Perioperative Nivolumab in Resectable Lung Cancer.

BACKGROUND: Standard treatment with neoadjuvant nivolumab plus chemotherapy significantly improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Perioperative treatment (i.e., neoadjuvant therapy followed by surgery and adjuvant therapy) with nivolumab may further improve clinical outcomes. METHODS: In this phase 3, randomized, double-blind trial, we assigned adults with resectable stage IIA to IIIB NSCLC to receive neoadjuvant nivolumab plus chemotherapy or neoadjuvant chemotherapy plus placebo every 3 weeks for 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for 1 year. The primary outcome was event-free survival according to blinded independent review. Secondary outcomes were pathological complete response and major pathological response according to blinded independent review, overall survival, and safety. RESULTS: At this prespecified interim analysis (median follow-up, 25.4 months), the percentage of patients with 18-month event-free survival was 70.2% in the nivolumab group and 50.0% in the chemotherapy group (hazard ratio for disease progression or recurrence, abandoned surgery, or death, 0.58; 97.36% confidence interval [CI], 0.42 to 0.81; P<0.001). A pathological complete response occurred in 25.3% of the patients in the nivolumab group and in 4.7% of those in the chemotherapy group (odds ratio, 6.64; 95% CI, 3.40 to 12.97); a major pathological response occurred in 35.4% and 12.1%, respectively (odds ratio, 4.01; 95% CI, 2.48 to 6.49). Grade 3 or 4 treatment-related adverse events occurred in 32.5% of the patients in the nivolumab group and in 25.2% of those in the chemotherapy group. CONCLUSIONS: Perioperative treatment with nivolumab resulted in significantly longer event-free survival than chemotherapy in patients with resectable NSCLC. No new safety signals were observed. (Funded by Bristol Myers Squibb; CheckMate 77T ClinicalTrials.gov number, NCT04025879.).

Clinical predictors of response to single­agent immune checkpoint inhibitors in chemotherapy­pretreated non­small cell lung cancer.

Single-agent immune checkpoint inhibitors (ICIs) are the standard option for chemotherapy-pretreated metastatic non-small cell lung cancer (NSCLC), however only a subset of patients responds to this treatment. The present study aimed at the development of a tool for personalized prediction of the efficacy of ICIs. The study included 181 epidermal growth factor receptor/anaplastic lymphoma kinase-negative patients with metastatic NSCLC receiving single-agent ICI in the second or later line of therapy. For the comparison, a total of 63 metastatic patients with NSCLC treated by chemotherapy were also analyzed. Multivariate analysis revealed that Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, never-smoking status and the baseline neutrophil-to-lymphocyte ratio (NLR) ≥4.3 were associated with reduced progression-free survival (PFS) and overall survival (OS) [ECOG PS: Hazard ratio (HR)=2.09; P=0.028 and HR=2.02; P=0.035, respectively; never-smoking: HR=3.53; P=0.007 and HR=1.80; P=0.004, respectively; NLR ≥4.3: HR=4.34; P<0.0001 and HR=4.89; P<0.0001 respectively]. Patients with an NLR <4.3, who had a favorable ECOG PS (0-1) and smoking history in the past, derived the utmost benefit from ICI [n=77; objective response rate (ORR)=35%; PFS and OS: 17.1 and 33.7 months, respectively]. The worst efficacy of ICI was observed in patients who had an NLR ≥4.3 coupled with poor ECOG PS and/or never-smoking status (n=38; ORR=8%; PFS=3.2 months and OS=7.2 months). The remaining patients belonged to the group with intermediate outcomes (n=66; ORR=17%; PFS and OS: 4.3 and 12.2 months, respectively). While combination of these factors was highly predictive for ICIs, it was not associated with outcomes of chemotherapy treatment. Easily available characteristics of the patients allow for highly accurate predictions of outcomes of single-agent ICI therapy in chemotherapy-pretreated NSCLC.

Discrimination between Complete versus Non-Complete Pathologic Response to Neoadjuvant Therapy Using Ultrasensitive Mutation Analysis: A Proof-of-Concept Study in BRCA1-Driven Breast Cancer Patients.

