VEGF and VEGFR polymorphisms affect clinical outcome in advanced renal cell carcinoma patients receiving first-line sunitinib

Background:

Currently, sunitinib represents one of the therapeutic strongholds for renal cell carcinoma, but the criteria for treatment selection are lacking. We assessed the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms in the prediction of the clinical outcome in metastatic renal cell carcinoma (mRCC) patients.

Methods:

A total of 84 tumour samples from mRCC patients receiving first-line sunitinib were tested for VEGF and VEGFR single-nucleotide polymorphisms (SNPs). The SNP results were correlated with progression-free survival (PFS) and overall survival (OS).

Results:

Median PFS was 8.22 months, although whereas median OS was 32.13 months. The VEGF A rs833061 resulted significant in PFS (17 vs 4 months; P<0.0001) and OS (38 vs 10 months; P<0.0001). The VEGF A rs699947 was significant for PFS (18 vs 4 months; P=0.0001) and OS (37 vs 16 months; P<0.0001). The VEGF A rs2010963 was significant in PFS (18 vs 8 vs 2 months; P=0.0001) and OS (31 vs 36 vs 9 months; P=0.0045). The VEGR3 rs6877011 was significant in PFS (12 vs 4 months; P=0.0075) and OS (36 vs 17 months; P=0.0001). At multivariate analysis, rs833061, rs2010963 and rs68877011 were significant in PFS, and rs833061 and rs68877011 were independent factors in OS.

Conclusions:

In our analysis, patients with TT polymorphism of rs833061, CC polymorphism of rs699947, CC polymorphism of rs2010963 and CG polymorphism of rs6877011 seem to have a worse PFS and OS when receiving first-line sunitinib.     

A Q-TWiST analysis comparing panitumumab plus best supportive care (BSC) with BSC alone in patients with wild-type KRAS metastatic colorectal cancer

Background:

Panitumumab+best supportive care (BSC) significantly improved progression-free survival (PFS) vs BSC alone in patients with chemo-refractory wild-type KRAS metastatic colorectal cancer (mCRC). We applied the quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. As the trial design allowed patients on BSC alone to receive panitumumab after disease progression, which confounded overall survival (OS), the focus of this analysis was on PFS.

Methods:

For each treatment group, the time spent in the toxicity (grade 3 or 4 adverse events; TOX), time without symptoms of disease or toxicity (TWiST), and relapse (after disease progression; REL) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQoL 5-dimensions measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.

Results:

There was a significant difference between groups favouring panitumumab+BSC in quality-adjusted PFS (12.3 weeks vs 5.8 weeks, respectively, P<0.0001) and quality-adjusted OS (P=0.0303).

Conclusion:

In patients with chemo-refractory wild-type KRAS mCRC, panitumumab+BSC significantly improved quality-adjusted survival compared with BSC alone.     

Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib

BackgroundThis phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure.Patients and methodsPatients were randomized 2 : 1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC + imatinib, or BSC + sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib.ResultsTwo hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P = 0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P = 0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P = 0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days; P = 0.02). Nilotinib was well tolerated.ConclusionIn the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.     

Active Smoking May Negatively Affect Response Rate,Progression‐Free Survival,and Overall Survival of Patients With Metastatic Renal Cell Carcinoma Treated With Sunitinib

Background.

Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC).

Methods.

An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors.

Results.

Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002).

Conclusion.

Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.     

Risk of lymph node metastasis and prognostic outcome in early gastric cancer patients with mixed histologic type

