Tag: Lung Cancer: Non-Small Cell

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

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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 Perioperative KEYTRUDA® for Resectable Early Stage Non Small Cell Lung Cancer

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SUMMARY: The FDA on October 16, 2023, approved KEYTRUDA® (Pembrolizumab) with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent KEYTRUDA® as post-surgical adjuvant treatment for resectable (tumors 4 cm or more or node positive) Non-Small Cell Lung Cancer (NSCLC). 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 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 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. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

The present FDA approval was based on the KEYNOTE-671 trial, which is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival (OS). Secondary end points included major pathological response, pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. The Event-Free Survival (EFS) at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group. The median EFS was not reached in the Pembrolizumab group and was 17.0 months in the placebo group (HR=0.58; P<0.001). The EFS benefit with Pembrolizumab was consistent across all subgroups examined. The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02) at this first interim analysis.

A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Adjuvant KEYTRUDA® in Resected NSCLC Irrespective of PD-L1 Expression

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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 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. 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.

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The dual Primary endpoints were Disease-Free Survival (DFS) in the overall population and in the population with PD-L1 Tumor Proportion Score (TPS) of 50% or greater. An additional efficacy outcome was Overall Survival (OS). The median follow up for this interim analysis was 35.6 months.

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In the overall population, median DFS was 53.6 months in the KEYTRUDA® group versus 42.0 months in the placebo group (HR=0.76; P=0.0014), reducing the risk of disease recurrence or death by 24% versus placebo, regardless of PD-L1 expression. In the PD-L1 TPS of 50% or greater population, median DFS was not reached in either the KEYTRUDA® group or the placebo group. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage Non Small Cell Lung Cancer following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091):an interim analysis of a randomised, triple-blind, phase 3 trial. O’Brien M, Paz-Ares L, Marreaud S, et al. Lancet Oncol. 2022;10:1274-1286.

Osimertinib Plus Chemotherapy Superior to Osimertinib Alone in Advanced EGFR Mutated Non Small Cell Lung Cancer

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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 (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor 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. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.

In the Phase III FLAURA trial, among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with Osimertinib significantly improved median Overall Survival, compared with Erlotinib and Gefitinib, and should therefore has been the preferred regimen in this patient group. The FLAURA2 trial builds on the favorable results observed in the Phase III FLAURA trial.

FLAURA2 is a randomized, open-label, multi-center, global, ongoing Phase III trial, in which 557 enrolled treatment naïve patients (N=557) with nonsquamous locally advanced (Stage IIIB-IIIC) or metastatic EGFR mutated NSCLC were randomly assigned 1:1 to receive Osimertinib plus chemotherapy (N=279) or Osimertinib monotherapy (N=278). Patients in the combination group received Osimertinib 80 mg oral tablets once daily in combination with chemotherapy consisting of Pemetrexed 500 mg/m2 IV plus Cisplatin 75 mg/m2 IV or Carboplatin (AUC5), every three weeks for four cycles, followed by Osimertinib with Pemetrexed maintenance every three weeks. The median patient age was 62 years, approximately 62% were women and 64% were Asian. Approximately 76% of patients completed four cycles of platinum therapy. The Primary end point was investigator-assessed Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety.

In this final analysis of the Primary endpoint of PFS, results from this study showed a significant improvement in Progression Free Survival (PFS) with the Osimertinib plus chemotherapy combination versus Osimertinib alone, with an 8.8-month improvement in median PFS with the combination regimen (HR=0.62; P<0.0001). This represented a 38% reduction in disease progression risk, compared to Osimertinib monotherapy. In addition, median PFS determined by blinded Independent Central Review showed a 9.5-month improvement with the combination regimen. The Objective Response Rate with the combination regimen was 83%, compared to 76%, in the Osimertinib monotherapy group. Grade 3 or higher hematologic adverse events occurred more frequently in the combination regimen group and were manageable. Data for Overall Survival were immature at the time of the analysis, and this ongoing trial will continue to assess the Secondary endpoint of Overall Survival.

The authors concluded that FLAURA2 provides compelling evidence that the addition of chemotherapy to Osimertinib in the first line treatment of nonsquamous, locally advanced or metastatic EGFR mutated NSCLC, can further improves outcomes, compared to Osimertinib alone, and can delay resistance to therapy and disease progression.

FLAURA2 results demonstrate osimertinib plus chemotherapy superior compared to osimertinib alone (press release). Available at: https://www.iaslc.org/iaslc-news/press-release/flaura2-results-demonstrate-osimertinib-plus-chemotherapy-superior. Published Sept.10, 2023.

FDA Approves Pralsetinib for Non Small Cell Lung Cancer with RET gene fusions

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SUMMARY: The FDA on August 9, 2023, granted regular approval to Pralsetinib (GAVRETO®) for adult patients with metastatic Rearranged during Transfection (RET) fusion-positive Non-Small Cell Lung Cancer (NSCLC) as detected by an FDA approved test. Pralsetinib was previously granted accelerated approval for the NSCLC indication in Sept. 2020, based on initial Overall Response Rate (ORR) and Duration of Response (DOR) in 114 patients enrolled in the ARROW trial. The conversion to regular approval was based on data from an additional 123 patients and 25 months of additional follow up, to assess Durability of Response.

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 accounts for approximately 85% of all lung cancers.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, MET, KRAS, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

Patients without a driver mutation are often treated with a platinum-doublet cytotoxic chemotherapy with/without Immune checkpoint inhibitors, or with Immune checkpoint inhibitor monotherapy. However, outcomes with immune checkpoint inhibitors remain poor in patients with RET fusion–positive NSCLC, regardless of PD-L1 expression.

