Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non–small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified.

Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations.

Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.     

Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: Comparative pharmacokinetics and drug–drug interactions

The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50–60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls – afatinib and dacomitinib – covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug–drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies.     

Should epidermal growth factor receptor tyrosine kinase inhibitors be considered ideal drugs for the treatment of selected advanced non-small cell lung cancer patients?

An ideal target-based agent for the treatment of cancer patients should fulfil a number of requirements, including the availability of biomarkers to select the target population, superiority over existing treatments and specific advantages in terms of pharmacokinetics and/or metabolism. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and afatinib, have been investigated in the treatment of non-small cell lung cancer (NSCLC), and to date a large amount of clinical data are available. The activity of EGFR-TKIs was initially investigated in unselected patients leading to unsatisfactory results. However, the discovery that response to EGFR-TKIs is associated with the presence of activating EGFR mutations in NSCLC, has led to the design of clinical trials in which patients were selected on the basis of the EGFR mutational status or of clinical and pathological features that are highly associated with the presence of EGFR mutations. In this respect, several phase III randomized trials have demonstrated that first-line EGFR-TKIs, compared to chemotherapy, is associated with longer progression-free survival, higher response rate, better toxicity profile and quality of life in patients carrying EGFR mutations. Although no survival advantage was demonstrated, all the trials suffered of a high post-progression treatment cross-over, which predictably undermined the results. This review will summarize the current evidence that strongly support the hypothesis that gefitinib, erlotinib and afatinib are ideal drugs for NSCLC patients carrying EGFR mutations.     

Differential sensitivities of trastuzumab (Herceptin<Superscript>®</Superscript>)-resistant human breast cancer cells to phosphoinositide-3 kinase (PI-3K) and epidermal growth factor receptor (EGFR) kinase inhibitors

Her2 (erbB2/neu) is overexpressed in 25–30% of human breast cancers. Herceptin is a recombinant humanized Her2 antibody used to treat breast cancer patients with Her2 overexpression. Over a 5-month selection process, we isolated clones of BT474 (BT) human breast carcinoma cells (BT/Her^R) that were resistant to Herceptin in vitro. In BT/Her^R subclones, cell-surface, phosphorylated and total cellular Her2 protein remained high in the continuous presence of Herceptin. Likewise, the levels of cell-surface, phosphorylated, and total cellular Her3 and EGFR were either unchanged or only slightly elevated in BT/Her^R subclones relative to BT cells. One BT/Her^R subclone had substantially upregulated cell-surface EGFR, but this did not correlate with a higher relative resistance to Herceptin. In looking at the downstream PI-3K/Akt signaling pathway, phosphorylated and total Akt levels and Akt kinase activities were all sustained in BT/Her^R subclones in the presence of Herceptin, but significantly downregulated in BT cells exposed to Herceptin. Whereas BT cells lost sensitivity to the PI-3K inhibitor LY294002 in the presence of Herceptin, BT/Her^R subclones were equally sensitive to this agent in the presence and absence of Herceptin. This suggests that BT/Her^R subclones acquired a Herceptin-resistant mechanism of PI-3K signaling. BT/Her^R subclones were also sensitive to the EGFR kinase inhibitor AG1478 in the presence of Herceptin, to the same extent as BT cells. The BT/Her ^R subclones provide new insights into mechanisms of Herceptin resistance and suggest new treatment strategies in combination with other inhibitors targeted to signal transduction pathways.     

Which is false: Oxaliplatin or fluoropyrimidine? An analysis of patients with KRAS wild‐type metastatic colorectal cancer treated with first‐line epidermal growth factor receptor monoclonal antibody

This meta‐analysis was performed to determine whether the addition of monoclonal antibodies (mAbs) of epidermal growth factor receptor (EGFR) to oxaliplatin‐based chemotherapy treatment improves efficacy in KRAS wild‐type metastatic colorectal cancer (mCRC), and whether infusional 5‐fluorouracil (5‐FU) and oxaliplatin is a preferred combination for EGFR mAbs. Oxaliplatin (including treatment), EGFR mAbs, first‐line treatment, KRAS wild‐type, and mCRC were used as key words. The PRIME, OPUS, COIN, and NORDIC VII trials were identified by two independent authors. Time‐to‐event outcomes of overall survival (OS) and progression‐free survival (PFS) were analyzed using HRs (hazard ratios) with fixed effect, and response rate (RR) using odd ratios (OR) with fixed effect. A total of 1767 patients who were KRAS wild‐type were included in this meta‐analysis, with 866 patients in the mAbs and chemotherapy combination group and 901 patients in the chemotherapy alone group. The addition of mAbs to oxaliplatin‐based chemotherapy in patients with KRAS wild‐type mCRC as first‐line treatment resulted in significant improvements in PFS (HR = 0.88; 95% confidence interval (CI), 0.79–0.99; P = 0.03) and response rate (RR) (OR = 1.38; 95% CI, 1.14–1.66; P = 0.009) compared with chemotherapy alone, but the difference in OS was not significant (HR = 0.96; 95% CI, 0.85–1.08; P = 0.48). However, the differences in OS and PFS were not significant when mAbs were added to bolus 5‐FU or capecitabine‐based regimens compared with chemotherapy alone, whereas PFS improved with an infusional 5‐FU and oxaliplatin combination (P = 0.06; PFS, HR = 0.76; 95% CI, 0.65–0.86; P = 0.0002), and even OS was marginally significant, which was consistent with the subgroup analysis of cetuximab and panitumumab. EGFR mAbs combined with oxaliplatin and an infusional 5‐FU regimen was associated with significantly improved RR, PFS and OS as first‐line treatment in KRAS wild‐type mCRC.