Vaccine therapy in non—small-cell lung cancer

Lung cancer is the leading cause of death from cancer worldwide. First-line therapy is based on stage at diagnosis can include chemotherapy, radiation, and surgery. Despite advances, the prognosis for advanced-stage lung cancer is very poor. Vaccines with the capability to activate the host immune system may have a role in second-line therapy. Advances in the understanding of cellular and molecular immunology are forming the basis for improving vaccine therapy. Most trials to date have demonstrated safety but inconsistent efficacy. Further research is needed to enhance this potential.     

Tumor immune microenvironment predicts the pathologic response of neoadjuvant chemoimmunotherapy in non–small-cell lung cancer

The clinical outcome of resectable non–small-cell lung cancer (NSCLC) patients receiving neoadjuvant chemoimmunotherapy is good but varies greatly. In addition, the pathological response after neoadjuvant chemoimmunotherapy is significantly associated with survival outcomes. The aim of this retrospective study was to identify which population of patients with locally advanced and oligometastatic NSCLC has a favorable pathological response after neoadjuvant chemoimmunotherapy. NSCLC patients treated with neoadjuvant chemoimmunotherapy were enrolled between February 2018 and April 2022. Data on clinicopathological features were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment puncture specimens and surgically resected specimens. In total, 29 patients with stages III and IV locally advanced or oligometastatic NSCLC who received neoadjuvant chemoimmunotherapy and R0 resection were enrolled. The results showed that 55% (16/29) of patients had a major pathological response (MPR) and 41% (12/29) of patients had a complete pathological response (pCR). In the stroma area of the pre-treatment specimen, the higher infiltration of CD3⁺PD-L1⁺ tumor-infiltrating lymphocytes (TILs) and the lower infiltration of CD4⁺ and CD4⁺FOXP3⁺ TILs were more likely to appear in patients with pCR. However, in the tumor area, the higher infiltration of CD8⁺ TILs was more likely to appear in patients with non-MPR. In the post-treatment specimen, we found increased infiltration of CD3⁺CD8⁺, CD8⁺GZMB⁺, and CD8⁺CD69⁺ TILs and decreased infiltration of PD-1⁺ TILs both in the stroma and tumor areas. Neoadjuvant chemoimmunotherapy achieved an MPR rate of 55% and induced greater immune infiltration. In addition, we observed that the baseline TILs and their spatial distribution correlate to the pathological response.     

Nodal recurrences after stereotactic body radiotherapy for early stage non–small-cell lung cancer

Lobectomy is considered the standard of care for early stage non–small-cell lung cancer. However, for those patients who remain unfit to undergo surgery due to advanced age, poor performance status, comorbidities, poor pulmonary reserve or a combination of these are now treated with stereotactic body radiation therapy (SBRT). Due to its noninvasive nature, lower cost, lower toxicity, reduced recovery time and equivalent efficacy, even medically operable patients are attracted to the option of SBRT despite the lack of level I evidence. Thus, studying the incidence and patterns of recurrence after SBRT help in understanding the magnitude of the problem, risk factors associated with the different patterns of recurrence, and aid in devising strategies to prevent them in future. Nodal recurrences are not uncommon after SBRT and can potentially lead to further seeding for distant metastases and ultimately poor survival. This review is aimed at reviewing the published data on the incidence of nodal recurrences after SBRT and compare it to surgery, identify potential risk factors for recurrence, salvage treatment options and prevention strategies.     

QT interval prolongation related to afatinib treatment in a patient with metastatic non–small-cell lung cancer

Afatinib improves survival in metastatic non–small-cell lung cancer driven by activating epidermal growth factor receptor mutations. QT interval prolongation is a possible side effect of targeted anticancer drugs, but this has not been reported before with afatinib. We report a case of metastatic pulmonary adenocarcinoma with epidermal growth factor receptor exon 19 deletion who was treated with first-line afatinib. The patient was started on afatinib with a total dose of 40 mg/day and experienced grade 3 (>500 ms) QT interval prolongation in the seventh week. Dose was interrupted and then reduced to 30 mg/day after the event repeated. QT prolongation occurred only once with the reduced dose and radiologic oligoprogression was detected. Local therapy was performed and afatinib was continued as 30 mg/day. To the best of our knowledge, this case marks the first QT interval prolongation associated with afatinib. It is prudent to perform a baseline cardiologic evaluation and electrocardiogram monitoring in non-small cell lung cancer patients treated with this drug.     

