TKI Group Research Articles

Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial.

This multicenter, randomized, phase III clinical trial (Northern Radiation Oncology Group of China-002) focused on patients with oligo-organ metastatic non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. We aimed to investigate whether first-line concurrent thoracic radiotherapy (TRT) and EGFR-tyrosine kinase inhibitors (TKIs), compared with TKIs alone, could achieve better survival. The patients in the TKI plus TRT group received 60 Gy to primary lung tumor and positive regional lymph nodes. Radiotherapy for metastases to other sites was determined by clinicians. The primary end point was the progression-free survival (PFS). Secondary end points included overall survival (OS) and treatment-related adverse events (TRAEs). The first and second interim analyses were performed in March 2021 and March 2022. Between April 14, 2016, and February 25, 2022, a total of 118 patients were enrolled. Compared with the TKI alone group, the TKI plus TRT group achieved significantly better PFS (hazard ratio [HR], 0.57; P = .004) and OS (HR, 0.62; P = .029). The median PFS was 10.6 months in the TKI alone group and 17.1 months in the TKI plus TRT group. The median OS was 26.2 months and 34.4 months in the TKI alone group and TKI plus TRT group, respectively. The TKI plus TRT group showed better local control but was associated with a higher incidence of severe TRAEs (11.9% v 5.1%). For patients with EGFR-mutated oligo-organ metastatic NSCLC treated with first-line EGFR-TKIs, concurrent TRT improves the PFS and OS, and TRAEs are acceptable and tolerable.

Efficacy and safety of transcatheter arterial chemoembolization followed by hepatic arterial infusion chemotherapy combined with TKI and PD-1 inhibitors as first-line treatment for advanced hepatocellular carcinoma

To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) followed by hepatic arterial infusion chemotherapy (HAIC) combined with TKI drugs and PD-1 inhibitors as the first-line treatment for advanced hepatocellular carcinoma (HCC). We retrospectively analyzed the data of 70 patients with advanced HCC treated in the Department of Oncology of Guangdong Provincial Hospital of Integrated Traditional Chinese and Western Medicine between July, 2020 and June, 2023. 23 of the patients received TACE combined with HAIC and TKI (TACE+HAIC+ TKI group) and 47 received TACE combined with HAIC, PD-1 inhibitors and TKI (TACE+HAIC+PD-1+TKI group). The clinical characteristics, laboratory test results, efficacy, outcomes and adverse events of the patients were compared between the two groups. The TACE+HAIC+TKI and TACE+HAIC+PD-1+TKI groups had significantly different objective remission rates (ORR; 60.87% vs 36.17%, P=0.031), comparable disease control rates (95.65% vs 93.62%, P=0.068), and different median progression-free survival (PFS) time (10.2 vs 11.8 months, P=0.003) and median overall survival (OS) time (15.7 vs 19.5 months, P=0.035). After propensity score matching (PSM), the median PFS and OS time of the two groups was 10.1 vs 14.5 months (P= 0.024) and 14.2 vs 21.2 months (P=0.221), respectively. The 1-year PFS rates of the 2 groups were 24.0% vs 52.2%, and the 1-, 2-and 3-year OS rates were 72.3% vs 93.1%, 23.9% vs 63.8%, and 23.9% vs 36.5%, respectively. The incidence of proteinuria was significantly higher in TACE+HAIC+PD-1+TKI group than in TACE+HAIC+TKI group (21.28% vs 0, P=0.025), but the incidences of grade 3-4 treatment-related adverse events were all similar between the two groups. The first-line treatment with TACE+HAIC+PD-1+TKI is safe and effective for advanced HCC and can significantly prolong the survival of the patients.

Clinical outcomes and prognostic factors in metastatic nonclear cell renal cell carcinoma treated with immuno-oncology combination therapy.

