The predictive value of PIK3CA mutations in HER2 positive (HER2+) breast cancer treated with neoadjuvant anti-HER2 and chemotherapy has been reported, but the power for subgroup analyses was lacking.
...We combined individual patient data from five clinical trials evaluating PIK3CA mutations and associations with pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Patients received either trastuzumab (T), lapatinib (L) or the combination T/L in addition to a taxane-based chemotherapy. PIK3CA was genotyped in tumour biopsies taken before therapy.
A total of 967 patients were included in this analysis; the median follow-up is 47 months. Overall, the pCR rate was significantly lower in the PIK3CA mutant compared with the wild-type group (16.2% versus 29.6%; P < 0.001). Within the hormone-receptor positive (HR+) subgroup, the PIK3CA mutant group had a pCR rate of only 7.6% compared with 24.2% in the wild-type group (P < 0.001). In contrast, in the HER2+/HR– group, there was no difference in pCR (27.2% versus 36.4%; P = 0.125) according to PIK3CA mutation status (interaction test P = 0.036). According to treatment arm, the pCR rate for mutant versus wild-type was 20.3% versus 27.1% for T (P = 0.343), 11.3% versus 16.9% for L (P = 0.369) and 16.7% versus 39.1% for T/L (P < 0.001). In the HR+ T/L group, the pCR rate was 5.5% versus 33.9% (interaction between HR and PIK3CA genotype P = 0.008). DFS and OS were not significantly different by mutation status, though the incidence rate of events was low. However, HR+/PIK3CA mutant patients seemed to have significantly worse DFS {hazard ratio (HR) 1.56 95% confidence interval (CI) 1.00–2.45, P = 0.050; Pinteraction = 0.021}. T/L tended to improve DFS compared with T in the wild-type cohort, especially in the HR– group HR 0.72, 95% CI (0.41–1.25), P = 0.242.
Overall PIK3CA mutant/HER2+ tumours had significantly lower pCR rates compared with wild-type tumours, however mainly confined to the HR+/PIK3CA mutant population. No definite conclusions can be drawn regarding survival.
•VEGFR-TKIs + PD-1 ICIs combinations are a new first-line standard of care in mRCC.•The benefit of VEGFR-TKIs + ICIs is unclear in IMDC favorable mRCC patients.•We performed a meta-analysis to assess ...VEGFR-TKIs + ICIs vs. sunitinib in IMDC favorable patients.•VEGFR-TKI + ICI combinations improved PFS as first-line therapy.•No OS advantage was observed in this subgroup.
Combinations of PD-1/PD-L1 immune checkpoint inhibitors (ICI) with VEGFR-TKIs as first-line therapy significantly improve outcomes of metastatic renal cell carcinoma (mRCC) patients. The benefit of these combinations is well evident in the IMDC intermediate- and poor-risk population, but remains unclear in the subgroup of patients with favorable prognosis. Our meta-analysis aims at evaluating whether the addition of ICIs to VEGFR-TKIs is able to improve the outcome compared to VEGFR-TKIs alone in mRCC patients with favorable prognosis.
This meta-analysis searched MEDLINE/PubMed, the Cochrane Library and ASCO Meeting abstracts for randomized clinical trials (RCTs) testing the combination of VEGFR-TKI + ICI in mRCC. Data extraction was conducted according to the PRISMA statement. Summary hazard ratio (HR) was calculated using random- or fixed-effects models, depending on studies heterogeneity.
Four RCTs were selected. VEGFR-TKI + ICI combinations improved PFS compared to sunitinib (fixed-effect, HR = 0.63; p < 0.00001). However, VEGFR-TKI + ICI combinations did not significantly prolong OS (fixed-effect; HR = 0.99; 95% CI 0.74–1.33; p = 0.95).
VEGFR-TKI + ICI combinations improved PFS but not OS as first-line therapy for mRCC patients with favorable IMDC prognosis. Longer follow-up and further studies will increase the power of our analysis, suggesting the best first-line therapy for mRCC patients with favorable prognosis.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are effective as first-line treatment of advanced non-small-cell lung cancer patients with EGFR mutations (EGFR-M+).
We ...conducted a literature-based meta-analysis to quantify the magnitude of benefit with upfront EGFR TKI in EGFR-M+ patients. Meta-regression and sensitivity analyses were also carried out to identify additional predictors of outcome and to assess the influence of trial design.
Five trials (805 patients) were identified (three trials prospectively enrolling EGFR-M+ patients and two retrospective analyses of EGFR-M+ patients). TKI significantly increased progression-free survival (PFS) hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.36–0.58, P < 0.0001 and overall response rate (ORR) (HR 2.08, 95% CI 1.75–2.46, P < 0.0001) over chemotherapy, while significantly decreasing neutropenia. No significant difference was observed in overall survival. The rate of exon-19 mutations, female gender, and nonsmoking status were identified as additional predictors of outcome at meta-regression analysis. A significant interaction with trial design was found for both PFS (P = 0.028) and ORR (P = 0.008), suggesting a larger advantage for patients treated within prospective trials.