The role of surgery in the treatment of stage III non—small-cell lung cancer

Stage III, locally advanced non—small-cell lung cancer represents an incredibly heterogeneous group of patients. The majority of patients are treated with curative intent, but optimal therapy is controversial and the role of surgery is not well defined. Consensus has shown that the majority of patients with IIIB disease are not amenable to resection. The exceptions are selected patients with tumor stage 4 (T4) by virtue of a satellite nodule or those with isolated invasion of the spine, superior sulcus, carina, or vena cava. Surgery is more widely used for stage IIIA disease. Patients with nodal stage 2 (N2) disease represent the largest population of patients in stage III. Increasing evidence supports the use of surgery as part of a multimodality approach for N2 disease. The impact of surgery is partially determined by the bulk of the mediastinal node involvement. Patients with micrometastatic disease and single-station nodal involvement have the greatest chance for cure, and surgery appears to play a significant role in their treatment. Patients with bulky multistation disease are frequently not amenable to complete resection and may be best approached with definitive chemotherapy and radiation. In addition, the ability to sterilize mediastinal lymph nodes with induction therapy correlates strongly with survival following resection, but the ideal induction regime that balances the safety and efficacy has yet to be determined.     

Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non–small-cell lung cancer: KEYNOTE-189 Japan Study

Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Survival Disparities in Black Patients With EGFR-mutated Non–small-cell Lung Cancer

BackgroundLittle is known about the difference between black and non-black patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC), particularly regarding survival. We thus characterized the EGFR expression profile, clinical characteristics, and survival outcome in these patients.Patient and MethodsWe reviewed the cancer registry and patient charts at a New York-Bronx network (n = 2773) treating a large population of minority patients, for non-squamous NSCLC (n = 1986) diagnosed between 2009 and 2015. Survival was adjusted for smoking, gender, age, weight, and stage.ResultsThe EGFR mutation rate was 15% (98/652) in tested patients (black, 14%; non-black, 16%). There was no significant difference between the 2 cohorts with respect to age at diagnosis, gender, presenting stages, and socioeconomic status. On the other hand, weight was noted to be heavier in black patients with EGFR-mutated NSCLC than their non-black counterparts (P = .012). After adjusting for gender, age, smoking status, weight, and stage, the multivariate analysis revealed no racial disparity in survival among patients with wild-type EGFR (P = .774); However, among patients with EGFR-mutated NSCLC, black patients had shorter survival in comparison with non-black patients (P = .001), with 2-year survival rates being 33% versus 61%, respectively. Such shorter survival was also observed among EGFR-inhibitor treated patients with common EGFR mutations (P = .040).ConclusionsTo our knowledge, this is the first report of inferior survival among black patients with NSCLC with EGFR mutations, relative to non-black patients. The survival disparities suggest the need of more tailored management for this patient population.     

Impact of functional ABCG2 polymorphisms on the adverse effects of gefitinib in Japanese patients with non–small-cell lung cancer

Purpose

ABCG2 is a half-size ATP-binding cassette transporter implicated in cellular gefitinib transport. Reportedly, the c.421C > A ABCG2 gene polymorphism was associated with gefitinib-induced diarrhea in Caucasian patients with non–small-cell lung cancer. Since c.421C > A ABCG2, resulting in p.Q141K substitution, is more prevalent in Asian populations, the putative relationship between gefitinib-induced adverse effects and this functional polymorphism was investigated in Japanese patients. c.376C > T, resulting in truncated, non-functional ABCG2, was also investigated.

Methods

ABCG2 gene polymorphisms were evaluated in 75 patients with non–small-cell lung cancer treated with gefitinib 250 mg/day orally, and results were correlated with treatment-related adverse effects.