Metastatic nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with poor prognosis. The clinical characteristics and prognostic factors of immuno-oncology (IO) combination therapy for nccRCC are not well known. This study analyzed patients with metastatic nccRCC treated with IO combination therapy. We retrospectively collected data from 447 patients with metastatic RCC treated with IO-based combination therapy as first-line treatment between September 2018 and July 2023 in a Japanese multicenter study. The primary endpoints were objective response rate, progression-free survival (PFS), and overall survival (OS), comparing groups treated with IO-IO and IO-tyrosine kinase inhibitor (TKI) therapies. Seventy-five patients with metastatic nccRCC were eligible for analysis: 39 were classified into the IO-IO group and 36 into the IO-TKI group. Median PFS was 5.4months (95% CI: 1.6-9.1) for the IO-IO group and 5.6 (95% CI: 3.4-12.0) for the IO + TKI group. Median OS was 24.2months (95% CI: 7.5-NA) for the IO-IO group and 23.4 (95% CI: 18.8-NA) for the IO + TKI group, with no significant difference. In univariate analysis, International Metastatic Renal Cell Carcinoma Database Consortium scores, Karnofsky performance status, neutrophil-to-lymphocyte ratio, and the presence of liver metastases were significantly associated with OS, whereas in multivariate analysis, only the presence of liver metastases was significantly associated with OS (P = .035). There was no significant difference in OS or PFS between IO-IO and IO-TKI combination therapy as first-line treatment for patients with nccRCC. Liver metastasis is a poor prognostic factor for such patients.

Efficacy and Safety of TACE Combined with a Tyrosine Kinase Inhibitor for the Treatment of TACE-Refractory Hepatocellular Carcinoma: A Retrospective Comparative Study.

Combining angiogenesis inhibitors may enhance therapeutic efficacy synergistically after TACE refractoriness. The purpose of this study was to compare the outcomes of transarterial chemoembolization (TACE) plus a tyrosine kinase inhibitor (TACE-TKI) with TKI only for patients with TACE-refractory hepatocellular carcinoma (HCC). From January 2019 to March 2022, 101 HCC patients confirmed with TACE-refractory were retrospectively reviewed in the study. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were evaluated between groups. Fifty-two patients undergoing TACE-TKI, while 32 patients receiving TKI alone were included. The objective response rate (ORR) was higher in the TACE-TKI group compared with the TKI group (55.8% vs. 25.0%, P = 0.006). The median PFS in the TACE-TKI group was significantly longer than that in the TKI group (7.6months vs. 4.9months, P = 0.018). The median OS was non reach to statistical longer than that in the TKI alone group (19.5months vs. 17.7months, P = 0.055). Subgroup analysis showed that TACE-TKI treatment resulted in a significantly longer median PFS and OS for Barcelona Clinic Liver Cancer (BCLC) stage B patients (PFS 11.8months vs. 5.1months, P = 0.017; OS 30.3months vs. 19.4months, P = 0.022). For patients with TACE-refractory HCC, TACE-TKI appeared to be superior to TKI monotherapy with regard to tumor control and PFS. Furthermore, for the BCLC stage B subgroup, TACE-TKI therapy was superior to TKI monotherapy in both OS and PFS.

Additional local therapy before disease progression for EGFR-mutated advanced lung cancer: a systematic review and meta-analysis.

International guidelines recommend the use of local therapy (LT) to limited progression in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). However, the use of LT before disease progression has not been extensively analyzed. This meta-analysis evaluates the efficacy and safety of administering additional LT in conjunction with first-line EGFR-tyrosine kinase inhibitors (TKIs) before disease progression in patients with EGFR-mutated advanced NSCLC. We systematically searched PubMed, Embase, and the Cochrane Library for studies published up until May 31, 2023. The LT group consisted of patients who received first-line EGFR-TKIs in conjunction with additional LT, while the TKI group comprised participants treated with first-line EGFR-TKIs alone. Studies comparing the survival outcomes of the LT and TKI groups were included in this analysis. The primary outcomes were progression-free survival (PFS) and overall survival (OS). This review was registered on PROSPERO (registration number CRD42023439913). Among the 11 investigated studies covering 1,313 patients, the LT modalities included radiotherapy, surgery, and ablation therapy, which accounted for 91%, 27%, and 27% of the studies, respectively. The pooled hazard ratios of median PFS and OS were 0.34 [95% confidence interval (CI): 0.22-0.53; P<0.001] and 0.42 (95% CI: 0.36-0.48; P<0.001), respectively, which indicated significant benefits for the LT group compared to the TKI group. There was no significant difference between the LT and TKI groups (P=0.473) regarding the incidence of grade 3 or higher adverse events. This study suggests that the strategic use of additional LT before disease progression is a promising approach for the treatment of EGFR-mutated advanced NSCLC.

Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive formicro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

Clinical efficacy and safety of adjuvant EGFR-TKIs for resected stage IB lung adenocarcinoma: A real-world study based on propensity score matching.

Adjuvant therapy for stage IB non-small cell lung cancer remains debatable. In this real-world study, we evaluate the efficacy and safety of adjuvant epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for resected stage IB lung adenocarcinoma. This real-world study recruited 249 patients diagnosed with stage IB disease after surgical resection between January 2013 and September 2021. Sixty-six (26.5%) patients received adjuvant targeted therapy (TKIs group), and 183 (73.5%) were enrolled in the clinical observation (CO) group. Propensity scores were matched to minimize the observed confounder effects between the two groups, and 59 patient pairs were matched. The primary endpoint was disease-free survival (DFS). In the TKI group, 38 (64.4%) patients chose to receive icotinib, 27.1% (16/59) received gefitinib, and 5 patients (8.5%) chose osimertinib. The median follow-up time was 30.8 months (range: 7-107 months). Two (3.4%) patients in the TKI group and 10 (16.9%) in the CO group experienced disease relapse. The 3-year DFS rates were 98.3% in the TKI group and 83.0% in the CO group (HR: 0.10; 95% CI: 0.01-0.78; p = 0.008). DFS differences were found in the entire cohort (p = 0.005) and the matched cohort (p = 0.024) between the two groups. Multivariate analysis showed that adjuvant EGFR-TKIs was an independent factor for DFS (HR: 0.211; 95% CI: 0.045-0.979; p = 0.047), along with poor cell differentiation (HR: 5.256; 95% CI: 1.648-16.769; p = 0.005), and spread through air spaces (HR: 5.612; 95% CI: 1.137-27.700; p = 0.034). None of the patients discontinued EGFR-TKIs owing to the low occurrence rate of treatment-related serious adverse events. Adjuvant EGFR-TKIs could significantly improve DFS among patients with stage IB lung adenocarcinoma compared with CO, with a safe and tolerable profile.

Upfront Use of First-/Second-Generation EGFR-TKI Followed by Osimertinib Shows Better Prognosis than Upfront Osimertinib Therapy in Japanese Patients with Non-small-cell Lung Cancer with Exon 19 Deletion: A Single-Center Retrospective Study.

Clinical evidence on the increased efficacy of sequential epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) is limited. This study aimed to compare the efficacy of upfront use of first-/second-generation TKI followed by osimertinib with upfront osimertinib therapy for each representative EGFR mutation in Japanese patients with NSCLC. Patients with EGFR-mutated NSCLC were classified into two groups: first-/second-generation TKI followed by osimertinib (sequential TKI group) and upfront osimertinib groups. The total time to treatment failure (TTF) of TKI therapies, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated. Of the 74 patients included in the analysis, 38 and 34 patients had exon 19 deletion and L858R, respectively, and other two patients had minor mutations. The sequential TKI group had a significantly longer TTF than the upfront osimertinib group in overall patients (33.2 vs. 11.2 months; p = 0.007) and in the subgroup of exon 19 deletion (36.7 vs. 10.0 months; p = 0.004), but not in the subgroup of L858R (22.6 vs. 15.6 months; p = 0.37). The similar tendency was observed in PFS. OS of the sequential TKI group was significantly longer compared with the upfront osimertinib group in overall patients, the subgroup of exon 19 deletion, and the subgroup of L858R. The upfront use of first-/second-generation TKI followed by osimertinib is one of the feasible and effective strategies in Japanese patients with EGFR-mutated NSCLC, especially in patients with exon 19 deletion.

Assessment of Tyrosine Kinase Inhibitors and Survival and Cardiovascular Outcomes of Patients With Non–Small Cell Lung Cancer in Taiwan