Neoadjuvant chemotherapy (NACT) for breast cancer (BC) often results in pathologic complete response (pCR), i.e., the complete elimination of visible cancer cells. It is unclear whether the use of ultrasensitive genetic methods may still detect residual BC cells in complete responders. Breast carcinomas arising in BRCA1 mutation carriers almost always carry alterations of the TP53 gene thus providing an opportunity to address this question. The analysis of consecutive BC patients treated by NACT revealed a higher pCR rate in BRCA1-driven vs. BRCA1-wildtype BCs (13/24 (54%) vs. 29/192 (15%), p < 0.0001). Twelve pre-/post-NACT tissue pairs obtained from BRCA1 mutation carriers were available for the study. While TP53 mutation was identified in all chemonaive tumors, droplet digital PCR (ddPCR) analysis of the post-NACT tumor bed revealed the persistence of this alteration in all seven pCR-non-responders but in none of five pCR responders. Eleven patients provided to the study post-NACT tissue samples only; next-generation sequencing (NGS) analysis revealed mutated TP53 copies in all six cases without pCR but in none of five instances of pCR. In total, TP53 mutation was present in post-NACT tissues in all 13 cases without pCR, but in none of 10 patients with pCR (p < 0.000001). Therefore, the lack of visible tumor cells in the post-NACT tumor bed is indeed a reliable indicator of the complete elimination of transformed clones. Failure of ultrasensitive methods to identify patients with minimal residual disease among pCR responders suggests that the result of NACT is a categorical rather than continuous variable, where some patients are destined to be cured while others ultimately fail to experience tumor eradication.

Changes in the concentration of EGFR-mutated plasma DNA in the first hours of targeted therapy allow the prediction of tumor response in patients with EGFR-driven lung cancer.

PURPOSE: This study aimed to analyze changes in the plasma concentration of EGFR-mutated circulating tumor DNA (ctDNA) occurring immediately after the start of therapy with EGFR tyrosine kinase inhibitors (TKIs). METHODS: Serial plasma samples were collected from 30 patients with EGFR-driven non-small cell lung cancer before intake of the first tablet and at 0.5, 1, 2, 3, 6, 12, 24, 36 and 48 h after the start of the therapy. The content of EGFR alleles (exon 19 deletions or L858R) in ctDNA was measured by ddPCR. RESULTS: ctDNA was detected at base-line in 25/30 (83%) subjects. Twelve (50%) out of 24 informative patients showed > 25% reduction of the ctDNA content at 48 h time point; all these patients demonstrated disease control after 4 and 8-12 weeks of therapy. The remaining 12 individuals showed either stable content of EGFR-mutated ctDNA (n = 5) or the elevation of ctDNA concentration (n = 7). 10 of 12 patients with elevated or stable ctDNA level achieved an objective response at 4 weeks, but only 5 of 10 evaluable patients still demonstrated disease control at 8-12 weeks (p = 0.032, when compared to the group with ctDNA decrease). The decline of the amount of circulating EGFR mutant copies at 48 h also correlated with longer progression-free survival (14.7 months vs. 8.5 months, p = 0.013). CONCLUSION: Comparison of concentration of EGFR-mutated ctDNA at base-line and at 48 h after the start of therapy is predictive for the duration of TKI efficacy.

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation.

Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.

Redefining Treatment Paradigms in First-line Advanced Non-Small-Cell Lung Cancer.

Metastatic non-small-cell lung cancer is still a devastating disease; however, treatment options have diversified dramatically in the past two decades. From unselected platinum-based chemotherapy for all patients, several different treatment groups have evolved, that is, those with "druggable" targets, those with a promising immune signature, and those without any predicting factors outlined in this article. Challenge includes the intersections between these groups and the optimal treatment path. These issues will be addressed in this review.

Variability in lung cancer response to ALK inhibitors cannot be explained by the diversity of ALK fusion variants.

