Background

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with EGFR-T790M mutantion non-small-cell lung cancer (NSCLC) who fail treatment with first-generation EGFR TKIs. Identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. One of the major resistant mechanisms is EGFR-C797S mutation. Other mechanisms, such as MET amplifications and BRAF, and PIK3CA mutations, were also reported. In this study, we performed gene mutational profiling in a cohort of 117 EGFR-T790M NSCLC patients and acquired resistance to osimertinib using targeted NGS.

Methods

A total of 117 patients with stage IIIb-IV EGFR-T790M NSCLC were undergoing tumor biopsies, blood or serous effusions withdrawing by the time of acquiring resistance to osimertinib. We used targeted NGS to detect genes status of patients.

Results

In total, we identified 213 genetic alterations with a median of 4 mutations per patient. 58.12% (68/117) of patients still exhibit EGFR-T790M, 71.79% (84/117) of patients still exhibit EGFR sensitive mutations and 23.08% (27/117) of patients acquired EGFR-C797S mutations [Cis structure: 51.85% (14/27); Trans structure: 66.67% (18/27); Cis and trans structure coexistence: 18.52% (5/27)]. Besides other known resistance mechanisms, we identified MET amplification 16.24% (19/117) of patients, PIK3CA mutations in 10.26% (12/117) of patients, and KRAS mutations in 8.55% (10/117) of patients. Interestingly, we also observed TMPRSS2 and KIAA0226 mutations in EGFR-C797S/L718Q/L844V/L792F wild patients, which are restricted to osimertinib treatment resistance.

Conclusions

Our study uncovered mutational profiles of NSCLC patients with osimertinib resistance with potential therapeutic implications, and this study also is first study to depict the genetic landscapes comprehensively in Chinese NSCLC population resistant to osimertinib. Our analysis strongly suggests that MET amplification, PIK3CA mutations and KRAS mutations may serve as bypass resistance mechanisms in patients who are EGFR-C797S/L718Q/L844V/L792F wild type.

Legal entity responsible for the study

Chunwei Xu

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors (ICIs) significantly prolong the survival of patients with non-small cell lung cancer (NSCLC), both those receiving second-line as well as first-line chemotherapy. In KEYNOTE 024, pembrolizumab showed a survival benefit in patients undergoing first-line chemotherapy for NSCLC, with a ≥ 50% proportion of PD-L1 tumor staining compared with chemotherapy. Moreover, progression free survival (PFS) in the second-line was also improved for patients in the pembrolizumab arm, suggesting that ICIs may have some effect on subsequent chemotherapy. In this study, we performed a multicentre collaborative and retrospective analysis of patients with NSCLC for whom chemotherapy was administered after ICIs.

Methods

To investigate the efficacy and safety of chemotherapy after ICIs, we retrospectively analysed 48 patients with NSCLC who received chemotherapy after nivolumab treatment from December 2015 to December 2016 in several centres including Okayama University Hospital.

Results

The histological diagnosis was adenocarcinoma in 33 (68.8%), squamous cell carcinoma in 9 (18.8%), and other in 6 (12.5%) patients. Thirteen patients harboured an EGFR mutation and one patient an ALK mutation. The median administration line of nivolumab was 3.5 (range: 2–11), and the median number of administrations was 4 (range: 1–16) courses. Treatment regimens after nivolumab were platinum doublet in 8 (24.2%), non-platinum doublet in 4 (8.3%), single agent in 29 (60.4%), and tyrosine kinase inhibitors (TKIs) in 7 (14.6%) patients. The objective response rate was 8.3% (CR: 0, PR: 4, SD: 25, PD: 15, and NE: 4). The median PFS and overall survival (OS) of patients who received cytotoxic chemotherapy were 99 days [95% confidence interval (CI): 63–118] and 313 days [95% CI: 225–NA], respectively. The median PFS of patients who used a TKI was 140.0 days, and no interstitial lung disease occurred. No correlation was detected between the response to nivolumab and subsequent chemotherapy.