BackgroundWhether early gastric cancer with mixed histologic type should be considered for endoscopic submucosal dissection (ESD) remains controversial. The objective of this study was to evaluate the risk of lymph node metastasis (LNM) and prognostic significance for early gastric cancer with mixed histologic type.MethodsWe retrospectively reviewed clinicopathologic and survival data of 302 patients who underwent surgical resection for early gastric cancer. Based on the histologic components, all patients were classified as pure differentiated type, pure undifferentiated type and mixed histologic type. The prognostic differences between different types were compared and predictive factors for LNM were evaluated.ResultsHistopathologically, the proportion of mixed histologic type was 12.3% in early gastric cancer. In terms of LNM, mixed histologic type had a more frequent incidence than pure differentiated type (32.4% vs 11.1%, P < 0.01). However, there was no significant difference between mixed type and pure undifferentiated type for LNM (32.4% vs 21.1%, P = 0.139). Multivariate analysis revealed that tumor size >2 cm (odds ratio [OR]: 2.153, 95% confidence interval [CI]: 1.113-4.164, P < 0.05), submucosal invasion (OR: 3.881, 95%CI: 1.832-8.222, P < 0.001), lymphovascular invasion (OR: 8.797, 95% CI: 2.643-29.277, P < 0.001), undifferentiated type (OR: 3.146, 95% CI: 1.352-7.320, P < 0.01), and mixed histologic type (OR: 3.635, 95% CI: 1.272-10.390, P < 0.05) were independent risk factors for LNM in early gastric cancer patients. However, mixed histologic type did not affect the survival outcome of these patients (hazard ratio: 0.629, 95% CI: 0.074-5.311, P > 0.05).ConclusionMixed histologic type was an independent risk factor for lymph node metastasis in early gastric cancer patients. The decisions regarding endoscopic submucosal dissection for mixed histologic type should be carefully considered.     

Epiregulin gene expression as a biomarker of benefit from cetuximab in the treatment of advanced colorectal cancer

Background:

Anti-EGFR antibody, cetuximab, improves overall survival (OS) in K-ras wild-type chemotherapy–refractory colorectal cancer. Epidermal growth factor receptor ligand epiregulin (EREG) gene expression may further predict cetuximab benefit.

Methods:

Tumour samples from a phase III clinical trial of cetuximab plus best supportive care (BSC) vs BSC alone (CO.17) were analysed for EREG mRNA gene expression. Predictive effects of high vs low EREG on OS and progression-free survival (PFS) were examined for treatment–biomarker interaction.

Results:

Both EREG and K-ras status were ascertained in 385 (193 cetuximab, 192 BSC) tumour samples. Within the high EREG and K-ras wild-type status (‘co-biomarker'')-positive group (n=139, 36%), median PFS was 5.4 vs 1.9 months (hazard ratio (HR) 0.31; P<0.0001), and median OS was 9.8 vs 5.1 months (HR 0.43; P<0.001) for cetuximab vs BSC, respectively. In the rest (n=246, 64%), PFS (HR 0.82; P=0.12) and OS (HR 0.90; P=0.45) were not significantly different. Test for treatment interaction showed a larger cetuximab effect on OS (HR 0.52; P=0.007) and PFS (HR 0.49; P=0.001) in the co-biomarker-positive group.

Conclusion:

In pre-treated K-ras wild-type status colorectal cancer, patients with high EREG gene expression appear to benefit more from cetuximab therapy compared with low expression. Epiregulin as a selective biomarker requires further evaluation.     

Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma

Background:

Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and the outcome of patients treated with everolimus for mRCC.

Methods:

Ninety-seven patients with mRCC were treated with everolimus till April 2013 in our institutions. Patients were stratified in two groups with NLR >3 (Group A) vs <3 (Group B). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier method. Gender, age, Motzer prognostic group, PFS on first-line therapy, neutrophilia and NLR were included in the Cox analysis to investigate their prognostic relevance.

Results:

Median OS and PFS were 10.6 and 5.3 months, respectively. Median OS was 12.2 months in Group A and 24.4 months in Group B (P=0.001). Median PFS was 3.4 months in Group A and 9.9 months in Group B (P<0.001). At multivariate analysis, only Motzer prognostic group and NLR were independent prognostic factors for OS and PFS.

Conclusion:

Pre-treatment NLR is an independent prognostic factor for patients with mRCC treated with second- or third-line everolimus. This should be investigated and validated in prospective studies.     

Nanoparticle Albumin-bound Paclitaxel Plus Carboplatin Induction Followed by Nanoparticle Albumin-bound Paclitaxel Maintenance in Squamous Non–Small-cell Lung Cancer (ABOUND.sqm): A Phase III Randomized Clinical Trial

BackgroundWe evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non–small-cell lung cancer.Patients and MethodsPatients with treatment-naive squamous non–small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m² on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m² (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS).ResultsOverall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator’s discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC).ConclusionsThe results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.     

Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma

Background:

Prognostic factors for progression-free survival (PFS), overall survival (OS), and long-term OS (⩾30 months) were investigated in sunitinib-treated patients with metastatic renal cell carcinoma (RCC).