Multiple laboratory evidences indicate that distinct variants of ALK translocations differ in their biochemical properties and responsiveness to ALK tyrosine kinase inhibitors (TKIs). These data are supported by some clinical studies, which showed improved responses to crizotinib in non-small cell lung cancer (NSCLC) patients carrying particular variants of ALK translocation. We retrospectively considered 64 Russian patients with ALK-rearranged NSCLC, who were treated by crizotinib (n = 23), ceritinib (n = 39) or alectinib (n = 2). ALK fusion variants were genotyped by PCR. Median progression-free survival (PFS) approached to 18 and 21 months in subjects with "short" (v.3a/b, v.5a/b) vs. "long" (TAPE-domain containing) fusion variants (p = 0.783), respectively; similar data were obtained while comparing EML4/ALK variant 1 vs. other ALK translocations (19 and 21 months, respectively; p = 0.604). Objective response rates were also strikingly similar in the above groups ("short": 88%, "long": 77%, p = 0.479; variant 1: 76%, other translocations: 81%, p = 0.753). Furthermore, ALK variants did not influence the disease outcomes when patients treated by crizotinib and ceritinib were analyzed separately. Overall, PFS on ALK TKI did not depend on whether the drug was administered upfront or after chemotherapy. Ceritinib produced significantly longer PFS than crizotinib (p = 0.022). In conclusion, this study revealed that distinct ALK translocation variants render similar clinical responsiveness to ALK inhibitors.

EGFR T790M Mutation in TKI-Naïve Clinical Samples: Frequency, Tissue Mosaicism, Predictive Value and Awareness on Artifacts.

BACKGROUND: This study evaluated the distribution of epidermal growth factor receptor (EGFR) T790M mutations in treatment-naïve tumor and normal samples obtained from cancer patients. METHODS: We utilized allele-specific PCR (AS-PCR), digital droplet PCR (ddPCR) and next generation sequencing (NGS) to detect EGFR T790M allele in several collections of tumor and normal human tissues. RESULTS: AS-PCR analysis of treatment-naïve tumor samples revealed somatic T790M mutation in 3/394 (1%) non-small cell lung carcinomas (NSCLC) carrying the tyrosine kinase inhibitor (TKI)-sensitizing EGFR mutation, but in none of 334 NSCLC lacking EGFR exon 19 deletions (ex19del) or L858R substitutions and in none of 235 non-lung tumors. Use of highly sensitive and quantitative assays, such as ddPCR and NGS, produced a high number of T790M-specific signals even in presumably T790M-negative DNA specimens. This background noise was evidently higher in degraded DNA isolated from formalin-fixed paraffin-embedded tissues as compared to high molecular weight DNA. A combination of AS-PCR, ddPCR and NGS revealed mosaic EGFR T790M allele in 2/68 (3%) NSCLC treated with the first-generation TKI. Both these tumors produced evident and durable response to gefitinib. CONCLUSION: Detection of mosaic EGFR T790M mutation in treatment-naïve samples may be compromised by yet unresolved technical issues and may have limited clinical value.

"Lazarus Response" to Olaparib in a Virtually Chemonaive Breast Cancer Patient Carrying Gross BRCA2 Gene Deletion.

This report describes an estrogen receptor-positive breast cancer patient, who relapsed at two and a half years after the completion of adjuvant chemotherapy while being on the aromatase inhibition. Based on the clinical evidence for potential sensitivity of the tumor to hormone ablation, everolimus was added to continuing exemestane treatment. Oral chemotherapy was administered at further disease progression, however, it lasted only for 10 days due to rapidly deteriorating condition of the patient. BRCA test was performed just before the failure of endocrine therapy and revealed a gross deletion within BRCA2 gene. Since the patient already developed contraindications to the standard chemotherapy, olaparib (300 mg twice a day) was given as a last hope option. The patient demonstrated a "Lazarus response": the performance status and the results of the biochemical tests went back to the norm within first two weeks of treatment. Positron emission tomography-computed tomography (PET-CT) was performed at one month after the start of olaparib therapy, and revealed complete metabolic response for all multiple metastatic lesions located in the liver, bones, small pelvis, lungs, mediastinum, retroperitoneum, etc. Cytotoxic therapy and poly ADP-ribose polymerase (PARP) inhibitors are known to have virtually identical mechanisms of tumor escape from the treatment, which are confined to the restoration of BRCA proficiency within cancer cells. The pronounced tumor response to the treatment in this patient can be attributed to the lack of recent exposure to standard cytotoxic treatment as well as to the inability of tumors with gross BRCA rearrangements to restore BRCA function via secondary mutation. This observation calls for comprehensive evaluation of PARP inhibitors in chemonaive patients with hereditary cancer.

