Every year, thousands of people gather in Chicago, Illinois, for the American Society of Clinical Oncology (ASCO) Annual Meeting. The largest meeting of its kind, ASCO brings together doctors, researchers, nurses, patient advocates, pharmaceutical company representatives, and more to discuss the latest in cancer research. Here are some of the most exciting new developments in lung cancer research presented last week at ASCO 2014:
Discussion of new lung cancer drugs at ASCO 2014 focused on overcoming resistance to targeted therapies that have already been approved for regular use by the U.S. Food and Drug Administration (FDA). These include erlotinib (prescribed to patients whose tumors have mutations in the EGFR protein) and crizotinib (for tumors with ALK protein mutations). Patients who take these drugs may experience tumor shrinkage at first, but tumors can become resistant and grow back. Most frequently, this resistance is due to new, additional mutations in the targeted protein, such as the infamous T790M in EGFR (see my previous post for more information on resistance). The solution is to create new drugs that can inhibit these newly mutated targets, keeping them from promoting tumor growth.
At ASCO 2014, no fewer than three new drugs were reported to successfully target T790M: AstraZeneca’s AZD9291, Clovis’ CO-1686, and Hanmi’s HM61713. In a clinical trial, tumors shrank or disappeared in 64% of 205 patients with a T790M mutation who took AZD9291; in a different trial, CO-1686 shrank or obliterated tumors in 58% of 72 patients. Even though they are still in clinical testing, AZD9291 and CO-1686 have already received ‘breakthrough status‘ from the FDA, meaning that the FDA will help to expedite the approval process so that the drugs may soon be widely prescribed in the U.S. Both drug companies have phase II and III clinical trials already running, so the race is on.
Patients with ALK-mutated tumors that have become resistant to crizotinib (brand name Xalkori) also have a couple of new choices: as we reported earlier, the FDA recently approved a new so-called ‘ALK-inhibitor’ called ceritinib (brand name Zykadia). In a clinical trial reported at ASCO, ceritinib shrank or wiped out tumors in 55% of patients who had previously been treated with crizotinib and in 66% of those who had not been exposed to it. Another new drug that targets Xalkori-resistant ALK-mutated tumors is X-396 from Xcovery, also presented at ASCO. Only 27 patients were enrolled in the phase I clinical trial to determine a safe dose of the drug, but responses were encouraging.
Several new results of clinical trials testing targeted therapies were described with varying degrees of excitement at ASCO 2014. An EGFR-targeted drug called necitumumab was combined with chemotherapy in patients with squamous lung carcinoma, a type of lung cancer that had not seen any significant improvements in treatment over 20 years. Adding of necitumumab to chemotherapy led to a 16% increase in progression-free survival (survival without worsening of disease), a disappointingly low percentage, but nevertheless of some significance in this difficult-to-treat cancer.
The already FDA-approved EGFR inhibitor afatinib (Gilotrif) performed well in a phase III trial, providing patients 1 year more of overall survival compared to standard chemotherapy.
Ramucirumab is a drug that targets not a protein mutated in cancer, but a protein called VEGFR-2, which is important in the formation of the blood vessels that feed cancer cells. In a phase III clinical trial, a combination of ramucirumab and a chemotherapy drug called docetaxel was compared to treatment with docetaxel alone. Tumors shrank in 23% of the patients who took the combination treatment versus 13.6% in the docetaxel-only group.
Another target in lung cancer is a protein called MET, which is sometimes found at high levels in tumors that become resistant to erlotinib. Sometimes the gene that contains instructions for the cell to make the protein is amplified (more than 2 copies of the gene are present per cell) producing very high amounts of MET protein. We recently wrote on the failure of an anti-MET drug called onartuzumab, but one piece of good news at ASCO 2014 was that crizotinib (an ALK inhibitor) worked for patients whose tumors have amplified MET. Ironically, crizotinib, originally developed as a MET inhibitor and later found to be active against ALK, might be making a comeback to its original target.
Immunotherapies are treatments that boost a patient’s own immune system to fight cancer. Last year, the ASCO conference was abuzz with excitement about immunotherapy treatments using drugs known as immune checkpoint antibodies, including so-called anti-PD-1 and anti-PD-L1 drugs. PD-L1 is a protein found on some cancer cells that binds to a protein called PD-1 on immune system cells, and inhibits their ability to destroy cancer cells. Both PD-1 and PD-L1 now serve as targets for different cancer drugs. Importantly, high levels of PD-L1 emerged this year as a critical factor in predicting responses to anti-PD-1 drugs. Based on reported studies, PD-L1 is found in about 60% to 70% of non-small cell lung cancer (NSCLC) tumors and is associated with worse prognosis, but is also associated with tumor shrinkage in response to the anti-PD-1 drugs nivolumab (made by the company Bristol-Myers Squibb) and MK3475 (made by Merck).
At ASCO 2014, preliminary results from a clinical trial testing nivolumab as a first-line treatment for advanced-stage NSCLC showed that tumors shrank or disappeared in 30% of 20 patients. The rate was higher for patients with non-squamous NSCLC. Nivolumab also showed promise for previously treated patients with advanced NSCLC, but with a lower tumor shrinkage rate of 17%. A clinical trial testing MK-3475 was reported to have had encouraging results for previously untreated patients, with 36% experiencing tumor shrinkage or disappearance; MK-3475 also showed promise for previously treated NSCLC patients. Bristol-Myers Squibb has reported initiation of a large, phase III clinical trial comparing nivolumab to chemotherapy in patients whose tumors have high levels of PD-L1. Not to be outdone, Merck has initiated similar trials of MK-3475 versus docetaxel.
Researchers at ASCO 2014 also reported that a combination of two immune checkpoint antibodies—nivolumab and ipilimumab—produced some positive results in a clinical trial, with tumors shrinking or disappearing in 22% of enrolled patients. This result is evidently less exciting than the results of similar trials in melanoma patients, with tumor shrinkage/disappearance rates of up to 80%.
Clinical trial results for other immunotherapy drugs were also reported. MEDI4736, an anti-PD-L1 drug from the company MedImmune, showed strong activity in NSCLC, even though no tumor shrinkage rate has yet been reported. MEDI4736 is also being tested in combination with ipilimumab to establish the largest dose that can safely be given to patients. A rival anti-PD-L1 drug from Genentech called MPDL3280A is also being tested in patients with advanced NSCLC.
Other promising ASCO news
Combining targeted therapy with immunotherapy is an exciting opportunity in cancer treatment. A phase I trial combining erlotinib with nivolumab produced some encouraging preliminary results, even though all but one of the 20 patients enrolled had already been exposed to EGFR inhibitor drugs and developed resistance prior to enrolling in the trial. Tumors shrank in four of the patients.
Rounding out lung cancer reports at ASCO 2014 was a rare snippet of potentially good news for mesothelioma patients from Aduro BioTech, which conducted a small clinical trial combining chemotherapy and CRX-207, a cancer vaccine based on a disabled strain of Listeria bacteria. Of 16 patients enrolled, 69% had lasting tumor shrinkage or disappearance, with 25% experiencing stable disease—a very high rate for patients with this fatal cancer.