Results

Forty (53.3%) patients harbored c.421A ABCG2 on at least one allele, while the remaining 35 (46.7%) were wild type for c.421C > A. No significant group difference was observed in frequency of gefitinib-related diarrhea or other adverse effects. In addition, the only one patient homozygous for the c.421A allele in this study was not affected with gefitinib-induced diarrhea or interstitial lung disease. Two patients (2.7%) were found to harbor the c.376T allele heterozygously. One of the two patients harbored both the c.376T and the c.421A genotypes on distinct alleles. Gefitinib-related interstitial lung disease and severe diarrhea were noted in neither of the two patients.

Conclusions

In this Japanese population, we did not find an evident association between ABCG2 polymorphisms, c.376C > T and c.421C > A, and susceptibility to gefitinib-induced adverse effects.     

Comparing the effectiveness of different EGFR-TKIs in patients with EGFR mutant non–small-cell lung cancer: A retrospective cohort study in Taiwan

The study was to compare the effectiveness of different epidermal growth factor receptor—tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced non-small-cell lung cancer (NSCLC) and received EGFR-TKIs as first-line therapy. This retrospective cohort study was conducted using data from real-world settings. Patients with stage IIIB and IV NSCLC and first received gefitinib, erlotinib, or afatinib between 2011 and 2015 were included. The date of the first claim for EGFR-TKIs was set as the index date. Study endpoints were all-cause death and treatment failure that was defined when patients added on or switched to chemotherapy or terminal care. A total of 5,940 patients, including 3,982 (67.0%) receiving gefitinib, 1,207 (20.3%) receiving erlotinib, and 751 (12.7%) receiving afatinib, were eligible for this study. The 1-year overall survival (OS) rates for gefitinib, erlotinib, and afatinib groups were 74% (95% confidence interval [CI]: 72–75%), 75% (95% CI: 73–77%), and 80% (95% CI: 77–83%), respectively. Compared to gefitinib, afatinib was associated with a lower risk of all-cause death (adjusted hazard ratio [aHR] = 0.82, 95% CI: 0.72–0.93) but not erlotinib (aHR = 0.95, 95% CI: 0.86–1.05). Similar results were also found regarding the effectiveness of treatment. All the three EGFR-TKIs showed no differences for both outcomes among patients with an Eastern Cooperative Oncology Group Performance Score of 2. The real-world data exhibited afatinib was more likely to be used for younger patients in a better condition than other EGFR inhibitors, and observed prolonged OS and treatment effectiveness compared to gefitinib after performing a multivariate Cox regression analysis.     

Inhibitors of the EGFR pathway in non small cell lung cancer: what's new in 2007?

Non small cell lung cancer (NSCLC) is a major health public issue because of its frequency and related mortality. Progress with chemotherapy in advanced NSCLC has reached a plateau and more effective and better tolerated therapeutic strategies are needed. Epidermal growth factor receptor (EGFR) is overexpressed in 80% of NSCLC and inhibitors of EGFR tyrosine kinase have now an important place in the management of NSCLC. Most significant results have been obtained with oral inhibitors like erlotinib or gefitinib. Erlotinib role in second and third line setting is firmly established. Recent data suggests that in the first line setting, interesting overall response rates improving survivals can be obtained, in specific subpopulations defined either by histology (adenocarcinomas, adenocarcinomas with bronchioloalveolar features), sex (women), non-smoking status (never-smokers) or biological markers (tumours with EGFR mutations in exons 18-21). Such improvements are especially valuable because inhibitors of EGFR tyrosine kinase are better tolerated than chemotherapy. The exact contribution of monoclonal antibodies like cetuximab is still unclear in NSCLC.     

Management of stage III non–small cell lung cancer

Optimal management of patients with locally advanced non–small cell lung cancer remains challenging in the context of this heterogeneous disease. Despite aggressive therapeutic approaches, survival benefits are still unsatisfactory for what might be viewed as a localized malignancy. A combined modality approach offers patients superior outcomes, especially because technological advances and refined surgical procedures now provide better results with fewer complications. Nevertheless, several features of therapy remain controversial and lack formal prospective data. Traditional cytotoxic chemoradiation therapy may have reached a plateau and future perspectives opting to integrate molecularly targeted agents and immunotherapy might be the way to improve outcomes in this disease subset.     

Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non–small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria

BackgroundCentral nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase–positive (ALK+) non–small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.MethodsBoth studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.ResultsBaseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2–77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7–68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).ConclusionAlectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.