Conclusions

Administration of nivolumab had no effect on the response rate or PFS of subsequent chemotherapy, but there was a good trend for OS. Since ICIs may have long-term influences for sequential treatment, further examination is required by increasing the number of cases and the observation period.

Clinical trial identification

none

Legal entity responsible for the study

N/A

Funding

None

Disclosure

T. Ninomiya: I received Research funding from AstraZeneca, Boehringer Ingelheim, Nippon Kayaku, Daiichi Sankyo, Shionogi and Honoraria from Chugai Pharmaceutical, Boehringer Ingelheim, Merck Serono, outside the submitted work. K. Ohashi: I received Research funding from Boehringer-Ingelheim, Novartis, Lilly, and Honoraria from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical, outside the submitted work. K. Hotta: I received personal fees from Nihon Kayaku, Sanofi-Aventis, during the conduct of the study; grants and personal fees from Merck, Chugai Pharmaceutical, Lilly, personal fees from AstraZeneca, Daiichi-Sankyo Pharmaceutical, Boehringer-Ingelheim, Taiho Pharmaceutical, Kyowa-Kirin, Ono, BMS, Novartis, and Pfizer, outside the submitted work. K. Kiura: I received grants and personal fees from Eli Lilly Japan, AstraZeneca, Chugai Pharmaceutical, Boehringer-Ingelheim, Kyowa Hakko Kirin, personal fees from Taiho Pharmaceutical, Pfizer Inc. Japan, grants from Ono Pharmaceutical, Astellas Pharmaceutical, outside the submitted work.

All other authors have declared no conflicts of interest.

Background

Pancreatic cancer (PC) is one of the most aggressive and death-relating malignancy. Gemcitabine (GEM) is the key agent in the first-line standard regimen for advanced PC, which is mostly diagnosed at advanced stage and unsuitable for curative resection. The objective responsive rate (ORR) and medium progression free survival (PFS) of various GEM-based regimens are still unsatisfied. Therefore, development of new therapeutic modalities, including immunotherapy, is needed. This study is to investigate the efficacy, safety and clinical beneficial of combination personalized immunotherapy with GEM and radiotherapy in locally advanced and metastatic PC patients.

Methods

Three locally advanced unresectable and seven metastatic PC patients received at least two cycles of GEM (1000mg/m² on day 1 and day 6), radiotherapy combing with personalized peptide vaccine induced DC vaccination on day 7 and cytotoxic T lymphocyte transfer from day 12 to 15 (repeated every 21 days). The locally advanced unresectable PC patients received stereotactic body radiotherapy (SBRT) with a total amount of 50-66Gy during the first cycle. For metastatic patients, their partial lesions received a low dose radiation (0.5Gy bid*2 days) on day 10 and 11 in each cycle.

Results

Two cases were observed with partial remission (PR), five with stable disease (sd), and three with progressive disease (PD). The disease control rate (DCR) was 70%. Median progression free survival (PFS) was 6.4 months. After the first treatment cycle, the total effectiveness for pain easement and increasing appetite are 100% (8/8) and 66.7%, respectively. Haematotoxicities with a 40% incidence rate were the most common adverse drug reactions. Two patients had grade 1 to 2 neutropenia, two with grade 3 to 4 thrombocytopenia. Three patients suffered grade 1 to 2 gemcitabine-induced skin rash. No treatment-related mortality occurred.

Conclusions

Personalized adoptive immunocyte transfer combined chemoradiotherapy demonstrated an acceptable response and safety in advanced pancreatic cancer patients.

Legal entity responsible for the study

The Comprehensive Cancer Centre of Drum Tower Hospital

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The expression of human epidermal growth factor receptors 2 (HER2) and hormonal receptors (estrogen receptor and progesterone receptors) on breast cancer are important markers that always be determined on breast cancer patients. Association between HER2 and hormonal receptors (ER and PR) expression are used as a prognostic and predictive factor on breast cancer. This research aimed to determine the association between HER2, ER, and PR on breast cancer.

