Background First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. Methods In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy...

/pdf/pembrolizumab-plus-chemotherapy-in-metastatic-non-small-cell-wdf5x3v6gq.pdf

Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

Background The cancer-cell–killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor–mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non–small-cell lung cancer (NSCLC) who had not previously received chemotherapy. Methods We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group. Results In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines. Conclusions The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann–La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1716948

Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC

Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low, particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.

The biology and management of non-small cell lung cancer

Purpose
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).

Patients and Methods
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).

Results
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatmentrelated adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.

Conclusion
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations

BackgroundPatients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. MethodsIn this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. ResultsThe median overall survival in the total population was 10.3 months (95% confidence interval [C...

/pdf/pembrolizumab-as-second-line-therapy-for-advanced-urothelial-1q1wickbej.pdf

Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

1040P Nivolumab or atezolizumab in the second-line treatment of advanced non-small-cell lung cancer? Prognostic index based on real-world data

Small-cell lung cancer is the most aggressive form of lung cancer. Most patients are diagnosed at a late disease stage when the prognosis is poor. The treatment algorithm for small-cell lung cancer remained unchanged for years, with chemotherapy as the first-line option. However, progress has been made with the recent development of immune checkpoint inhibitors, two of which — atezolizumab and durvalumab — have been approved in combination with chemotherapy as first-line treatment for advanced small-cell lung cancer. This review presents detailed data concerning the efficacy and safety of atezolizumab and durvalumab from both registration trials and real-world studies, as well as the results of clinical trials of other immune checkpoints inhibitors. Finally, the issue of identifying biomarkers to predict the efficacy of immunochemotherapy is discussed. 

Immune checkpoint inhibitors in the first-line treatment of metastatic small-cell lung cancer

Simple Summary Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase that shows targetable mutations and gene fusions in a few types of cancers. Multiple kinase inhibitors, which target RET kinase, show little efficiency in tumors with RET gene alterations. Therefore, the new RET-specific inhibitors have been developed. Selpercatinib and pralsetinib showed high effectiveness in clinical trials, but their efficacy was shown to be reduced by the occurrence of secondary alterations such as resistance mutations or activation of different signaling pathways. New drugs that could be used in patients with secondary mutated RET gene are under investigation and show promising results. Abstract Mutations and fusions of RET (rearranged during transfection) gene are detected in a few common types of tumors including thyroid or non-small cells lung cancers. Multiple kinase inhibitors (MKIs) do not show spectacular effectiveness in patients with RET-altered tumors. Hence, recently, two novel RET-specific inhibitors were registered in the US and in Europe. Selpercatinib and pralsetinib showed high efficacy in clinical trials, with fewer adverse effects, in comparison to previously used MKIs. However, the effectiveness of these new drugs may be reduced by the emergence of resistance mutations in RET gene and activation of different activating signaling pathways. This review presents the function of the normal RET receptor, types of molecular disturbances of the RET gene in patients with various cancers, methods of detecting these abnormalities, and the effectiveness of modern anticancer therapies (ranging from immunotherapies, through MKIs, to RET-specific inhibitors).

/pdf/ret-proto-oncogene-not-such-an-obvious-starting-point-in-3sllgk8d.pdf

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

<h3>Purpose/Objective(s)</h3> Primary analysis (database cutoff, Oct 28, 2020) of the global KEYNOTE-799 study (NCT03631784) in patients (pts) with unresectable, locally advanced stage III NSCLC, showed that pembrolizumab (pembro; anti–PD-1) + cCRT resulted in an ORR of 70.5% in cohort A (n = 112; squamous and nonsquamous) and 70.6% in cohort B (n = 102; nonsquamous only) and grade ≥3 pneumonitis in 9 (8.0%) and 7 (6.9%) pts, respectively. We evaluated outcomes with 1 y of additional follow-up. <h3>Materials/Methods</h3> In this nonrandomized, phase 2 study, eligible pts were aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA-C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received carboplatin AUC 6 + paclitaxel 200 mg/m<sup>2</sup> and pembro 200 mg for one 3-wk cycle, followed by carboplatin AUC 2 + paclitaxel 45 mg/m<sup>2</sup> QW for 6 wks + 2 cycles of pembro 200 mg Q3W + standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous) received 3 cycles of cisplatin 75 mg/m<sup>2</sup>, pemetrexed 500 mg/m<sup>2</sup>, and pembro 200 mg Q3W + standard TRT in cycles 2 and 3. All pts received 14 additional cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). <h3>Results</h3> Of 216 pts enrolled, 112 in cohort A and 102 in cohort B received treatment. Median (range) time from first dose to database cutoff (Oct 18, 2021) was 30.2 (25.3–35.5) mo in cohort A and 25.4 (14.5–35.2) mo in cohort B. ORR (95% CI) was 71.4% (62.1%–79.6%) and 75.5% (66.0%–83.5%), respectively. Median duration of response (DOR) and OS were not reached (NR) in both cohorts; median PFS was 30.6 mo in cohort A, and NR in cohort B (<b>Table</b>). ORR was 66.7% in pts with PD-L1 TPS <1% and 77.3% in pts with PD-L1 TPS ≥1% in cohort A and 78.6% and 72.5%, respectively, in cohort B. ORR was similar by histology (squamous, 72.0%; nonsquamous, 74.1%). Grade ≥3 pneumonitis occurred in 16 pts (7.5%) overall; 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Treatment-related grade ≥3 AEs occurred in 64.3% and 51.0% of pts in cohort A and B, respectively. Data on TRT, including techniques utilized and details for organs at risk with and without pneumonitis, will be presented. <h3>Conclusion</h3> With >2 y of follow-up, pembro + cCRT continues to demonstrate robust and durable responses, regardless of PD-L1 TPS and tumor histology, promising survival outcome and manageable safety in pts with previously untreated, locally advanced stage III NSCLC. 

Pembrolizumab plus Concurrent Chemoradiation Therapy (cCRT) for Unresectable, Locally Advanced, Stage III NSCLC: KEYNOTE-799 2-Year Update

W Polsce rak pluca jest najczestszą przyczyną zgonow z powodu nowotworow zlośliwych. W zdecydowanej wiekszości (80–85%) rozpoznawany jest niedrobnokomorkowy rak pluca (NDRP). Podczas podejmowania decyzji o leczeniu — oprocz klasycznych czynnikow prognostycznych (stan sprawności fizycznej, stopien zaawansowania klinicznego, stopien utraty masy ciala) — u chorych starszych nalezy wziąc pod uwage czynniki dodatkowe. Nalezą do nich: choroby wspolwystepujące, stan czynnościowy i mentalny, sprawnośc pod wzgledem funkcji poznawczych, stan odzywienia i zapotrzebowanie na pomoc socjalną. Są to elementy tak zwanej calościowej oceny geriatrycznej i mogą one wplywac na czas przezycia chorych na NDRP. W pracy przedstawiono poszczegolne metody leczenia NDRP w aspekcie wieku chorego.

/pdf/elderly-patients-treatment-with-non-small-cell-lung-cancer-2yi1257mhz.pdf

Dariusz M. Kowalski

Papers

1040P Nivolumab or atezolizumab in the second-line treatment of advanced non-small-cell lung cancer? Prognostic index based on real-world data

Immune checkpoint inhibitors in the first-line treatment of metastatic small-cell lung cancer

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

Pembrolizumab plus Concurrent Chemoradiation Therapy (cCRT) for Unresectable, Locally Advanced, Stage III NSCLC: KEYNOTE-799 2-Year Update

Elderly patients treatment with non-small-cell lung cancer