Like most medical conferences, the 19th Annual World Conference on Lung Cancer (WCLC) in Toronto was the typical mix of high-profile phase III studies with a large number of earlier-stage programs looking to disrupt the current treatment paradigm.
The phase III programs were largely dominated by the large pharmas with their PD-L1 inhibitors that added on to previous data presented by others at the American Association for Cancer Research and American Society of Clinical Oncology meetings earlier this year, which showed the checkpoint offers an opportunity to elicit an immune response to attack lung cancer. (See BioWorld, April 17, 2018, and June 5, 2018.)
At WCLC, in the Impower132 study testing Tecentriq (atezolizumab) in combination with carboplatin and pemetrexed in previously untreated patients with stage IV nonsquamous non-small-cell lung cancer (NSCLC), which was followed by Tecentriq plus pemetrexed as maintenance, Roche Holding AG, of Basel, Switzerland, showed the Tecentriq treatment produced a median progression-free survival (PFS) of 7.6 months compared to 5.2 months for the chemotherapy-only control group (p<0.0001). Adding Tecentriq was associated with a 40 percent reduction in risk for progression.
At the interim analysis, overall survival (OS) data weren't fully mature, but Vassiliki Papadimitrakopoulou, professor of medicine in the department of thoracic/head and neck medical oncology at the University of Texas MD Anderson Cancer Center, noted in a press conference that "there was numerical improvement of 4.5 months with a hazard ratio of 0.81." The final analysis is expected in the first half of 2019.
Likewise in NSCLC, Astrazeneca plc, of Cambridge, U.K., presented data from its Pacific study testing its PD-L1 antibody, Imfinzi (durvalumab), in stage III patients who responded to chemoradiotherapy. The median OS of patients treated with Imfinzi hadn't been reached yet, but treatment was associated with a 32 percent reduction in the risk of death compared to placebo. PFS was 17.2 months for Imfinzi-treated patients, substantially longer than the 5.6 months for patients treated with placebo.
"There was a clear separation of the survival curves," Scott Antonia, chairman of the department of thoracic oncology at the H. Lee Moffitt Cancer Center and Research Institute, told the audience at a press conference. "This is a new standard of care treatment for the patients with this disease."
In addition to NSCLC data, Roche also presented results of its phase I/III Impower133 study testing Tecentriq as an adjunctive therapy to the standard of care, carboplatin and etoposide, in 403 first-line (1L) patients with extensive-stage small-cell lung cancer (SCLC). Tecentriq plus chemotherapy produced an OS of 12.3 months compared to 10.3 months for chemotherapy alone, producing a 30 percent reduction in the risk of death (p=0.0069). Tecentriq also improved PFS from 4.3 month for chemotherapy alone to 5.2 months when Tecentriq was added (p=0.017).
"As the first to demonstrate an improvement in OS, Roche are now ahead of competitors in 1L SCLC with both Merck and Astrazeneca's phase III 1L SCLC studies not due to complete until Q1 2019," Jefferies analyst Ian Hilliker pointed out in a note to clients.
In addition to the phase III immune checkpoint data, there were plenty of presentations from companies with drugs earlier in the development cycle.
Rather than compete with the immune checkpoint inhibitors, Syndax Pharmaceuticals Inc., of Waltham, Mass., is testing its class 1 HDAC inhibitor, entinostat, in combination with Keytruda (pembrolizumab, Merck & Co. Inc.) in NSCLC patients who were previously treated with both chemotherapy and PD-(L)1 therapy. In the Encore 601 study, the combination produced an objective response rate (ORR) of just 10 percent. But looking at the pre-treatment baseline levels of peripheral classical blood monocytes, patients with high monocyte levels had a PFS of 5.3 months and an ORR of 21 percent, compared to 2.7 months and an ORR of 7 percent for patients with low initial monocyte levels.
"These data continue to support a possible emphasis on the subgroup of patients that have failed PD-1 therapy and have high baseline classical peripheral monocyte levels within this NSCLC population," H.C. Wainwright & Co. analyst Edward White wrote in a note to clients, adding that he expected management to give an update on the next steps for the combination before year-end.
In a phase II investigator-initiated study at the University of Texas MD Anderson Cancer Center (MDACC), poziotinib, an EGFR tyrosine kinase inhibitor developed by Spectrum Pharmaceuticals Inc., of Henderson, Nev., appears to be helping first-line, locally advanced or metastatic NSCLC patients with EGFR or HER2 exon 20 insertion mutations.
Of the patients with EGFR mutations, 55 percent had a best response of partial response, while 43 percent had a confirmed ORR. The poziotinib treatment produced a median PFS of 5.5 months with six patients experiencing durable responses of more than a year. Initial data in 12 patients with HER2 mutations were also promising with half of them responding, producing a median PFS of 5.1 months.
As analysts are apt to do despite the difficulty of cross-trial comparisons, H.C. Wainwright's White matched up the data to Kadcyla (trastuzumab emtansine, TDM-1, Roche Holding AG). "TDM-1 has slightly better results, so far, than poziotinib in HER2 exon 20 mutation patients, but not the EGFR patients. However, if approved, we think physicians will use it in both EGFR and HER2 patients," he wrote in a note to clients.
Jefferies analyst Roger Song said he thinks a separate ongoing Spectrum-run global study, dubbed Zenith20, could produce even stronger data. "The patients enrolled in the global study could be healthier than those enrolled in the MDACC study, as MDACC treated patients from six countries and those outside the U.S. tend to be sicker with more prior treatments, including checkpoint inhibitors (they view MDACC as the last resort)," Song wrote, adding that there were also patients in the MDACC study lost to follow up and that Spectrum's study will measure response rate at an earlier timepoint.
Checkpoint Therapeutics Inc., of New York, also has an EGFR inhibitor, CK-101, in development for lung cancer. At WCLC, the company presented preliminary data from a phase I/II study showing the drug produced an ORR of 42 percent in the 19 evaluable patients with EGFR mutation-positive NSCLC, although the ORR was substantially higher, 75 percent, in eight treatment-naïve patients.
"As a whole, these data point to CK-101 as a possible competitor to Tagrisso, and support Checkpoint's planned phase III study evaluating CK-101 in [first]-line EGFR-mutant NSCLC, which is planned to initiate in 2019," noted Lifesci Capital's Sam Slutsky, adding that CK-101 doesn't seem to have the safety warnings associated with Astrazeneca's EGFR inhibitor Tagrisso.