A recent study suggests that crizotinib (Xalkori) can reduce kidney function. Lung cancer patients treated with Xalkori saw their kidney function decrease by 23.9% on average. Kidney function recovered when Xalkori was discontinued. However, as patients usually have to take Xalkori for months or years, these findings still warrant caution, especially in patients taking other medications that affect kidney function or with preexisting kidney damage. In an earlier study, investigators had found that Xalkori decreased testosterone levels in 84% of male patients. Because cancer drugs like Xalkori increasingly receive accelerated approval, not all of their side effects are known by the time they are approved. Doctors therefore need to carefully monitor their patients for possible adverse effects.
The U.S Food and Drug Administration (FDA) has granted regular approval to the drug crizotinib (Xalkori) for the treatment of advanced non-small cell lung cancer (NSCLC) in patients who have mutations in the ALK gene. Xalkori received accelerated approval for this application in August 2011. Regular approval was awarded based on the results of a study examining patients with advanced NSCLC whose cancer had progressed despite first-line chemotherapy. Patients treated with Xalkori went an average of 7.7 months without further cancer worsening, compared to 3.0 months in those receiving the chemotherapy agents pemetrexed (Alimta) or docetaxel (Taxotere). Tumors shrank in 65% of the Xalkori-treated patients, compared to 20% with Alimta or Taxotere. However, overall survival did not differ between the Xalkori group and the chemotherapy group.
Drugs known as EGFR inhibitors—such as erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif)—are very effective in treating non-small cell lung cancer (NSCLC) with mutations in the EGFR gene. However, patients eventually develop drug resistance, usually caused by new EGFR mutations. T790M is the most common EGFR drug resistance mutation. CO-1686 is a novel drug that inhibits EGFR with the T790M mutation, as well as other mutant EGFR. A small study showed that eight of nine patients who had the T790M resistance mutation experienced more than 10% tumor shrinkage when treated with CO-1686. And, a new formulation of CO-1686 has been found to produce higher, more consistent, well-tolerated drug concentrations in patients.
Drugs known as EGFR inhibitors—like erlotinib (Tarceva) and gefitinib (Iressa)—are used to treat non-small cell lung cancer (NSCLC) with so-called ‘activating mutations’ in the EGFR gene. Unfortunately, drug resistance develops relatively quickly in most patients. Resistance is often due to additional EGFR mutations, so-called ‘resistance mutations,’ such as EGFR T790M. Researcher have developed a new EGFR inhibitor, AZD9291, which targets both activating and resistance mutant forms of EGFR. AZD9291 inhibited the growth of EGFR-mutant NSCLC cell cultures and eradicated lung cancer tumors with either activating or resistance mutations in mice. Because AZD9291 is less active against normal, non-mutant EGFR, it may have fewer side effects than other EGFR inhibitors. Initial tests of AZD9291 in patients have been promising.
The drug crizotinib (Xalkori) is used to treat non-small cell lung cancer (NSCLC) with mutations in the ALK gene. However, most patients develop resistance to the drug, usually because of further mutations in the ALK gene. A new ALK inhibitor drug, PF-06463922, may offer a solution. PF-06463922 blocked a variety of Xalkori-resistant mutant versions of ALK in cell cultures, and inhibited the growth of Xalkori-resistant ALK-mutant tumors in mice. PF-06463922 also combated tumor cells driven by mutations in ROS1, a gene closely related to ALK, in mouse models. Like Xalkori, PF-06463922 may therefore also be effective for NSCLC patients with ROS1 mutations. Finally, PF-06463922 was able to penetrate into the brain in multiple animal species–important because lung cancer often spreads to the brain.
The cell protein MET is overexpressed in more than half of non-small cell lung cancer (NSCLC) tumors. MET overexpression is associated with worse prognoses and plays a role in drug resistance to EGFR inhibitors like erlotinib (Tarceva). A recent clinical trial examined the effects of onartuzumab, which inhibits MET function, on recurrent NSCLC. Patients received either onartuzumab and Tarceva or Tarceva only. In patients who overexpressed MET, adding onartuzumab increased the time until cancer progression and prolonged overall survival. In contrast, in patients without MET overexpression, adding onartuzumab worsened outcomes. This finding highlights the importance of diagnostic testing in choosing the best cancer treatment. A clinical trial investigating the onartuzumab-Tarceva combination in MET-overexpressing patients only is currently enrolling participants.
Results from the ATLAS clinical trial indicate that adding erlotinib (Tarceva) to maintenance therapy with bevacizumab (Avastin) does not increase survival in non-small cell lung cancer (NSCLC). Patients with advanced NSCLC who had been successfully treated with chemotherapy and Avastin received continued treatment with Avastin plus either Tarceva or a placebo. In patients who received both Avastin and Tarceva, the cancer took longer to start progressing again than in the patients given only Avastin (4.8 vs 3.7 mo, on average), but overall survival was not significantly different. Moreover, patients treated with both Tarceva and Avastin experienced more side effects. However, the benefits of added Tarceva were greater in the subgroup of patients with mutations in the EGFR gene.
This review provides an overview of recent experience in the field of resistance to tyrosine kinase inhibitors (TKI) on lung cancer, focusing on results from preclinical resistance models and studies of patient-derived, TKI-resistant tumor specimens.