Methods

This study was an analytical with cross-sectional design. This study was conducted from May 2015 – December 2015 in oncology division of surgery department RSUP DR. M. Djamil, Padang. Research subjects were 373 of breast cancer patients from 2011 – 2015. Chi square analysis test was used to determine the significant relationship between the variables.

Results

This study involved 124 cases with HER2+ and 249 cases with HER2-. Significant differences in the cases were ER+/HER2- (85.2%) compared with ER+/HER2 (14.8%) with p < 0.001. We also obtained the same tendency on PR+/HER2- (82.7%) compared with PR+/HER2 + (17.3%) with p < 0.001.

Conclusions

This study concluded that there were significant differences between expression of HER2 and hormonal receptors (ER and PR).

Clinical trial identification

This is not a trial idetification research

Legal entity responsible for the study

Medical Faculty of Andalas University

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Hospice Africa Uganda has three branches, Mobile Hospice Mbarara, Hospice Kampala, and Little Hospice Hoima project to help patients get treatment for cancer (palliative care). In view of this we aimed to find out the factors which influence their late presentation at Hospitals. The World Health Organization (2015) has reported that cancer is the second most common cause of death and was responsible for over 25000 deaths in 2015, approximately 80% occurring in developing countries. It was projected that thiswill increase by 25% over the next 10 years if nothing is done such as putting adequate screening, treatment and prevention measures in place.

Methods

The study took place across the three sites of Hospice Africa Uganda. It has cared for about 70500 patients of which 55300 are cancer patients. A qualitative study was used to interview the patients so as to get a deep understanding of the reasons why patients with cancer present late for treatment at regional hospitals and national referral hospitals. Using the semi structured questionnaire guided the interviewers because it helped the patients to discuss freely the reasons why they report late. Then, data was transcribed and analyzed. A report was written and shared with the team of Hospice Africa Uganda across the three branches. These patients were interviewed at the three sites of hospice because come for the palliative care and during the outreach only patients with cancer were elegible for the study. The researchers used local language during the interviews since the majority of patients are more fluent in local language than English. A recording tape was used to store all the discussions for flexibility.

Results

Of theses patients, 68.5% did not have financial support to carry out early investigation, were peasant farmers, with little knowledge of cancer,17.9% had the financial support but were lazy to go to the hospital for checkup.14.3% did not give clear reason, while others were coming far away from the health units.

Conclusions

There is a very big role for the government, and health workers to sensitize the public, set up more health facilities and train more healthcare workers.

Legal entity responsible for the study

Hospice

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

Prognostic nutritional index (PNI), based on serum lymphocyte counts and albumin levels, has been introduced as a simple and easily measurable biomarker, representing the nutritional and immunological status of cancer patients. However, the nutritional and inflammatory conditions can be different between pre- and post-operative statuses because of eradication of primary tumors, and major surgeries can influence the general condition and immune reaction of a host. Here, we aimed to examine the prognostic role of prognostic nutritional index (PNI) dynamics in the pre- and postoperative periods in patients with renal cell carcinoma (RCC) who underwent radical nephrectomy (RN).

Methods

We analyzed 324 patients with RCC who underwent RN. Overall population was classified into 4 groups according to 4 types of pre- to postoperative PNI dynamics as follows: Group 1 (low → low PNI), 2 (low → high PNI), 3 (high → low PNI) and 4 (high → high PNI). The level of PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte counts in blood (/mm³). Primary and secondary endpoints were cancer-specific survival (CSS) and overall survival (OS), respectively.