In EGFR-M+ patients, first-line TKI increase both PFS and ORR by ∼25%, while significantly decreasing toxicity. The role of additional predictive factors and the influence of trial design on the magnitude of the observed benefit warrant further investigation.
•The identification of new effective targets in lung cancer remains a high priority.•No impactful results have been achieved with anti-MET agents in unselected NSCLC patients.•MET exon 14 skipping ...mutations recently emerged as a novel actionable oncogenic target.•MET exon 14 mutant patients should be enrolled in clinical trials with anti-MET agents.•Emerging mechanisms of resistance to MET inhibition support the combinatorial strategy.
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) asa group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified asa potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients.
In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants asan actionable oncogenic target.
•Optimal treatment for refractory metastatic colorectal cancer is still questioned.•We directly compared the prognostic performance of CTr/r, REG and FTD/TPI.•Two data sets were analyzed and a ...propensity score adjustment was accomplished.•CTr/r provided superior outcomes compared to standard agents (REG and FTD/TPI).•CTr/r might be considered in the continuum of care of selected refractory mCRC.
The optimal treatment for metastatic colorectal cancer (mCRC) beyond second line is still questioned. Besides the standard of care agents (regorafenib, REG, or trifluridine/tipiracil, FTD/TPI), chemotherapy rechallenge or reintroduction (CTr/r) are commonly considered in clinical practice, despite weak supporting evidence. The prognostic performance of CTr/r, REG and FTD/TPI in this setting are herein evaluated.
PROSERpYNa is a multicenter, observational, retrospective study, in which patients with refractory mCRC, progressing after at least 2 lines of CT, treated with CTr/r, REG or FTD/TPI, are considered eligible and were enrolled in 2 independent data sets (exploratory and validation). Primary endpoint was overall survival (OS); secondary endpoints were investigator-assessed progression-free survival (PFS), objective response rate (RR) and safety. A propensity score adjustment was accomplished for survival analyses.
Data referring to patients treated between Jan-10 and Jan-19 from 3 Italian institutions were gathered (341 and 181 treatments for exploratory and validation data sets respectively). In the exploratory cohort, median OS (18.5 vs. 6.5 months), PFS (6.1 vs. 3.5 months) and RR (28.6% vs. 1.4%) were significantly longer for CTr/r compared to REG/FTD/TPI. Survival benefits were retained at the propensity score analysis, adjusted for independent prognostic factors identified at multivariate analysis. Moreover, these results were confirmed within the validation cohort analyses.
Although the retrospective fashion, CTr/r proved to be a valuable option in this setting in a real-world context, providing superior outcomes compared to standard of care agents at the price of a moderate toxicity.
Optimal treatment for refractory mCRC is questioned. We directly compared the prognostic performance of standard of care (regorafenib or trifluridine/tipiracil) and chemotherapy rechallenge or reintroduction in 2 independent data sets and performed a propensity score adjustment. Chemotherapy rechallenge or reintroduction proved superior compared to standard agents and might be considered in the continuum of care of selected refractory mCRC.
A precision medicine approach has been successfully applied in medical oncology for the treatment of non-small-cell lung cancer (NSCLC) through the identification of targetable driver molecular ...aberrations; activating mutations of epidermal growth factor receptor (EGFR) are the most common. Osimertinib, a third-generation, wild-type sparing, irreversible EGFR tyrosine kinase inhibitor (TKI), originally showed a striking activity after progression to first- and second-generation EGFR-TKIs when T790M resistance mutation was identified. Thereafter, upfront use of osimertinib became the standard of care based on overall survival benefit over first-generation TKIs erlotinib and gefitinib as reported in the FLAURA trial. For patients progressing on osimertinib, identification of resistance mechanisms is crucial to develop novel targeted therapeutic approaches. Moreover, innovative drugs or combination therapies are being developed for cases in which a specific resistance mechanism is not identifiable. In this review, the post-osimertinib treatment options for EGFR-mutated NSCLC are analyzed, with an outlook to ongoing clinical trials. An algorithm to guide clinicians in managing progression on osimertinib is proposed.
•Acquired resistance mechanisms to osimertinib can be EGFR dependent or independent.•First- and fourth-generation EGFR-TKIs are able to overcome EGFR-dependent resistance.•MET and MEK inhibitors may overcome EGFR-independent resistance.•Anti-HER/MET novel monoclonal antibody seems effective across multiple resistance mechanisms.•Carboplatin/paclitaxel ± bevacizumab/atezolizumab represents a feasible option in ‘fit’ patients progressing on osimertinib.
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