Tag: Lung Cancer: Non-Small Cell

SUMMARY: The FDA on November 15, 2023, approved AUGTYRO® (Repotrectinib) for locally advanced or metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This is the first FDA approval that includes patients with ROS1-positive NSCLC who have previously received a ROS1 Tyrosine Kinase Inhibitor (TKI), in addition to patients who are TKI naïve.

Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years), and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. There are currently two FDA-approved treatment options for ROS1-positive metastatic NSCLC- Crizotinib and Entrectinib.

Repotrectinib is a next-generation TKI targeting ROS1 or NTRK-positive locally advanced or metastatic solid tumors, including NSCLC. Repotrectinib was designed to improve durability of response and with favorable properties to enhance intracranial activity.

The FDA approval was based on the results of the TRIDENT-1 global, multicenter, single-arm, Phase I/II, open-label, multi-cohort clinical trial, designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib, in patients with advanced solid tumors, including locally advanced or metastatic NSCLC. Phase I component of the trial evaluated the safety and pharmacokinetics, whereas in the Phase II component of the study included six distinct expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Eligibility requirements included locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Patients with asymptomatic CNS metastases were allowed. Patients received Repotrectinib 160 mg once daily, orally for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicities. The Primary endpoint was Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR), and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and Clinical Benefit Rate (CBR). The efficacy was evaluated in ROS1 TKI-naïve patients (N=71) who received up to one prior line of platinum-based chemotherapy and/or immunotherapy, and in patients who received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (N=56).

In TKI-naïve patients with median follow-up of 24.0 months, the confirmed Objective Response Rate by BICR was 79%, median Duration of Response was 34.1 months and PFS was 35.7 months. In patients with measurable brain metastases at baseline (N=9), intracranial ORR per BICR was 89% and these responses were prolonged.

In patients who received one prior ROS1 TKI with no prior chemotherapy or immunotherapy, at a median follow-up of 21.5 months, the confirmed Objective Response Rate by BICR was 38%, median Duration of Response was 14.8 months and PFS was 9.0 months. In this subset of patients with measurable brain metastases at baseline (N=13), intracranial ORR per BICR was 38%.

The most common adverse reactions were fatigue, dizziness, dyspnea, dysgeusia, peripheral neuropathy, constipation, ataxia, cognitive disorders, and muscular weakness.

It was concluded that the TRIDENT-1 trial demonstrated the efficacy of Repotrectinib in both, TKI-naïve and previously treated patients, showcasing high response rates and durable outcomes. These data will provide physicians with valuable insights into the clinical benefits with Repotrectinib , paving the way for its potential adoption as a new standard of care, in the treatment of ROS1-positive NSCLC. TRIDENT-1 trial is ongoing to assess long term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC, and NTRK-positive advanced solid tumors.

Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: Update from the pivotal phase 1/2 TRIDENT-1 trial. Cho BC, Camidge DR, Lin JJ, et al. Presented at the IASLC 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA03.06.

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 Osimertinib 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. About 61% had Exon 19 deletion and 38% had L858R substitution mutation in Exon 21, 40% had CNS metastases and 53% had extrathoracic metastases. 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. The median follow-up for progression-free survival was 19.5 months in the osimertinib–chemotherapy group and 16.5 months in the osimertinib group.

In this final analysis of the Primary endpoint of PFS, results from this study showed a significant improvement in PFS with the Osimertinib plus chemotherapy combination versus Osimertinib alone (HR=0.62; P<0.001). The median PFS was 25.5 months versus 16.7 months respectively. This represented a 38% reduction in disease progression risk, compared to Osimertinib monotherapy. The PFS benefit with Osimertinib plus chemotherapy was consistent across prespecified subgroups, including the subgroups defined according to EGFR mutation type and the presence or absence of CNS metastases at baseline. The Objective Response Rate with the combination regimen was 83%, compared to 76%, in the Osimertinib monotherapy group. The median response duration was 24 months and 15.3 months respectively. 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 significantly improve outcomes, compared to Osimertinib alone, and can delay resistance to therapy and disease progression.

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC. Planchard D, Jänne PA, Cheng Y, et al. for the FLAURA2 Investigators. N Engl J Med 2023; 389:1935-1948

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