ImportanceTyrosine kinase inhibitors (TKIs) have been recognized as the standard treatment for patients with non–small cell lung cancers (NSCLCs) and epidermal growth factor receptor (EGFR) sequence variation. Although TKIs have been reported to cause cardiotoxicity, they are widely administered owing to the high prevalence of EGFR sequence variation in Taiwan.ObjectiveTo compare the outcomes of death and major adverse cardiac and cerebrovascular events among patients with NSCLC who use and do not use TKIs in a national cohort.Design, Setting, and ParticipantsUsing data from the Taiwanese National Health Insurance Research Database and National Cancer Registry, patients treated for NSCLC from 2011 to 2018 were identified, and their outcomes were analyzed, including death and major adverse cardiac and cerebrovascular events (MACCEs; such as heart failure, acute myocardial infarction, and ischemic stroke) after adjusting for age, sex, cancer stage, comorbidities, anticancer therapies, and cardiovascular drugs. The median follow-up duration was 1.45 years. The analyses were performed from September 2022 to March 2023.ExposuresTKIs.Main Outcomes and MeasuresCox proportional hazards models were used to estimate death and MACCEs in patients treated with and without TKIs. Given that death may reduce the incidence of cardiovascular events, the competing risk method was used to calculate the MACCE risk after adjustment for all potential confounders.ResultsOverall, 24 129 patients treated with TKIs were matched with 24 129 patients who did not receive TKIs (24 215 [50.18%] were female; and the mean [SD] age was 66.93 [12.37] years). Compared with those not receiving TKIs, the TKI group presented with a significantly lower hazard ratio (HR) of all-cause death (adjusted HR, 0.76; 95% CI, 0.75-0.78; P < .001), and the reason for death was primarily cancer. In contrast, the HR of MACCEs significantly increased (subdistribution HR, 1.22; 95% CI, 1.16-1.29; P < .001) in the TKI group. Furthermore, afatinib use was associated with a significantly reduced risk of death among patients receiving various TKIs (adjusted HR, 0.90; 95% CI, 0.85-0.94; P < .001) compared with those receiving erlotinib and gefitinib, although the outcomes of MACCEs were similar between the 2 groups.Conclusions and RelevanceIn this cohort study of patients with NSCLC, TKI use was associated with reduced HRs of cancer-related death but increased HRs of MACCEs. These findings suggest the importance of close monitoring of cardiovascular problems in individuals receiving TKIs.

Hypophosphatemia related to the use of ibrutinib.

Tyrosine kinase inhibitors (TKis) and Bruton's TKi (BTKis) constitute broadly used antitumor drug groups with almost completely tolerable and manageable side-effect profiles. Mainly side effects are cardiovascular and gastrointestinal for the TKi group. Hypophosphatemia is documented frequently in many studies with TKis but rarely mentioned with ibrutinib use up to the present. A 61-year-old patient with the diagnosis of chronic lymphocytic leukemia had hypophosphatemia-related complaints and symptoms when ibrutinib use was preferred for his second relapse of the disease. After drug discontinuation, we started ibrutinib again with an alternating dose. We managed to control hypophosphatemia, and the patient has been following up for 2 years in remission status without any support or a second drug need. We have presented here a chronic lymphocytic leukemia case that developed mild-severe hypophosphatemia associated with ibrutinib use. By using an alternating dose of ibrutinib, we managed to control the disease and drug side effects. TKis and BTKis are widely in use for different indications. Hypophosphatemia is rare but it can cause drug discontinuation or change if it is not manageable. It is mentioned that hypophosphatemia can be seen due to a common group effect with the mechanism of causing secondary hyperparathyroidism and renal tubulopathy. In our case, we could explain the side effect of hypophosphatemia with secondary hyperparathyroidism and renal tubulopathy. Prospective, large-group studies are needed to explain the hypophosphatemia and other side effects of ibrutinib and new BTKis in detail.

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis.

Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.

Immunomodulatory Effects of IFNα on T and NK Cells in Chronic Myeloid Leukemia Patients in Deep Molecular Response Preparing for Treatment Discontinuation