First-Line Cetuximab Monotherapy in KRAS/NRAS/BRAF Mutation-Negative Colorectal Cancer Patients.

BACKGROUND: Colorectal carcinomas (CRCs) are sensitive to treatment by anti-epidermal growth factor receptor (EGFR) antibodies only if they do not carry activating mutations in down-stream EGFR targets (KRAS/NRAS/BRAF). Most clinical trials for chemo-naive CRC patients involved combination of targeted agents and chemotherapy, while single-agent cetuximab or panitumumab studies included either heavily pretreated patients or subjects who were not selected on the basis of molecular tests. We hypothesized that anti-EGFR therapy would have significant efficacy in chemo-naive patients with KRAS/NRAS/BRAF mutation-negative CRC. METHODS: Nineteen patients were prospectively included in the study. RESULTS: Two (11%) patients experienced partial response (PR) and 11 (58%) subjects showed stable disease (SD). Median time to progression approached 6.1 months (range 1.6-15.0 months). Cetuximab efficacy did not correlate with RNA expression of EGFR and insulin-like growth factor 2 (IGF2). Only one tumor carried PIK3CA mutation, and this CRC responded to cetuximab. Exome analysis of patients with progressive disease (PD) revealed 1 CRC with high-level microsatellite instability and 1 instance of HER2 oncogene amplification; 3 of 4 remaining patients with PD had allergic reactions to cetuximab, while none of the subjects with PR or SD had this complication. Comparison with 19 retrospective KRAS/NRAS/BRAF mutation-negative patients receiving first-line fluoropyrimidines revealed no advantages or disadvantages of cetuximab therapy. CONCLUSIONS: Cetuximab demonstrates only modest efficacy when given as a first-line monotherapy to KRAS/NRAS/BRAF mutation-negative CRC patients. It is of question, why meticulous patient selection, which was undertaken in the current study, did not result in the improvement of outcomes of single-agent cetuximab treatment.

Survival Outcomes in EGFR Mutation-Positive Lung Cancer Patients Treated with Gefitinib until or beyond Progression.

BACKGROUND: Discontinuation of gefitinib treatment is often accompanied by a disease flare. Some studies have demonstrated a benefit of the use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) beyond progression; however, long-term results of these investigations remain limited. PATIENTS AND METHODS: We observed 70 patients with EGFR-mutated (EGFR-M+) non-small cell lung cancer (NSCLC) receiving single-agent gefitinib in a routine clinical setting; 56 patients were experiencing RECIST progression at the time of the analysis. RESULTS: There was a significant increase (p = 0.00001) in overall survival (OS) in patients continuing on gefitinib beyond progression (n = 21; median duration of continued gefitinib use: 4.2 months; median OS: not reached; expected OS: 29.7 months) as compared to those who stopped gefitinib treatment upon disease progression (n = 35; median OS: 14.0 months). The association between extended gefitinib use and improved OS remained true in multivariate Cox regression analysis (hazard ratio = 4.49, 95% confidence interval 1.25-16.09; p = 0.021). Patient selection bias constitutes an essential limitation of this clinical observational study, given that patients with a more favorable disease course and/or high initial tumor sensitivity to TKI treatment were more likely to be considered for prolonged gefitinib use. CONCLUSION: This study confirms that continued administration of gefitinib beyond progression is a viable treatment option for some patients with EGFR-M+ NSCLC, in particular those who cannot be rescued by novel EGFR mutation-specific inhibitors such as osimertinib.

High efficacy of cisplatin neoadjuvant therapy in a prospective series of patients carrying BRCA1 germ-line mutation.

Development of malignancies in BRCA1 germ-line mutation carriers usually involves somatic inactivation of the remaining BRCA1 allele. This feature leads to a tumor-specific deficiency of double-strand DNA break repair and underlies pronounced sensitivity of BRCA1-driven cancers to cisplatin. BRCA1-specific activity of cisplatin has been repeatedly demonstrated in cell culture and animal experiments; however, corresponding clinical evidence remains limited. We applied neoadjuvant monotherapy by cisplatin (75-100 mg/m(2), 4-6 cycles) to six breast cancer patients carrying BRCA1 5382insC mutation. Pronounced reduction in tumor size was observed in all treated women. Three patients (T2N0M0, T4N2M0 and T4N2M0) showed pathologic complete response, two women (T4N0M0 and T2N1M0) had partial pathologic response, and one woman (T3N2M0) declined surgery. This study and available literature data suggest that cisplatin is a preferable option for systemic treatment of BRCA1-related hereditary breast cancer.

Evidence for clinical efficacy of mitomycin C in heavily pretreated ovarian cancer patients carrying germ-line BRCA1 mutation.

Ovarian carcinomas (OC) arising in BRCA1 and BRCA2 mutation carriers demonstrate pronounced sensitivity to platinum-based therapy due to deficiency of double-strand break DNA repair. However, the choice of subsequent treatment lines for this category of women remains complicated. We considered mitomycin C for heavily pretreated hereditary OC patients, based on multiple evidence for BRCA-specific activity of this drug. Twelve patients carrying BRCA1 germ-line mutation were included in the study. All women had a history of surgical intervention followed by adjuvant platinum-based therapy; three patients also received platinating agents prior the operation. The number of preceding treatment lines for metastatic disease was one for three patients, two for four patients, three for two patients, four for two patients and six for one woman. Administration of mitomycin C (10 mg/m2, every 4 weeks) resulted in one complete response (duration 36 weeks), two partial responses (duration 36 and 48 weeks) and six instances of disease stabilization (duration 12, 16, 20, 24, 24 and 24 weeks). In addition, three patients with the stable disease showed a decline of CA-125 level. We conclude that mitomycin C may deserve further evaluation in clinical trials involving BRCA1/2-related cancers.

High efficacy of first-line gefitinib in non-Asian patients with EGFR-mutated lung adenocarcinoma.

BACKGROUND: Several Asian studies demonstrated feasibility of front-line administration of gefitinib for the treatment of non-small cell lung carcinomas (NSCLCs) harboring intragenic epidermal growth factor receptor (EGFR) mutations. The experience of the use of this EGFR tyrosine kinase inhibitor (TKI) in non-Asian subjects remains limited. PATIENTS AND METHODS: The study included lung adenocarcinoma (AC) patients treated at the N.N. Petrov Institute of Oncology (Russia). RESULTS: DNA analysis of 192 consecutive AC revealed 38 (20%) TKI-sensitizing mutations. Presence of the exon 19 deletion (del19) or L858R was strongly correlated with nonsmoking status (smokers: 8/98 (8%); non-smokers: 30/94 (32%); p = 0.00004). The efficacy of first-line gefitinib therapy was evaluated in 25 patients with EGFR-mutated advanced AC. Twelve (48%) cases demonstrated tumor response (1 (4%) complete response, 11 (44%) partial responses; 10/17 (59%) patients with del19 mutation vs. 2/8 (25%) cases with L858R substitution, p = 0.11). The remaining 13 (52%) patients experienced disease stabilization. Median progression-free survival was 8.0 months. Grade 3 toxicity was the maximal adverse event, being observed only in 4 (16%) cases. CONCLUSION: Gefitinib may be considered as an upfront treatment option for EGFR-mutated NSCLC.