Methods:

Data were pooled from 1059 patients in six trials. Baseline variables, including ethnicity, were analysed for prognostic significance by Cox proportional-hazards model.

Results:

Median PFS and OS were 9.7 and 23.4 months, respectively. Multivariate analysis of PFS and OS identified independent predictors, including ethnic origin, Eastern Cooperative Oncology Group performance status, time from diagnosis to treatment, prior cytokine use, haemoglobin, lactate dehydrogenase, corrected calcium, neutrophils, platelets, and bone metastases (OS only). Characteristics of long-term survivors (n=215, 20%) differed from those of non-long-term survivors; independent predictors of long-term OS included ethnic origin, bone metastases, and corrected calcium. There were no differences in PFS (10.5 vs 7.2 months; P=0.1006) or OS (23.8 vs 21.4 months; P=0.2135) in white vs Asian patients; however, there were significant differences in PFS (10.5 vs 5.7 months; P<0.001) and OS (23.8 vs 17.4 months; P=0.0319) in white vs non-white, non-Asian patients.

Conclusion:

These analyses identified risk factors to survival with sunitinib, including potential ethnic-based differences, and validated risk factors previously reported in advanced RCC.     

Survival and Prognostic Factors for Breast Cancer Patients with Regional Oligo-Recurrence

PurposeThis study aimed to evaluate survival outcomes and identify prognostic factors for regional oligo-recurrence in breast cancer patients who received salvage local treatment.MethodsIn the breast cancer registry of our institution, 18,790 patients received curative surgery for stage I–III breast cancer between January 1995 and June 2016. Of those patients, only 87 (0.5%)underwent salvage local treatment for isolated nodal recurrence on the axillary lymph nodes (ALNs) (n = 58), supraclavicular lymph nodes (SCNs) (n = 17), or internal mammary lymph nodes (IMNs) (n = 12).ResultsThe median follow-up duration after regional oligo-recurrence was 49 months (range: 6–194 months). For patients with recurrence of ALN, SCN, or IMN, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 40.0%, 32.1%, and 25.0%, respectively (p = 0.3) and 62.7%, 70.0%, and 58.3%, respectively(p = 0.97). In the multivariable analysis for PFS, age at recurrence ≥ 65 years, disease-free interval < 24 months, non-luminal A subtype, and in-field failure (marginally significant) were found to be risk factors (RFs). However, the location of the tumor was not a significant factor for PFS (p = 0.71). When we stratified patients by the number of RFs, the 5-year PFS rates were 67.5% for patients with ≤ 1 RF and 7.3% for those with > 1 RF (p < 0.01). For patients with ≤ 1 RF, the 5-year PFS rates were 73.5% in the ALN group and 51.1% in the SCN/IMN group (p = 0.09). For patients with > 1 RF, the 5-year PFS rates were 7.3% in the ALN group and 7.1% in the SCN/IMN group (p = 1.00).ConclusionIn breast cancer patients with regional oligo-recurrence, clinical outcomes after salvage treatment were favorable in patients with ≤ 1 RF, while patients with > 1 RF had poor prognoses irrespective of the location of recurrence.     

Preferred method of therapy for patients with early-stage high-grade neuroendocrine carcinoma of the cervix

High-grade neuroendocrine carcinoma of the uterine cervix (HGNECC) is a rare and overly aggressive malignancy. Due to its rarity, there is no standard treatment. A majority of early-stage patients receive radical hysterectomy and lymph node dissection (RH+LND), followed by adjuvant chemotherapy. To explore the most suitable methods of therapy, a multicenter retrospective review of HGNECC patients was conducted. A total of 133 patients (I-IIA, FIGO 2009) treated from March 2003 to September 2018 were enrolled in this study. The 5-year DFS and OS rates for stages IB and IIA were 44.8% and 39.5%, and 53.8% and 39.6%, respectively. The median DFS and OS for stages IB and IIA were 41 months and 12 months, and 63 months and 45 months, respectively. The RH+LND surgery procedure was associated with a significantly better DFS (P=0.015) and OS (P=0.006), while the bilateral salpingo-oophorectomy (BSOE) was also associated with a better OS (P=0.023). The efficacy of paclitaxel-platinum (TP/C) adjuvant chemotherapy regimens need to be confirmed using clinical trials, especially for tumors with a diameter of >4 cm (P=0.0005). Therefore, the RH+LND+BSOE procedure was recommended for HGNECC patients at stages IB-IIA. TP/C is an alternative chemotherapy regimen that results in optimal survival. Moreover, a tumor diameter of >4 cm, LNM, DSI, and LVSI were confirmed as high-risk factors for worse DFS and OS. Patients without risk factor, 1 or 2 or 3 risk factors, and 4 risk factors had significantly different DFS and OS values.     

Lymph node metastasis and pattern of recurrence in clinically early stage endometrial cancer with positive lymphovascular space invasion

ObjectiveTo investigate the rate, predictors of lymph node metastasis (LNM) and pattern of recurrence in clinically early stage endometrial cancer (EC) with positive lymphovascular space invasion (LVSI).MethodsWomen with clinically early stage EC and positive LVSI 2005 to 2012 were identified. Kaplan-Meier curves and logistic regression models were used.ResultsOne hundred forty-eight women were identified. Of them, 25.7% had LNM (21.7% pelvic LNM, 18.5% para-aortic LNM). Among patients with LNM who had both pelvic and para-aortic lymphadenectomy, isolated pelvic, para-aortic and both LNM were noted in 51.4%, 17.1%, and 31.4% respectively. Age and depth of myometrial invasion were significant predictors of LNM in LVSI positive EC. Node positive patients had high recurrence rate (47% vs. 11.8%, p<0.05) especially distant (60.9% vs. 7.9%, p<0.001) and para-aortic (13.2% vs. 1.8%, p=0.017) recurrences compared to node negative EC. LNM was associated with lower progression-free survival (p=0.002) but not overall survival (p=0.73).ConclusionEC with positive LVSI is associated with high risk of LNM. LNM is associated with high recurrence rate especially distant and para-aortic recurrences. Adjuvant treatments should target prevention of recurrences in these areas.     

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma

BackgroundThe efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1–3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC).Patients and methodsPatients with HCC and Child–Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS).ResultsThe estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646–1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2–14.9) versus 9.7 (5.9–11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival.ConclusionsAxitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC.Trial RegistrationClinicalTrials.gov, NCT01210495.     

Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive,submucosa-invasive early gastric carcinoma

Background

The prediction of biologic behavior of poorly cohesive early gastric carcinoma (EGC) is an important issue in the selection of the treatment modality. To elucidate the risk factors for lymph node metastasis (LNM) of poorly cohesive EGC, we focused on the histologic purity of the poorly cohesive component and evaluated the impact of this factor on LNM.

Methods

We divided poorly cohesive EGC into (1) pure signet ring cell (SRC) carcinoma, which was defined as composed only of signet ring cells or poorly cohesive cells and (2) mixed SRC carcinoma, defined as poorly cohesive carcinoma with minor tubular components. We reviewed the clinicopathologic features, including age, sex, location, size, depth, lymphovascular invasion (LVI), LNM, ulceration, and intestinal metaplasia between the two groups in a large series of poorly cohesive, submucosa-invasive EGC (n = 317).

Results

LNM was found in 58 cases (18.3 %). Mixed SRC carcinoma histologic type (p < 0.001), larger tumor size (more than 2 cm) (p = 0.012), and the presence of LVI (p < 0.001) were associated with LNM. Pure SRC carcinomas accounted for 56.2 % (178/317) of the cases. Fourteen pure SRC carcinomas (7.8 %) showed LNM, whereas 44 mixed SRC carcinomas (31.9 %) exhibited LNM (p < 0.001). On multivariate logistic regression, the presence of LVI (odds ratio 6.737; 95 % confidence interval 2.714–16.720; p < 0.001) and mixed SRC carcinoma histologic type (odds ratio 4.674; 95 % confidence interval 2.370–9.216; p < 0.001) were independent predictors of LNM in poorly cohesive, submucosa-invasive EGC.

Conclusions

The presence of a tubular component in SRC carcinoma was a risk factor for LNM in poorly cohesive, submucosa-invasive EGC. On the basis of this finding, we propose that the presence of a minor tubular component or the purity of the poorly cohesive/SRC carcinoma component should be reported in daily pathologic practice.