A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential candidates of successful TFR, we examined the phenotypic and functional host immune compartment in DMR patients who had received TKI treatment only (TKI-only) or had been previously treated with interferon-alpha (IFNα + TKI) or had received IFNα treatment only (IFNα-only). The T/NK-cell subset distribution, NK- and T-cell cytokine production, activation and maturation markers were measured in 44 patients in DMR treated with IFNα only (9), with IFNα + TKI (11) and with TKI-only (24). IFNα + TKI and TKI-only groups were eligible to TKI discontinuation according to the NCCN and ESMO guidelines (stable MR4 for more than two years). In IFNα-treated patients, we documented an increased number of lymphocytes capable of producing IFNγ and TNFα compared to the TKI-only group. In INFα + TKI patients, the percentage of NKG2C expression and its mean fluorescence intensity were significantly higher compared to the TKI-only group and to the INFα-only group in the CD56dim/CD16+ NK cell subsets (INFα + TKI vs. TKI-only p = 0.041, p = 0.037; INFα + TKI vs. INFα-only p = 0.03, p = 0.033, respectively). Furthermore, in INFα-only treated patients, we observed an increase of NKp46 MFI in the CD56bright/CD16- NK cell subset that becomes significant compared to the INFα + TKI group (p = 0.008). Our data indicate that a previous exposure to IFNα substantially and persistently modified the immune system of CML patients in memory T lymphocytes, differentiated NKG2C+ “long-lived” NK cells responses, even years after the last IFNα contact.

Extended neoadjuvant therapy in NSCLC achieved remarkable pathological complete response (pCR) rate and prolonged disease-free survival.

e20500 Background: Over 50% early stage NSCLC patients would suffer from recurrence and distant metastasis. Neoadjuvant TKI therapy had been explored aiming to reduce recurrence and metastasis. Erlotinib neoadjuvant therapy (NAT) significantly improved ORR, PFS and major pathologic response (MPR) rate in trial EMERGING/CTONG1103. In our hospital, some patients received extended neoadjuvant treatment because of continued lesion remission. These patients eventually received surgery when the lesions stopped remission and achieved remarkable pathologically complete remission (pCR) rate. Herein we analyzed the efficacy of extended NAT. Methods: 9 NSCLC patients who received extended neoadjuvant therapy in Department of Thoracic Surgery, Jiangsu Cancer Hospital from 2013-2020 were enrolled in this study. Extended neoadjuvant therapy was defined as duration of treatment longer than standard regimens (for TKI, longer than 42 days; for chemotherapy, longer than 2 cycles or 6 weeks). Pathological complete response, progression free survival (PFS), overall survival (OS) were evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Standard statistical methods, including descriptive statistics, x2 test, two-sided 95% CI were used. Results: Up to 9 patients were enrolled in this study. There were 5 patients in TKI group, 1 (20%) was male and 4 (80%) were female. There were 4 patients in chemo group, 2 (50%) were male and 2 (50%) were female. The median age of TKI and chemotherapy groups were 59 (47-70) and 62 (30-75), respectively. The median duration of treatment (DOT) were 185 (163-248) and 82 (29-98) days, respectively. Among TKI group, 4 patients were EGFR L858R positive and 1 was ALK rearrangement positive and they all received relative TKI treatment based on genetic feature. In the TKI group, all 5 patients achieved pCR, the pCR rate was 100%. In chemotherapy group, 1 out of 4 patients achieved pCR and the other 3 achieved major pathological response (MPR). The pCR rate was 25% and MPR rate was 100%. The pCR rate of TKI group was significantly higher than chemotherapy group (100% vs 25%, p &lt; 0.01). The pCR rate or MPR rate was higher than historical data. For instance, in trial CTONG 1103, neither TKI (Erlotininb) or chemotherapy (Gemcitabine) group achieved pCR, and the MPR rate was only 45% in TKI group and 51% in chemotherapy group. Extended NAT regimen in our study achieved much higher pCR rate (100% vs 0% for TKI and 25% vs 0% for chemotherapy) and MPR rate (100% vs 45%̃51%) than standard 42 days regimens used in CTONG-1103. Conclusions: Extended NAT resulted in better pCR rate and MPR rate than the standard 42-days duration of NAT. For patients with good response to TKI in the neoadjuvant stage, extending the duration neoadjuvant TKI treatment until lesions stopped remission might result in better pCR rate and might extend PFS and OS.

Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.

9114 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.

Second-line treatment with nivolumab, cabozantinib, regorafenib, or best supportive care in patients with advanced hepatocellular carcinoma: analysis at a Hispanic-majority NCI-designated cancer center.

