An ever-deeper understanding of the biology that drives NSCLC is sparking new treatment paradigms that include selecting targeted drugs based on patients' biomarkers.
Mark G. Kris, MD
An ever-deeper understanding of the biology that drives non—small cell lung cancer (NSCLC) is sparking new treatment paradigms that include selecting targeted drugs based on patients’ biomarkers; exploiting therapies developed and approved for other forms of cancer; and investigating the value of novel agents.
In a discussion at the 2012 Chemotherapy Foundation Symposium, a panel of medical experts summarized those developments with a focus on new drugs in the pipeline for both adenocarcinoma and the significantly less common squamous cell carcinoma (SCC), for which there are currently few treatments available.
Mark G. Kris, MD, chief of the Thoracic Oncology Service at the Memorial Sloan- Kettering Cancer Center (MSKCC) in New York City, shared his excitement about the growing number of treatment options for the two-thirds of adenocarcinoma patients and 45% of SCC patients in whom driver mutations are found.
While patients with unknown driver mutations are treated with chemotherapy, he said, there are targeted treatments available for adenocarcinomas driven by EGFR or RAS mutations, or by ALK rearrangements, and researchers are investigating ways to inhibit other drivers of adenocarcinoma, as well as the mutations that drive SCC.
“The one-size-fits-all treatment of lung cancers is over,” he said. “Precise pathologic diagnosis is a must. No patient profile works, period. Test, don’t guess.”
While several of the panelists focused on treatments for adenocarcinoma, others addressed drugs on the horizon for SCC and data about novel therapies that may be useful in both subtypes.
Gregory J. Riely, MD, PhD
Showing promise in early clinical testing is ridaforolimus, an mTOR inhibitor that targets downstream pathways of RAS, explained Gregory J. Riely, MD, PhD, associate attending in the Thoracic Oncology Service at MSKCC.
The drug is being investigated in patients whose disease is the result of mutations in KRAS, the most common driver in NSCLC (Figure), who tend to respond less vigorously to treatment than those with EGFR mutations, Riely said.
In a discontinuation trial of patients with advanced, chemotherapy-pretreated, KRAS-mutated lung cancers, Riely and coauthors demonstrated that those randomized to ridaforolimus had a 4-month median progression- free survival (PFS) versus 2 months for the placebo group, with a hazard ratio (HR) of 0.36 and a P value of .013 (J Clin Oncol. 2012;30 [suppl; abstr 7531]). The results also showed an improvement in overall survival (OS) for patients on ridaforolimus (HR = 0.47), although the P value for that endpoint was insignificant, