Review (BICR). Key Secondary end points included Overall Survival (OS) and Objective Response Rate (ORR).

After a median follow up of 7.8 months, both Sotorasib combinations (960 mg and 240 mg) plus Panitumumab demonstrated significantly longer PFS compared to standard of care therapy. The median PFS was 5.6 months and 3.9 months in the 960 mg Sotorasib/Panitumumab and 240 mg Sotorasib/Panitumumab groups, respectively, as compared with 2.2 months in the standard of care group (HR for 960 mg group=0 49; P=0.006) (HR for 240 mg group=0.58; P=0.03). The improvement in PFS was observed across key subgroups, including tumor sideness/primary tumor location, prior lines of therapy, and the presence or absence of liver metastases. The Objective Response Rate was 26.4%, 5.7%, and 0% in the 960 mg Sotorasib/Panitumumab, 240 mg Sotorasib/Panitumumab, and standard of care groups, respectively. Overall survival data is immature. While this trial was not powered to compare the two Sotorasib/Panitumumab groups directly, the 960-mg dose appeared to yield more clinically significant benefits than the 240-mg dose, across all efficacy endpoints, without additional toxic effects. Grade 3 or higher treatment-related adverse events occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with Sotorasib/Panitumumab.

It was concluded from this study that both doses of Sotorasib (960 mg and 240 mg) in combination with Panitumumab resulted in significantly longer Progression Free Survival and a higher incidence of Response Rate than standard treatment. Ongoing analysis and longer follow up will provide additional insights into Overall Survival outcomes.

Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. Fakih MG, Salvatore L, Esaki T, et al. N Engl J Med 2023;389:2125-2139.

TAGRISSO® after Chemoradiotherapy in Stage III EGFR Mutated 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 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. Approximately one third of all patients with NSCLC have Stage III, locally advanced disease at the time of initial presentation and 60 to 90% of these patients have unresectable disease. These patients are treated with concurrent chemoradiotherapy (CRT) followed by consolidation therapy with Durvalumab (IMFINZI®) in patients without progression, as this regimen confers an Overall Survival advantage, and is considered the standard of care (PACIFIC trial).

EGFR (Epidermal Growth Factor Receptor) mutations are found in up to one third of patients with unresectable Stage III NSCLC. There are currently no approved targeted treatments for patients with unresectable Stage III EGFR-mutated NSCLC. The current standard of care, which includes consolidation therapy with Durvalumab, may not offer clear benefits to this subset of patients with EGFR mutations.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (TKI), presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Osimertinib is also approved by the FDA as adjuvant treatment for resected Stage IB–IIIA EGFR-mutated NSCLC. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

LAURA was a global, randomized, double-blind, placebo-controlled, multicenter Phase III trial conducted to assess the efficacy and safety of Osimertinib in patients with unresectable Stage III NSCLC harboring EGFR mutations (EGFR exon 19 deletion or exon 21 L858R mutation). The trial enrolled patients who had not experienced disease progression during or after definitive platinum-based chemoradiotherapy (CRT). A total of 216 patients who had undergone CRT were randomly assigned 2:1 to receive Osimertinib 80 mg orally once daily (N=143) or placebo once per day (N=73). Treatment was continued until Blinded Independent Central Review (BICR)–assessed disease progression, unacceptable toxicity, or other discontinuation criteria were met. Upon disease progression, patients in the placebo arm were permitted to receive Osimertinib, allowing for crossover therapy. Stratification factors included method of CRT (concurrent versus sequential) and disease Stage (IIIA versus IIIB/C). Both treatment groups were well balanced. The median patient age was 63 years, approximately 60% of participants were female, 83% were Asian, 69% had never smoked and 85% had Stage IIIA and B disease. Majority of patients received concurrent CRT rather than sequential CRT. The Primary end point was Progression Free Survival (PFS) as assessed by BICR. Key Secondary end points included Overall Survival (OS), survival without progression of CNS disease (CNS Progression Free Survival), Objective Response Rate (ORR), Duration of Response, Quality of Life, and Safety.

Treatment with Osimertinib resulted in significant PFS improvement compared to placebo. The median PFS was 39.1 months in the Osimertinib group versus 5.6 months in the placebo group, representing an 84% reduction in the risk of disease progression or death (HR=0.16; P<0.001). Additionally, a higher percentage of patients in the Osimertinib group remained alive and progression-free at 12 months compared to the placebo group (74% versus 22% respectively). Subgroup analyses were conducted to evaluate the consistency of treatment effects across various demographic and clinical factors. The benefits of Osimertinib were observed across all prespecified subgroups, indicating a consistent treatment effect, regardless of patient characteristics. The incidence of new lesions was lower with Osimertinib compared to placebo (22% versus 68%), and this included new brain lesions (8% versus 29%) and new lung lesions (6% versus 29%) respectively. The Objective Response Rate was higher with Osimertinib than with placebo (57% versus 33%). The median Duration of Response was longer with Osimertinib (36.9 months) than with placebo (6.5 months). Interim OS data showed a favorable trend for Osimertinib, although maturity was limited at the time of analysis. Further follow-up will be conducted to assess OS as a secondary endpoint. The adverse event profile of Osimertinib was generally consistent with previous studies. Grade 3 or higher adverse events occurred more frequently in the Osimertinib group, with radiation pneumonitis being the most common. However, no new safety concerns emerged during the trial.