     

Role of HER3 expression and PTEN loss in patients with HER2-overexpressing metastatic breast cancer (MBC) who received taxane plus trastuzumab treatment

Background:

The aim of this study was to investigate the role of human epidermal growth factor receptor (HER3) and PTEN expression in patients with HER2-overexpressing metastatic breast cancer (MBC).

Methods:

One hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as first-line therapy were included in this analysis. Immunohistochemical (IHC) staining with HER3 and PTEN antibodies were conducted retrospectively.

Results:

Patients who had negative HER3 staining (62.4%) had a better progression-free survival (PFS) than did those who had positive HER3 staining (P=0.001; median PFS, 21 vs 11 months). Patients who had a PTEN score >20 (78.1%) showed longer PFS than did those with a PTEN score ⩽20 (P=0.006; median PFS, 13 vs 9 months). Patients who had a PTEN score >20 exhibited a longer overall survival (OS) than did those with a PTEN score ⩽20 (P=0.005; median OS, 48 vs 25 months). HER3 negativity and PTEN loss were identified as independent risk factors for PFS. PTEN loss was identified as an independent risk factor for OS.

Conclusion:

HER3 and PTEN expressions may be predictive markers, and PTEN expression may be a predictive and prognostic biomarker for trastuzumab treatment in HER2-positive MBCs.     

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC

Background:

Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.

Methods:

Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.

Results:

In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.

Conclusions:

Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.     

Chemotherapy Outcomes by Histologic Subtypes of Non–Small-Cell Lung Cancer: Analysis of the Southwest Oncology Group Database for Antimicrotubule-Platinum Therapy

ObjectiveHistologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non–small-cell lung cancer (NSCLC). To determine whether histologic subtype was associated with efficacy for the commonly used antimicrotubule (AMT) agents, paclitaxel, docetaxel, and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database.MethodsData from 4 randomized trials (S9308, S9509, S9806, and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced-stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan–Meier.ResultsOf 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%), and 165 had NSCLC not otherwise specified (NOS) (14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies.ConclusionsThis pooled analysis from 4 SWOG trials using an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted.     

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study

BackgroundAxitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified.Patients and MethodsRetrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed.ResultsIn total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data.ConclusionsThis study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.     

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients

Background:

Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities.

Methods:

In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand–foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points.

Results:

On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand–foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63−0.67) for IMDC classification alone and 0.72 (95% CI: 0.70−0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months).

Conclusions:

On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.     

Subsequent Chemotherapy Improves Survival Outcome in Advanced Non–Small-Cell Lung Cancer With Acquired Tyrosine Kinase Inhibitor Resistance

BackgroundEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) provide promising effect against non–small-cell lung cancer (NSCLC), although most tumors acquire resistance. Our objective was to assess the survival outcome of patients with NSCLC with or without subsequent chemotherapy after acquired TKI resistance.Patients and MethodsA total of 114 patients with pathologically confirmed stage IIIB or IV NSCLC who had had disease control with TKIs were retrospectively reviewed. After acquired TKI resistance, patients received either best supportive care (BSC) only or BSC plus subsequent chemotherapy. Both groups were well balanced in regard to performance status, age, sex, histology subtype, and smoking status.ResultsSixty-seven patients (58.8%) received subsequent chemotherapy, and 47 patients (41.2%) received BSC only. The median overall survival (OS) and progression-free survival (PFS) from the time of TKI resistance in the subsequent-chemotherapy group (11.2 months and 3.5 months, respectively) were longer than those of the BSC group (3.8 months and 1.5 months, respectively; P < .01). Patients who subsequently received taxane-based chemotherapy exhibited higher a response rate and disease control rate (48.7% and 79.5%, respectively) than patients treated with a nontaxane regimen (21.4% and 53.5%, respectively; P < .05). Overall survival and PFS in patients after taxane-based subsequent chemotherapy (12.7 months and 5.1 months, respectively) were longer than those of patients given a nontaxane regimen (7 months and 1.8 months, respectively; P < .01).ConclusionThis study suggests that acquired TKI resistance should be managed aggressively. The higher antitumor response and survival outcome with a taxane-based regimen in this retrospective study could encourage further prospective investigation to confirm the efficacy of taxane over nontaxane chemotherapy in patients with NSCLC whose disease progresses with EGFR TKI treatment.