HOLLYWOOD, FLA. – The ongoing exploration of immune therapy options for non–small cell lung cancer is a particularly exciting area of lung cancer research, because "traditionally, immune therapy hasn’t worked in lung cancer," according to Dr. Leora Horn.
The results of the exploration thus far suggest that is no longer the case.
A programmed death-1 (PD-1) inhibitor and a PD-1 ligand (PD-L1) inhibitor, for example, were shown in recent phase I studies to prolong progression-free and overall survival in NSCLC patients, and other similar agents are currently in development, Dr. Horn of the Vanderbilt-Ingram Cancer Center in Nashville, Tenn., said at the annual conference of the National Comprehensive Cancer Network.
In one study, median progression-free and overall survival among 129 heavily pretreated NSCLC patients who received the PD-1 inhibitor nivolumab – an IgG4 monoclonal antibody - were 2.3 and 9.6 months, respectively (N. Engl. J. Med. 2012;366:2455-65), Dr. Horn said.
The patients received intravenous nivolumab monotherapy at doses of 1, 3, or 10 mg/kg every 2 weeks for up to 12 cycles.
"These data presented a couple of years ago showed us a really impressive response rate of 17% for all patients treated with nivolumab. What we also saw was a slightly higher response rate in the patients treated with the 3-mg/kg dose of 24.3%," she said.
Stable disease was also seen in a significant number of patients (8.1% at 24 weeks and 5.4% at 48 weeks), and the median overall survival among those in the 3-g/kg group was 14.9 months, which is "very impressive for this heavily pretreated population," she noted.
The median overall survival among those with squamous cell lung cancer was 9.2 months, and the overall stable disease rate was 14.8%; among those with nonsquamous disease, the overall survival was 10.1 months, and the stable disease rate was 6.8%, Dr. Horn noted.
In this study, nivolumab was fairly well tolerated; the rate of grade 3-4 drug-related adverse events was 14%, the most common being fatigue in 24% of patients, decreased appetite in 12%, and diarrhea in 10%.
"Importantly for this group of patients, a new toxicity that we’re dealing with is pneumonitis, and drug-related pneumonitis occurred in eight NSCLC patients. Three patients had grade 3-4 pneumonitis, of which two cases were fatal," Dr. Horn said, noting that the deaths occurred early in the study, "before we were aware of this particular toxicity in this patient population."
The anti–PD-L1 agent MPDL3280A is also showing promise in an ongoing phase Ia expansion study. Patients in that study received 10, 15, or 20 mg/kg by IV every 3 weeks for up to 16 cycles for 1 year.
"Again, what we saw in this trial was rapid durable responses in both squamous and nonsquamous non–small cell lung cancer patients," she said.
Most responded by 12 or 21 weeks of therapy, and durable responses were seen even after discontinuation of therapy.
The response rate was best (83%) in patients in whom at least 10% of their tumor was positive for expression of PD-L1. The response rates were 46% and 31% in patients in whom at least 5% and 1% of their tumor was positive for expression of PD-L1, respectively.
"The overall response rate was 23% for the patient population, indicating that there were tumors that were PD-L1 negative that responded to therapy," Dr. Horn said.
Response rates were higher among former/current smokers than in never smokers (26% vs. 10%), but they did not differ significantly by EGFR or KRAS mutational status.
This agent was extremely well tolerated; the majority of adverse events were grade 1-2 and did not require intervention, and there was no maximum tolerated dose or dose-limiting toxicity.
"And importantly for patients on this trial, no grade 3-5 pneumonitis was observed, and this may have to do with differential expression of PD-1 vs. PD-2 within the lung."
A number of phase II and III studies involving these and other immune therapy agents for NSCLC are now underway, including studies of MPDL3180A in patients with PD-L1-positive NSCLC, in combination with bevacizumab and/or chemotherapy, and compared with docetaxel as second-line therapy in PD-L1-positive NSCLC.
Nivolumab is being compared with chemotherapy as first-line therapy in PD-L1-positive NSCLC, and is being evaluated with vs. without ipilimumab in SCLC.
Other immune therapy agents in development include the PD-1 inhibitor MK3475 and the PD-L1 inhibitors MEDI-4736 and MSB0010718C. MK3475 is being evaluated in PD-L1-positive NSCLC, is being compared with docetaxel as second-line therapy in PD-L1-positive NSCLC, and is being studied in combination with chemotherapy and targeted therapy. MEDI-4736 is currently being evaluated in a phase I dose-escalation study in expanded cohorts.