In the last four years, six regimens were approved by the Food and Drug Association as second-line therapies for advanced hepatocellular carcinoma (HCC). However, there are significant differences between real-world and clinical trial populations. We analyzed survival and toxicities among second-line therapies for HCC in our population. We performed a retrospective cohort study of patients with advanced HCC who received second-line therapies (tyrosine kinase inhibitor or TKI; immunotherapy or IO) or best supportive care (BSC) at a tertiary-referral cancer center serving the South Texas region. Progression-free survival (PFS) was determined, and adverse events were compared between therapies. In our cohort, median age was 60 years (n=65), and 49 (75%) were Hispanic. 58 (89%) patients received second-line therapy. Child-Pugh (CP) score of cohort: A, 18%; B, 55%; C, 26%. Median PFS (mPFS) was 3.1 months with TKI (n=6), 3.3 months with IO (n=27), and 1.3 months with BSC (n=25). There was improved survival with IO compared to BSC [hazards ratio (HR) =0.31; 95% confidence interval (CI): 0.15-0.63; P=0.0014]. There was no significant difference comparing IO to TKI (HR =0.94; 95% CI: 0.31-2.86; P=0.92), but a trend to improved PFS with TKI when compared to BSC (HR =0.33; 95% CI: 0.10-1.04; P=0.058). TKI group had significantly more rash (P=0.01) and hand-foot syndrome (P<0.001) compared to IO and BSC. Our Hispanic-majority cohort with varying liver dysfunction, including CP-B & C cirrhosis, were more likely to receive IO or BSC. Both second-line treatment groups, IO or TKI, demonstrated increased mPFS compared to BSC and were tolerable compared to BSC, with expected toxicity per class of drug.

Efficacy of EGFR-TKIs monotherapy versus TKI plus chemotherapy as first-line treatment in EGFR mutant lung adenocarcinoma with liver metastases.

e21099 Background: Liver metastasis is one of the most reasons for the poor prognosis of patients with advanced lung cancer. Seeking for active and effective treatment measures is very important for these patients. At present, the first-line standard treatment of the advanced NSCLC with EGFR mutation is EGFR-TKIs monotherapy. However, its efficacy is poor in the advanced non-small cell lung cancer with EGFR mutation and liver metastases. The objective of this study is to evaluate the efficacy of EGFR-TKIs plus chemotherapy in patients with EGFR mutation of advanced non-small cell lung cancer with liver metastases. Methods: The clinical data of a total of 384 advanced NSCLC patients with EGFR mutation positive who were admitted to The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital from February 2017 to June 2020 were retrospectively analyzed. There were 75 patients with liver metastases. Patients were divided into two groups, and accepted EGFR-TKIs monotherapy or EGFR-TKIs plus chemotherapy, respectively. All patients treatment response were evaluated by the RECIST1.1 Response evaluation criteria in solid tumors.Progression free-survival (PFS) were also analyzed. Results: In the study, 75 patients were finally screened. There were 37 patients in the EGFR-TKIs monotherapy group and 38 patients in the TKI plus chemotherapy group. The median follow-up time was 23.0 months. At the latest follow-up date (2021-01-01), 57 patients had disease progression and 35 patients had died. Comparing with EGFR-TKIs monotherapy,the first-line PFS of EGFR-TKI plus chemotherapy group was longer, and the median PFS was 12.7 months VS 7.4 months (P = 0.018).The ORR of primary lung lesions was no significant difference between these two groups（65.8%VS 51.4% P = 0.204), and DCR (97.4% VS 94.6% P = 0.981) also had no difference between two groups（P &gt; 0.05）. ORR of liver metastases in the EGFR-TKIs plus chemotherapy group was significantly higher than EGFR-TKIs monotherapy group ORR (65.8%VS 40.5%，P = 0.028). Conclusions: In advanced NSCLC patients with EGFR mutation and liver metastases, comparing with EGFR-TKIs monotherapy, taking EGFR-TKIs plus chemotherapy as first-line treatment had longer PFS, and better efficacy on liver lesions.

