Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC.

BACKGROUND: We evaluated whether tissue tumor mutational burden (tTMB) and STK11, KEAP1, and KRAS mutations have clinical utility as biomarkers for pembrolizumab monotherapy versus platinum-based chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive (tumor proportion score ≥1%) advanced/metastatic non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the phase III KEYNOTE-042 trial. PATIENTS AND METHODS: This retrospective exploratory analysis assessed prevalence of tTMB and STK11, KEAP1, and KRAS mutations determined by whole-exome sequencing of tumor tissue and matched normal DNA and their associations with outcomes in KEYNOTE-042. Clinical utility of tTMB was assessed using a prespecified cut point of 175 mutations/exome. RESULTS: Of 793 patients, 345 (43.5%) had tTMB ≥175 mutations/exome and 448 (56.5%) had tTMB <175 mutations/exome. No association was observed between PD-L1 expression and tTMB. Continuous tTMB score was associated with improved overall survival (OS) and progression-free survival among patients receiving pembrolizumab (Wald test, one-sided P < 0.001) but not those receiving chemotherapy (Wald test, two-sided P > 0.05). tTMB ≥175 mutations/exome was associated with improved outcomes for pembrolizumab versus chemotherapy, whereas tTMB <175 mutations/exome was not {OS: hazard ratio, 0.62 [95% confidence interval (CI) 0.48-0.80] and 1.09 (95% CI 0.88-1.36); progression-free survival: 0.75 (0.59-0.95) and 1.27 (1.04-1.55), respectively}. Improved OS [hazard ratio (95% CI)] for pembrolizumab versus chemotherapy was observed regardless of STK11 [STK11 mutant (n = 33): 0.37 (0.16-0.86), STK11 wild-type (n = 396): 0.83 (0.65-1.05)]; KEAP1 [KEAP1 mutant (n = 64): 0.75 (0.42-1.35), KEAP1 wild-type (n = 365): 0.78 (0.61-0.99)], or KRAS [KRAS mutant (n = 69): 0.42 (0.22-0.81); KRAS wild-type (n = 232): 0.86 (0.63-1.18)] mutation status. CONCLUSION: tTMB with a cut point of ≥175 mutations/exome is a potential predictive biomarker for pembrolizumab monotherapy for advanced/metastatic PD-L1 tumor proportion score ≥1% NSCLC. Pembrolizumab is a standard first-line treatment in this setting regardless of STK11, KEAP1, or KRAS mutation status.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Genomic origin and EGFR-TKI treatments of pulmonary adenosquamous carcinoma.

BACKGROUND: Adenosquamous carcinoma (ASC) of the lung is a heterogeneous disease that is composed of both adenocarcinoma components (ACC) and squamous cell carcinoma components (SCCC). Their genomic profile, genetic origin, and clinical management remain controversial. PATIENTS AND METHODS: Resected ASC and metastatic tumor in regional lymph nodes (LNs) were collected. The ACC and SCCC were separated by microdissection of primary tumor. The 1021 cancer-related genes were evaluated by next-generation sequencing independently in ACC and SCCC and LNs. Shared and private alterations in the two components were investigated. In addition, genomic profiles of independent cohorts of adenocarcinomas and squamous cell carcinomas were examined for comparison. We have also carried out a retrospective study of ASCs with known EGFR mutation status from 11 hospitals in China for their clinical outcomes. RESULTS: The most frequent alterations in 28 surgically resected ASCs include EGFR (79%), TP53 (68%), MAP3K1 (14%) mutations, EGFR amplifications (32%), and MDM2 amplifications (18%). Twenty-seven patients (96%) had shared variations between ACC and SCCC, and pure SCCC metastases were not found in metastatic LNs among these patients. Only one patient with geographically separated ACC and SCCC had no shared mutations. Inter-component heterogeneity was a common genetic event of ACC and SCCC. The genomic profile of ASC was similar to that of 170 adenocarcinomas, but different from that of 62 squamous cell carcinomas. The incidence of EGFR mutations in the retrospective analysis of 517 ASCs was 51.8%. Among the 129 EGFR-positive patients who received EGFR-TKIs, the objective response rate was 56.6% and the median progression-free survival was 10.1 months (95% confidence interval: 9.0-11.2). CONCLUSIONS: The ACC and SCCC share a monoclonal origin, a majority with genetically inter-component heterogeneity. ASC may represent a subtype of adenocarcinoma with EGFR mutation being the most common genomic anomaly and sharing similar efficacy to EGFR TKI.

Overview of current systemic management of EGFR-mutant NSCLC.

Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.

Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive patients with non-small-cell lung cancer.

Background: In clinical trials of patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) treated with crizotinib, evaluation of the relationship between the percentage of ALK-positive cells by fluorescence in situ hybridization (FISH)-particularly near the cut-off defining positive status-and clinical outcomes have been limited by small sample sizes. Patients and methods: Data were pooled from three large prospective trials (one single-arm and two randomized versus chemotherapy) of crizotinib in patients with ALK-positive NSCLC determined by Vysis ALK Break Apart FISH using a cut-off of ≥15% ALK-positive cells. Logistic regression and proportional hazards regression analyses were used to explore the association of percent ALK-positive cells with objective response and progression-free survival (PFS), respectively. Results: Of 11 081 screened patients, 1958 (18%) were ALK positive, 7512 (68%) were ALK negative, and 1540 (14%) were uninformative. Median percentage of ALK-positive cells was 58% in ALK-positive patients and 2% in ALK-negative patients. Of ALK-positive patients, 5% had 15%-19% ALK-positive cells; of ALK-negative patients, 2% had 10%-14% ALK-positive cells. Objective response rate for ALK-positive, crizotinib-treated patients with ≥20% ALK-positive cells was 56% (n = 700/1246), 55% (n = 725/1312) for those with ≥15% ALK-positive cells, and 38% for those with 15%-19% ALK-positive cells (n = 25/66). As a continuous variable, higher percentages of ALK-positive cells were estimated to be associated with larger differences in objective response and PFS between crizotinib and chemotherapy; however, tests for interaction between treatment and percentage of ALK-positive cells were not significant (objective response, P = 0.054; PFS, P = 0.17). Conclusions: Patients with ALK-positive NSCLC benefit from treatment with crizotinib across the full range of percentage of ALK-positive cells, supporting the clinical utility of the 15% cut-off. The small number of patients with scores near the cut-off warrant additional study given the potential for misclassification of ALK status due to technical or biologic reasons.

Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer).

BACKGROUND: Chemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC. PATIENTS AND METHODS: Patients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80-120 mg/day, depending on body surface area; days 1-28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2. RESULTS: A total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833-1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913-1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm. CONCLUSION: S-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC. CLINICAL TRIAL NUMBER: Japan Pharmaceutical Information Center, JapicCTI-101155.

Randomized phase II study of two intercalated combinations of eribulin mesylate and erlotinib in patients with previously treated advanced non-small-cell lung cancer.

BACKGROUND: This phase II, open-label study investigated intercalated combinations of eribulin and erlotinib in unselected patients with advanced non-small-cell lung cancer previously treated with platinum-based chemotherapies. PATIENTS AND METHODS: Eligible patients were randomized to eribulin mesylate 2.0 mg/m(2) on day 1 with erlotinib 150 mg on days 2-16 (21-day regimen) or eribulin mesylate 1.4 mg/m(2) on days 1 and 8 with erlotinib 150 mg on days 15-28 (28-day regimen). The primary end point was objective response rate (ORR). RESULTS: One hundred and twenty-three patients received ≥ 1 cycle of therapy (63, 21-day regimen; 60, 28-day regimen). ORRs were 13% [95% confidence interval (CI) 6%-24%] and 17% (95% CI 8%-29%), and disease control rates were 48% (95% CI 35%-61%) and 63% (95% CI 50%-75%) for the 21- and 28-day regimens, respectively. The median progression-free survival and overall survival were similar with both regimens. Both regimens were well tolerated with common grade ≥ 3 toxicities being neutropenia, asthenia/fatigue, and dyspnoea. Sequential administration of erlotinib did not interfere with the pharmacokinetic profile of eribulin. CONCLUSION: Intercalated combination of eribulin and erlotinib demonstrated modest activity and the addition of erlotinib did not appear to improve treatment outcome in an unselected population. The 28-day regimen is suitable for further investigation. Clinicaltrials.gov identifier: NCT01104155.

A phase II, multicenter, open-label randomized study of motesanib or bevacizumab in combination with paclitaxel and carboplatin for advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This phase II study estimated the difference in objective response rate (ORR) among patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) receiving paclitaxel-carboplatin (CP) plus motesanib or bevacizumab. PATIENTS AND METHODS: Chemotherapy-naive patients (N = 186) were randomized 1:1:1 to receive CP plus motesanib 125 mg once daily (qd) (arm A), motesanib 75 mg twice daily (b.i.d.) 5 days on/2 days off (arm B), or bevacizumab 15 mg/kg every 3 weeks (q3w) (arm C). The primary end point was ORR (per RECIST). Other end points included progression-free survival (PFS), overall survival (OS), motesanib pharmacokinetics, and adverse events (AEs). RESULTS: ORRs in the three arms were as follows: arm A, 30% (95% confidence interval 18% to 43%); arm B, 23% (13% to 36%); and arm C, 37% (25% to 50%). Median PFS in arm A was 7.7 months, arm B 5.8 months, and arm C 8.3 months; median OS for arm A was 14.0 months, arm B 12.8 months, and arm C 14.0 months. Incidence of AEs was greater in arms A and B than in arm C. More grade 5 AEs not attributable to disease progression occurred in arm B (n = 10) than in arms A (n = 4) and C (n = 4). Motesanib plasma C(max) and C(min) values were consistent with its pharmacokinetic properties observed in previous studies. CONCLUSIONS: The efficacy of 125 mg qd motesanib or bevacizumab plus CP was estimated to be comparable. Toxicity was higher but manageable in both motesanib arms. Efficacy and tolerability of motesanib 125 mg qd plus CP in advanced nonsquamous NSCLC are being further investigated in a phase III study.

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer.

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highlight the recent developments in the management of advanced-stage non-small cell lung cancer and to compare the differences in clinical practice between Eastern and Western countries.

A randomized study of aprepitant, ondansetron and dexamethasone for chemotherapy-induced nausea and vomiting in Chinese breast cancer patients receiving moderately emetogenic chemotherapy.

OBJECTIVES: This is a single center, randomized, double-blind placebo-controlled study to evaluate the NK(1)-receptor antagonist, aprepitant, in Chinese breast cancer patients. The primary objective was to compare the efficacy of aprepitant-based antiemetic regimen and standard antiemetic regimen for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients who received moderately emetogenic chemotherapy. The secondary objective was to compare the patient-reported quality of life in these two groups of patients. PATIENTS AND METHODS: Eligible breast cancer patients were chemotherapy-naive and treated with adjuvant AC chemotherapy (i.e. doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2)). Patients were randomly assigned to either an aprepitant-based regimen (day 1, aprepitant 125 mg, ondansetron 8 mg, and dexamethasone 12 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, aprepitant 80 qd) or a control arm which consisted of standard regimen (day 1, ondansetron 8 mg and dexamethasone 20 mg before chemotherapy and ondansetron 8 mg 8 h later; days 2 through 3, ondansetron 8 mg bid). Data on nausea, vomiting, and use of rescue medication were collected with a self-report diary, patients quality of life were assessed by self-administered Functional Living Index-Emesis (FLIE). RESULTS: Of 127 patients randomized, 124 were assessable. For CINV in Cycle 1 AC, there was no significant difference in the proportion of patients with reported complete response, complete protection, total control, 'no vomiting', 'no significant nausea' and 'no nausea'. The requirement of rescue medication appears to be lesser in patients treated with the aprepitant-based regimen compared to those with the standard regimen (11% vs. 20%; P = 0.06). Assessment of FLIE revealed that while there was no difference in the nausea domain and the total score between the two groups; however, patients receiving standard antiemetic regimen had significantly worse quality of life in the vomiting domain (mean score [SD] = 23.99 [30.79]) when compared with those who received the aprepitant-based regimen (mean score [SD] = 3.40 [13.18]) (P = 0.0002). Both treatments were generally well tolerated. Patients treated with the aprepitant-based regimen had a significantly lower incidence of neutropenia (53.2% vs. 35.5%, P = 0.0468), grade >or= 3 neutropenia (21.0% vs. 45.2, P = 0.0042) and delay in subsequent cycle of chemotherapy (8.1% vs. 27.4%, P = 0.0048). CONCLUSION: The aprepitant regimen appears to reduce the requirement of rescue medication when compared with the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide, and is associated with a better quality of life during adjuvant AC chemotherapy.

A Randomized Assessor-Blinded Wait-List-Controlled Trial to Assess the Effectiveness of Acupuncture in the Management of Chemotherapy-Induced Peripheral Neuropathy.

PURPOSE: Chemotherapy-induced peripheral neuropathy is a complex side effect with few available treatment options. The aim of the study was to test the effectiveness of an 8-week course of acupuncture in the management of chemotherapy-induced peripheral neuropathy in cancer patients who were receiving or had received neurotoxic chemotherapy. METHODS: Randomized assessor-blinded controlled trial with 2 arms; one arm received acupuncture twice weekly for 8 weeks, while the other arm was a wait-list control group receiving only standard care. Primary outcome was pain intensity and interference over the past week using the Brief Pain Inventory at the end of the intervention. Secondary outcomes included clinical assessment (CTCAE [Common Toxicity Criteria for Adverse Events] grading and Total Neuropathy Score-Clinical Version) and nerve conduction studies; and patient-reported outcome measures (Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity Quality of Life scale and Symptom Distress Scale) assessed at baseline, end of treatment (8 weeks), week 14, and week 20 from the beginning of treatment. RESULTS: Eighty-seven patients were randomized to the experimental arm (n = 44) and to the standard care wait-list control arm (n = 43). Significant changes at 8 weeks were detected in relation to primary outcome (pain), the clinical neurological assessment, quality of life domains, and symptom distress (all P < .05). Improvements in pain interference, neurotoxicity-related symptoms, and functional aspects of quality of life were sustained in the 14-week assessment ( P < .05), as were physical and functional well-being at the 20-week assessment ( P < .05). CONCLUSIONS: Acupuncture is an effective intervention for treating chemotherapy-induced peripheral neuropathy and improving patients' quality of life and experience with neurotoxicity-related symptoms with longer term effects evident.

Haem oxygenase-1 plays a central role in NNK-mediated lung carcinogenesis.

The tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung cancer inducer. However, how NNK induces lung cancer is still largely unknown. Haem oxygenase (HO)-1 was evaluated in 30 pairs of lung cancer tumour samples and matched nontumour tissues from patients with a history of cigarette smoking. Expression of HO-1, p21(Cip1/Waf1/Cid1) (p21), B-cell lymphoma (Bcl)-2 family members, mitogen-activated protein kinase and nuclear factor (NF)-kappaB was also studied in lung cancer cells treated with NNK. The levels of HO-1 and p21 were significantly increased in lung tumour tissues. There was a positive relationship between these two proteins in the tumour. NNK stimulated lung cell proliferation and elevated the levels of HO-1, p21, inhibitor of apoptosis protein (c-IAP)2 and Bcl-2, but downregulated Bad. These effects of NNK were blocked by zinc protoporphyrin-XII, an HO-1 inhibitor. The NNK-mediated expression of HO-1 was governed by NF-kappaB and extracellular signal-regulated kinase 1/2, since blocking either of these prevented the stimulatory effect of NNK on HO-1, as well as molecules downstream of HO-1, such as p21, c-IAP2, Bcl-2 and Bad. In conclusion, haem oxygenase-1 plays a central role in NNK-mediated cell proliferation by promoting the expression of p21(Cip1/Waf1/Cid1), inhibitor of apoptosis protein 2 and B-cell lymphoma-2 but inhibiting the activity of Bad. Nuclear factor-kappaB and extracellular signal-regulated kinase 1/2 function upstream of haem oxygenase-1. Therefore, haem oxygenase-1 is likely to be a potential target in the treatment of smoking-related lung cancer.