Results

Patients with higher pre- and postoperative PNI (> 45) had better survival outcomes than those with lower pre- and postoperative PNI (≤ 45). Notably, patients in Group 4 showed the best CSS and OS rates, whereas patients in Group 1 had the worst survival outcomes. Furthermore, PNI dynamics was identified as an independent predictor for CSS and OS outcomes, in addition to pre- and postoperative PNI, tumor size, and pathologic T (pT) stage. Patients with localized RCC (≤ pT2) showed significant differences in both CSS and OS estimates, while patients with advanced pT stage (≥ pT3) demonstrated a difference only in OS outcomes, according to PNI dynamics.

Conclusions

In summary, PNI dynamics in pre- and postoperative status was identified as a valuable predictor of survival outcomes in patients with RCC undergoing RN. Our study is the first that provides the independent prognostic importance of dynamics of nutritional status for patients with RCC.

Legal entity responsible for the study

Samsung Medical Center, Sungkyunkwan University School of Medicine.

Funding

Korea Health Industry Development Institute (KHIDI)

Disclosure

All authors have declared no conflicts of interest.

Background

Pembro monotherapy demonstrated promising antitumor activity and acceptable safety in pretreated patients (pts) with PD-L1⁺ mTNBC in the phase Ib KEYNOTE-012 study. The addition of pembro to chemo may enhance antitumor activity. KEYNOTE-355 is a global phase III study comparing pembro + chemo to PBO + chemo in pts with locally recurrent, inoperable, and previously untreated TNBC/mTNBC.

Trial design

Eligible pts are ≥18 y, have centrally confirmed, locally recurrent inoperable TNBC or mTNBC not treated previously with chemo (prior [neo]adjuvant chemo allowed); measurable disease per RECIST v1.1; ECOG PS 0-1; ≥6 mo between definitive breast surgery or last dose of adjuvant chemo (whichever was last) and first disease recurrence (≥12 mo if prior treatment with same-class agent). Part 1 is an open-label, unblinded safety run-in of ∼30 pts distributed over 3 arms (pembro + nab-paclitaxel, pembro + paclitaxel, pembro + gemcitabine/carboplatin). Part 2 is a double-blind, PBO-controlled study of ∼828 pts randomized 2:1 to pembro 200 mg Q3W + chemo (nab-paclitaxel 100 mg/m² on d 1, 8, and 15 every 28 d; paclitaxel 90 mg/m² on d 1, 8, and 15 every 28 d; or gemcitabine 1000 mg/m² + carboplatin AUC 2 on d 1 and 8 every 21 d) or PBO + chemo. Crossover is not allowed. Stratification factors are study chemo (taxane vs gemcitabine/carboplatin), prior therapy with same-class agent in (neo)adjuvant setting (yes/no), and tumor PD-L1 expression (+/-). Treatment will occur for ≤35 administrations (pembro/PBO only) or until confirmed disease progression, unacceptable toxicity, decision to discontinue, or withdrawal of consent. Primary end points are safety in part 1 and PFS (by RECIST v1.1, central radiology review) and OS in part 2. Secondary end points include ORR (by RECIST v1.1, central radiology review) and duration of response. AEs will be graded per NCI CTCAE v4.0. Responses will be assessed at wk 8, 16, 24, then at 9-wk intervals up to 1 y, and 12-wk intervals thereafter. An interim safety analysis will occur in part 1 after pts complete 1 treatment cycle.

Clinical trial identification

NCT02819518.

Legal entity responsible for the study

Merck & Co., Inc., Kenilworth, NJ, USA

Funding

Merck & Co., Inc., Kenilworth, NJ, USA

Disclosure

J. Cortes Castan: Advisory board: Roche, Celgene, AztraZeneca, Cellestia Biotech, and Biothera Honoraria: Roche, Novartis, Eisai, Celgene, Pfizer, Z. Guo, V. Karantza: Employment and stock ownership: Merck & Co., Inc. G. Aktan: Employment and stock ownership: Merck & Co., Inc. Travel expenses: Merck & Co., Inc.