P76.75 Clinical Outcome and Toxicity Profiles of Patients with EGFR-mutation Positive Non-Small-Cell Lung Cancer

Activating mutations of EGFR in advanced lung adenocarcinoma and its inhibition with specific tyrosine kinase inhibitors has been shown to generate clinically significant tumor responses. Treatment outcomes of advanced EGFR mutant lung carcinoma in Pakistani population are not previously reported. We conducted a study using the Real World Data (RWD) in patients with EGFR mutant advanced lung cancer treated at our institution. We evaluated clinical features, toxicity profile and outcome of these patients and compared it with those who were unable to receive TKI due to resource limitations. We identified 27 patients with advanced lung cancer harboring EGFR mutations that were treated at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, from January 2013 till April 2020. EGFR mutation detection was achieved by real time PCR. Data were collected through electronic medical record. Five patients were excluded from the analysis as they did not start treatment and were lost to follow-up. Progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier curves and log-rank analysis. Of the 22 patients analyzed, 54.5% were males and 45.5% were females. Twenty patients (90.9%) presented with de novo stage IV disease. Age ranged from 34-84 years. Frequency of Exon 19 deletion, Exon 21 L858R mutation, Exon18G7196 mutation and Exon 20 mutation was 50%, 32%, 9% and 4.5% respectively. One patient had compound Exon18G719X and Exon20S7681 mutation. 18.2% of patients had CNS metastasis at initial presentation. We identified 4 groups in our patient population. Group-1 consisted of patients who received first-generation TKI followed by third-generation TKI upon progression. Group-2 consisted of patients who received upfront first-generation TKI followed by chemotherapy upon progression. Group-3 consisted of patients who received upfront chemotherapy followed by a first-generation TKI upon progression and Group-4 consisted of patients who received upfront chemotherapy followed by second-line chemotherapy upon progression. These groups reflect the real world issues of TKI affordability in a Low Middle Income country (LMIC) such as Pakistan. Median PFS on first-line treatment (PFS1) was 10.7 months in the upfront chemotherapy group, versus 14.5 months in the upfront TKI group (p-value = 0.280). Median PFS on second-line treatment (PFS2) was 4.4 months in the chemotherapy group versus 23.7 months in the TKI group (p-value = 0.001). Median OS in Group 2, 3 and 4 was 20.0, 85.6 and 26.0 months respectively and not yet reached in Group 1 (p = 0.271). 27.8% patients developed grade I-II skin rash and diarrhea, 5.6% developed grade III-IV anemia, grade I-II neutropenia, and grade III-IV hyperbilirubinemia Within the constraints of a small sample size our real world data shows that the use of EGFR TKI in advanced EGFR mutant lung cancer is well tolerated in a Pakistani population. Use of EGFR TKI yields a superior PFS in both upfront and subsequent line of therapy which is consistent with the previously reported data. Preliminary overall survival favors superior outcome in the TKI group compared to chemotherapy alone or chemo-TKI combination groups.

A nomogram for predicting brain metastases of EGFR-mutated lung adenocarcinoma patients and estimating the efficacy of therapeutic strategies.

BackgroundTo establish a nomogram for predicting the outcome of EGFR-mutated lung adenocarcinoma patients with brain metastases (BMs) and to estimate the efficacy of different therapeutic strategies.MethodsThe data of 129 cases with BM from the period between January 1st 2011 and December 31st 2014 were collected, and all of the cases were pathologically confirmed to be lung adenocarcinoma, stages I–IV and with 19 and/or 21 exon mutations of EGFR. Cox regression analysis and log-rank test were used for data analysis. The nomogram was used to establish the progression models.ResultsIn the univariate analysis, the stage, ECOG score, interval between the diagnosis of lung cancer and BM, the number of brain metastatic lesions, and the diameter of the maximal brain metastatic lesion correlated well with overall survival (OS). In multivariate Cox proportional hazard analysis, the ECOG score, interval between the diagnosis of lung cancer and BM, and the number of brain metastatic lesions correlated well with the OS. Patients were divided into the poor prognostic group and the good prognostic group based on the nomogram prognostic model score. Subgroup analysis showed that in the poor prognostic group, the OS of patients who received radiotherapy was better than that of the patients who did not receive radiotherapy as the first-line treatment (30 vs. 19 months, P<0.05). The OS was 30 months in the TKI subgroup and 21 months in the no TKI subgroup, but no statistical difference was found (P>0.05). Patients in the good prognostic group who received radiotherapy had a better 3-y OS rate than the patients who received no radiotherapy as the first-line treatment (91.2% vs. 58.1%, P<0.05). The 3-y OS rate was 87.6% in the TKI subgroup and 67.8% in the no TKI group (P<0.05).ConclusionsWe established an effective nomogram model to predict the progression of EGFR-mutated lung adenocarcinoma patients with BM and the therapeutic effect of the individual treatments. Radiotherapy was beneficial for the patients of both the poor and good prognostic groups, but TKI may be better suited for treating the patients with good prognosis.