The Role of Radiotherapy in Epidermal Growth Factor Receptor Mutation-positive Patients with Oligoprogression: A Matched-cohort Analysis.

AIMS: Almost all patients with epidermal growth factor receptor (EGFR) mutations will develop resistance to first-line EGFR tyrosine kinase inhibitors (TKIs). The management of oligoprogression on EGFR TKI is controversial. Irradiating progressing tumours may potentially eradicate the resistant clone and allow continuation of EGFR TKI, but the clinical data remain sparse. We aimed to assess the effect of radiotherapy on survival outcomes in patients with oligoprogression in a matched-cohort study. MATERIALS AND METHODS: This was a retrospective matched-cohort study comparing patients with EGFR mutation-positive stage IV non-small cell lung cancer receiving radiotherapy versus chemotherapy for progression. Patients in the radiotherapy group received radiotherapy (mainly stereotactic ablative radiotherapy) for oligoprogression, whereas the chemotherapy group received only systemic chemotherapy upon progression. Key prognostic factors including gender, age, performance status, time to first progression and mutation subtypes were matched. RESULTS: Twenty-five patients with oligoprogression (radiotherapy group) were identified, and a matched chemotherapy group with the same number of patients was generated. The median duration of follow-up was 24.3 and 34 months for the radiotherapy and chemotherapy groups, respectively. The median overall survival of the radiotherapy group was significantly longer than the chemotherapy group, 28.2 versus 14.7 months (P = 0.026). The median progression-free survival (PFS) was 7.0 and 4.1 months after radiotherapy and chemotherapy, respectively (P = 0.0017). The use of radiotherapy was an independent predictive factor of overall survival and PFS in multivariate analysis. Only one patient had ≥grade 3 toxicity after radiotherapy. The frequency of secondary T790M mutation and subsequent Osimertinib exposure were similar in both groups. CONCLUSION: Radiotherapy may effectively extend EGFR TKI therapy for patients with oligoprogression on TKI. Improved PFS and overall survival were observed, although potential biases should not be overlooked. Further randomised studies are warranted.

Complete pathological remission is possible with systemic combination chemotherapy for inoperable hepatocellular carcinoma.

The purpose of this Phase II study was to determine the response rate, the toxicity, and the effect on survival of the combination of cisplatin, doxorubicin, 5-fluorouracil, and alpha-IFN (PIAF) in advanced unresectable hepatocellular carcinoma. Fifty patients with either unresectable or metastatic disease were treated with PIAF: cisplatin (20 mg/m2 i.v., days 1-4), doxorubicin (40 mg/m2 i.v., day 1), 5-fluorouracil (400 mg/m2 i.v., days 1-4), and alpha-IFN (5 MU/m2 s.c., days 1-4). Treatment was repeated every 3 weeks to a maximum of six cycles. All patients were evaluable for response, toxicity, and survival. As assessed by conventional imaging criteria, there were no complete responses, but 13 patients (26%) had a partial response. Among the 36 patients who had an initially high alpha-fetoprotein level (>500 ng/ml), 15 (42%) had a >50% fall after therapy. Nine patients underwent surgical resection after achieving partial response and, in 4 of these patients, histological examination of the resected specimens revealed no viable tumor cells. All these nine patients are alive, and eight patients remain in complete remission at between 7.6 and 25.8 months at the time of analysis. The overall median survival was 8.9 months. Toxicity was mainly myelosuppression and mucositis. There were two treatment-related deaths due to neutropenic sepsis. PIAF is active in hepatocellular carcinoma despite considerable hematological toxicity. Complete pathological remission is possible with this systemic combination. Apparently, persistent radiological lesions may still represent complete pathological resolution of active disease.