In summary, treatment with Osimertinib resulted in significantly longer Progression Free Survival than placebo in patients with unresectable Stage III EGFR-mutated NSCLC following definitive CRT, and should be considered the new standard of care for this group of patients. Overall, the LAURA study represents a major breakthrough in the treatment of EGFR-mutated Stage III NSCLC, addressing an unmet need for targeted therapies in this setting. Further follow-up will provide additional insights into the long-term efficacy and safety of Osimertinib in this patient population.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC. Lu S, Kato T, Dong X, et al. for the LAURA Trial Investigators. N Engl J Med 2024;391:585-597

Late Breaking Abstract – ASCO 2024: Sustained Improvement in Relapse Free Survival with Personalized mRNA Cancer Vaccine plus KEYTRUDA® in Resected High Risk Melanoma

RR

SUMMARY: The American Cancer Society estimates that for 2024, about 100,640 new cases of melanoma of the skin will be diagnosed in the United States and 8,290 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.

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

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk resected melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab (KEYTRUDA®) was 55.4% versus 38.3% with placebo. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab (OPDIVO®) versus 41.2% for ipilimumab (YERVOY®). Given the high relapse rates with the present adjuvant melanoma therapies, there is an unmet clinical need.

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. 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.

mRNA-4157 (V940) is a novel messenger RiboNucleic Acid (mRNA)-based individualized neoantigen therapy consisting of a single synthetic mRNA coding for up to 34 neoantigens, that is designed and produced based on the unique mutational signature of the DNA sequence of the patients tumor. Individualized neoantigen therapies are designed to prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) was designed to stimulate an immune response by generating specific T cell responses based on the unique mutational signature of a patients tumor. Early clinical studies demonstrated that combining mRNA-4157 (V940) with Pembrolizumab may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.

KEYNOTE-942 is an ongoing randomized, open-label, Phase IIb trial, designed to evaluate the efficacy and safety of mRNA-4157, an individualized neoantigen therapy, in combination with Pembrolizumab, in patients with completely resected high-risk Stage III/IV cutaneous melanoma. This study included 157 patients who were randomly assigned (2:1) to receive mRNA-4157 in combination with Pembrolizumab (N=107) or Pembrolizumab alone (N=50). The vaccine was administered 1 mg every three weeks for a total of nine doses, and Pembrolizumab was given at 200 mg IV every three weeks for up to 18 cycles (approximately one year). All patients had tumor sample (Formalin Fixed Paraffin Embedded-FFPE) available for Next Generation Sequencing and patients were stratified by disease stage. mRNA-4157 was successfully prepared for more than 99% of patients in the combination arm. The median patient age was 62 years and 84% of patients had Stage IIIC disease. Approximately 64% of patients were PD-L1 positive and 74% had high Tumor Mutational Burden-TMB (10 or more mutations/Mb) in the combination treatment group, whereas 54% were PD-L1 positive and 60% had high TMB in the single agent Pembrolizumab group, respectively. HLA genotyping was performed to explore associations between specific HLA alleles and treatment response. Additionally, subgroup analyses were conducted based on TMB, PD-L1 expression, and circulating tumor DNA (ctDNA) status.

The Primary endpoint was Relapse Free Survival (RFS), defined as the time from first dose of Pembrolizumab until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause. Secondary endpoints included Distant Metastasis-Free Survival and Safety. Exploratory endpoints included distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint.

At a median follow up of 23 months for the mRNA-4157/V940 plus Pembrolizumab group, and 24 months for Pembrolizumab alone group, the Relapse Free Survival at 18 months was 78.6% for the immunotherapy combination versus 62.2% for Pembrolizumab alone (HR=0.56; P=0.0266), and this equated to a 44% reduction in the risk of recurrence or death with 2 years of follow-up. mRNA-4157/V940 and Pembrolizumab combination treatment demonstrated an improvement in RFS, irrespective of PD-L1 status and TMB status.

In the recent data presented at ASCO 2024, with an additional year of planned follow-up, at a median of approximately 34.9 months, the combination of mRNA-4157 and Pembrolizumab demonstrated a significant clinically meaningful and durable improvement in RFS, the Primary endpoint of the study, compared to Pembrolizumab alone. The risk of recurrence or death was reduced by 49% (HR=0.51; P=0.019), compared to Pembrolizumab monotherapy. The 2.5-year RFS rate for the combination group was 74.8% compared to 55.6% in the Pembrolizumab alone group. The RFS improvement was observed across subgroups irrespective of TMB and PD-L1 levels.

The combination therapy also showed a meaningful improvement in Distant Metastasis-Free Survival, which was a key Secondary endpoint, compared to Pembrolizumab alone (HR=0.38; P=0.015). This represented a 62% reduction in the risk of developing distant metastases or death compared to Pembrolizumab alone.

While not formally tested as a Primary endpoint, Overall Survival trended favorably with the combination therapy, with a 2.5-Year OS Rate of 96.0% for combination versus 90.2% for Pembrolizumab alone (HR=0.425).

The safety profile of mRNA-4157 in combination with Pembrolizumab was consistent with previous analyses and the common adverse events were fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). Grade 3 or higher adverse events occurred in 25% of patients receiving combination therapy and 18% in the Pembrolizumab alone group. Immune-related adverse events were reported by approximately 37.5% of patients in the combination group and 36% in the Pembrolizumab alone group, with no new safety signals identified.

The KEYNOTE-942 trial demonstrated that mRNA-4157 in combination with Pembrolizumab significantly improved Recurrence-Free Survival and Distant Metastasis-Free Survival in patients with resected high-risk Stage III/IV melanoma, compared to Pembrolizumab alone. These findings suggest a potential benefit across various patient subgroups based on TMB, PD-L1 expression, and ctDNA status. The safety profile was manageable and consistent with expectations for both treatments. Based on these positive results, further investigation in the Phase III INTerpath-001 trial is underway to validate these findings and potentially transform the adjuvant treatment landscape for melanoma patients.

Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial.Weber JS, Khattak MA, Carlino MS, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA9512). DOI 10.1200/JCO.2024.42.17_suppl.LBA9512