The Efficacy of First-Generation EGFR-TKI Combined With Brain Radiotherapy as the First-Line Treatment for Lung Adenocarcinoma Patients With Brain Metastases and EGFR Sensitive Mutations: A Retrospective study.

Background:It was controversial that whether LUAD patients with brain metastases (BMs) and EGFR sensitive mutations should be conducted using brain radiotherapy when treated with first-generation EGFR-TKI. Herein, a retrospective study was designed to compare the efficacy of first-generation EGFR-TKI combined with brain radiotherapy and EGFR-TKI alone as first-line treatment for these LUAD patients.Patients and Methods:We retrospectively analyzed the status of patients with advanced LUAD carrying EGFR sensitive mutations who received first-generation EGFR-TKI treatment in our center. iPFS was the first time of intracranial progression or death from the diagnosis of BMs, PFS was the time of progression of any site or death from the diagnosis of BMs, and OS was the time of confirmed BMs to death or the last follow-up time. Differences in characteristics between groups were compared using the Chi-square test. The Kaplan-Meier method was used to calculate the iPFS, PFS, and OS. Univariate analysis, multivariate analysis, and subgroup analysis were conducted by Cox regression model.Results:There were 77 patients (77/134, 57.5%) in the TKI + RT group and 57 patients (57/134, 42.5%) in the TKI group. TKI + RT group had a significant higher intracranial ORR and DCR, and the combination therapy was independently significantly associated with a longer iPFS (18.9 vs. 10.5 months, P = 0.0009), systematic PFS (12.5 vs. 8.4 months, P = 0.0071) and OS (30.8 vs. 22.7 months, P = 0.0183). Females, non-smokers, and younger patients benefited more from the combination therapy. Subgroup analysis demonstrated that the combination therapy could improve the iPFS in patients with more than 3 BMs (P = 0.005); however, it couldn’t improve the OS for these patients.Conclusion:Our study confirmed the effect of the combination of EGFR-TKI and brain radiotherapy as first-line treatment for LUAD patients with BMs and EGFR sensitive mutations.

Tumor genomics and response to chemotherapy in advanced non-small cell lung cancer with exon 20 insertion epidermal growth factor receptor mutations.

BackgroundTo characterize the effects of mutation subtypes and concomitant pathogenic mutations on progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations treated with chemotherapy.MethodsWe retrospectively found that patients who underwent genomic analysis from January 2017 to December 2019, and 101 patients with advanced EGFR ex20ins NSCLC were found. Binary logistic regression and Cox regression were used to determine how EGFR ex20ins mutation subtypes and concomitant mutations are associated with PFS and OS.ResultsA total of 8,348 patients were screened and 101 advanced EGFR ex20ins NSCLC patients were detected. Fifty-five patients who received chemotherapy (n=49) or TKIs (n=6) as first-line treatment were recorded for PFS and OS. PFS and OS were significantly longer in the platinum-based chemotherapy group (median PFS: 7.6 versus 5.6 months; P=0.001; median OS: 19.9 versus 7.4 months; P=0.027) than in the TKI group. Common mutations include Ala767_Val769dupAlaSerVal (A767_V769dupASV), Ser768_Asp770dupSerValAsp (S768_D770dupSVD) and Ala763_Tyr764insPheGlnGluAla (A763_Y764insFQEA). On binary logistic regression, common mutations (OR =17.04, 95% CI: 1.39–209.56; P=0.027) and number of concomitant mutations ≤1 (OR =34.67, 95% CI: 2.02–595.48; P=0.015) is significantly associated with durable clinical benefit (DCB). On multivariable analysis, common mutations (HR =0.26, 95% CI: 0.0.10–0.63; P=0.003) and the number of concomitant mutations ≤1 (HR =0.33, 95% CI: 0.15–0.73; P=0.006) were significantly associated with longer PFS.ConclusionsCommon mutations and the number of concomitant mutations ≤1 correlate with a biomarker that predicts benefit from chemotherapy and confers excellent prognosis for advanced patients with advanced EGFR ex20ins NSCLC. Patients with common mutations and with only one concomitant mutation had the greatest PFS and patients with uncommon mutations, and with over one concomitant mutation had the worst prognosis.