Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

BackgroundAmivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory EGFR-mutated advanced non-small cell lung cancer (NSCLC) in phase 1 studies. These combinations were evaluated in a global phase 3 trial.Patients and methodsA total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2:2:1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.ResultsAll baseline characteristics were well balanced across the 3 arms, including by history of brain metastases and prior brain radiation. Progression-free survival was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (hazard ratio for disease progression or death [HR], 0.48 and 0.44, respectively; P<0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively). Consistent PFS results were seen by investigator assessment (HR, 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P<0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P<0.001 for both). Median intracranial progression-free survival was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (hazard ratio for intracranial disease progression or death, 0.55 and 0.58, respectively). Predominant adverse events in the amivantamab-containing regimens were hematologic, EGFR, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic adverse events than amivantamab-lazertinib-chemotherapy.ConclusionsAmivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved progression-free survival and intracranial progression-free survival versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen. 

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.

http://www.annalsofoncology.org/article/S0923753422017422/pdf

Immunotherapy in unresectable stage III non-small cell lung cancer: state of the art and novel therapeutic approaches.

Simple Summary Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is currently indicated as first-line therapy in patients with non-small-cell lung cancer (NSCLC) and sensitizing EGFR mutations; as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs; and as adjuvant therapy for patients with early stage, resected NSCLC, harboring EGFR mutations. Understanding the patterns of resistance, including both on-target and off-target mechanisms, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting. Standard therapeutic approaches after progression to osimertinib include other targeted therapies—when a targetable genetic alteration is detected—and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib. Abstract The development of tyrosine kinase inhibitors (TKIs) targeting the mutant epidermal growth factor receptor (EGFR) protein initiated the success story of targeted therapies in non-small-cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR-TKI, is currently indicated as first-line therapy in patients with NSCLC with sensitizing EGFR mutations, as second-line therapy in patients who present the resistance-associated mutation T790M after treatment with previous EGFR-TKIs, and as adjuvant therapy for patients with early stage resected NSCLC, harboring EGFR mutations. Despite durable responses in patients with advanced NSCLC, resistance to osimertinib, similar to other targeted therapies, inevitably develops. Understanding the mechanisms of resistance, including both EGFR-dependent and -independent molecular pathways, as well as their therapeutic potential, represents an unmet need in thoracic oncology. Interestingly, differential resistance mechanisms develop when osimertinib is administered in a first-line versus second-line setting, indicating the importance of selection pressure and clonal evolution of tumor cells. Standard therapeutic approaches after progression to osimertinib include other targeted therapies, when a targetable genetic alteration is detected, and cytotoxic chemotherapy with or without antiangiogenic and immunotherapeutic agents. Deciphering the when and how to use immunotherapeutic agents in EGFR-positive NSCLC is a current challenge in clinical lung cancer research. Emerging treatment options after progression to osimertinib involve combinations of different therapeutic approaches and novel EGFR-TKI inhibitors. Research should also be focused on the standardization of liquid biopsies in order to facilitate the monitoring of molecular alterations after progression to osimertinib.

/pdf/osimertinib-resistance-molecular-mechanisms-and-emerging-16ghft67.pdf

Osimertinib Resistance: Molecular Mechanisms and Emerging Treatment Options

PURPOSE We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)–mutated advanced non–small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases. Osimertinib plus chemotherapy enhances CNS efficacy vs osimertinib alone in EGFRm advanced NSCLC.

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

ESMO expert consensus statements on the management of EGFR mutant Non-Small Cell Lung Cancer.

Treatment of refractory DLBCL still represents a unique area of unmet need. Previous studies have shown synergistic antitumour effects between Bruton’s tyrosine kinase inhibitors (BTKi) and immune checkpoint inhibitors. However, it lacks data of zanubrutinib and tislelizumab. Herein, we present the premilitary results of an ongoing, multicenter, single-arm phase II study designed to assess the safety and efficacy of zanubrutinib in combination with tislelizumab in refractory DLBCL patients. 

106P Zanubrutinib in combination with tislelizumab in patients with refractory diffuse large B cell lymphoma (DLBCL): A phase II study

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ESMO expert consensus statements on the management of EGFR mutant Non-Small Cell Lung Cancer.

106P Zanubrutinib in combination with tislelizumab in patients with refractory diffuse large B cell lymphoma (DLBCL): A phase II study