Pralsetinib (GAVRETO®) is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of Pralsetinib was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either, Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). Phase I Pralsetinib dose escalation study determined 400 mg QD as the recommended Phase II trial dose. Phase II trial evaluated Pralsetinib in multiple expansion groups, defined by disease type and treatment history.

The FDA regular approval was based on the efficacy of Pralsetinib in a total of 237 patients (N=237) with locally advanced or metastatic RET fusion-positive NSCLC. Patients received Pralsetinib 400 mg once daily until disease progression or unacceptable toxicity. Among the patients studied, 107 (N=107) were treatment-naïve and 130 patients (N=130) were previously treated with platinum-based chemotherapy. The main efficacy outcome measures were Overall Response Rate (ORR) and Duration of Response, as determined by a Blinded Independent Review Committee, using RECIST criteria.

The median age of the 107 patients in the treatment-naïve group was 63 years and 28% of patients had a history of or active CNS/brain metastases. The ORR in this group was 78%, with a Complete Response (CR) rate of 7%. The median Duration of Response was 13.4 months and 45% of patients experienced a Duration of Response of 12 months or longer.

The median age of the 130 patients in the group that was previously treated with platinum-based chemotherapy, was 59 years and 41% had a history of or active CNS/brain metastases. The ORR in this group was 63% with a CR rate of 6%. The median Duration of Response of 38.8 months and 66% of patients experienced a Duration of Response of at least 12 months.

In patients with measurable intracranial metastases, the intracranial response rate was 70%.

The most common adverse reactions were fever, fatigue, cough, constipation, diarrhea, musculoskeletal pain, hypertension and edema.

It was concluded from this study that treatment with Pralsetinib produced robust efficacy including intracranial activity, in patients with advanced RET fusion–positive NSCLC who are treatment-naive or are refractory to standard-of-care chemotherapy. Results from the confirmatory Phase III AcceleRET Lung study of Pralsetinib versus standard of care in the first-line setting are eagerly awaited and may further support the use of Pralsetinib for RET fusion-positive NSCLC in the first-line setting.

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions

Perioperative Pembrolizumab for Early Stage Non Small Cell Lung Cancer

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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 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 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.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

KEYNOTE-671 trial is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival. Secondary end points included major pathological response, Pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. Event-Free Survival at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group (HR=0.58; P<0.001). The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02). A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and Pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Late Breaking Abstract – ASCO 2023: Tumor Treating Fields Plus Standard of Care Improves Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer

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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.

Tumor Treating Fields (TTFields) delivery system is a non-invasive novel external therapeutic device that slows and reverses tumor growth by disrupting mitosis. The battery operated portable at-home TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields delivered locoregionally to the tumors through 2 pairs of arrays applied to the chest. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Patients wear the device for at least 18 hours a day and for at least four weeks. Currently, TTF therapy is approved for Glioblastoma and Malignant Pleural Mesothelioma. Preclinical NSCLC studies have shown that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. Further, TTFields synergize with taxanes and Immune Checkpoint Inhibitors (ICIs). This was the rationale for the development and design of the LUNAR Phase III trial.

The LUNAR study is a global, randomized, Phase III trial in which the safety and efficacy of Tumor Treating Fields therapy with Standard of Care, was compared to Standard of Care alone, in patients with metastatic Non Small Cell Lung Cancer (NSCLC), who had progression on or after Platinum-based chemotherapy. In this study, 276 eligible patients (N=276) were randomized 1:1 to receive either Tumor Treating Fields therapy (150 kHz) plus Standard of Care, which included investigator’s choice of an Immune Checkpoint Inhibitor (ICI) or Docetaxel, or Standard of Care alone. To be eligible for this study, patients had to be 22 years or older, have metastatic NSCLC, should have progressed on or after a platinum-based therapy, and have an ECOG performance status of 0-2. Both treatment groups were well balanced. The median age was 64 years, 65% were male, 96% of patients had an ECOG PS of 0-1, 56% had non-squamous histology, 89% had one prior line of systemic therapy and 31% received prior therapy with ICI. Patients were followed every 6 weeks and continued on therapy until disease progression or intolerable toxicities. The Primary endpoint was Overall Survival (OS). Secondary endpoints included were OS in ICI and Docetaxel subgroups, Progression Free Survival (PFS) and toxicities.

This study met its Primary end point of Overall Survival and OS was significantly extended with Tumor Treating Fields therapy plus Standard of Care versus Standard of Care. After a minimum follow up of 12 months, the median Overall Survival with Tumor Treating Fields therapy plus Standard of Care was 13.2 months versus 10.0 months with Standard of Care alone (HR=0.74; P=0.037) and 1-year survival rates were 53% and 42% respectively (P=0.040). In patients receiving an Immune Checkpoint Inhibitor (N=134), the addition of Tumor Treating Fields therapy significantly improved median OS versus ICI alone (18.5 months versus 10.6 months; HR=0.63; P=0.032). In those patients treated with Docetaxel, the median OS was numerically higher at 11.1 months with Tumor Treating Fields therapy plus Docetaxel versus 8.9 months with Docetaxel alone (HR=0.87). There was no significant difference in the median PFS between the two treatment groups and were 4.8 months and 4.1 months respectively. The rate of Adverse Events was similar between the treatment groups and majority of the Tumor Treating Fields associated toxicities were Grade 1 and 2 local skin irritations.

The authors concluded that in this Phase III study, the addition of Tumor Treating Fields therapy to Standard of Care therapy significantly extended Overall Survival in patients with metastatic NSCLC following platinum failure, without increasing systemic toxicities, and Tumor Treating Fields therapy may be a potentially paradigm-shifting new treatment modality.

Tumor treating fields (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized phase 3 LUNAR study. Leal T, Kotecha R, Ramlau R, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA9005)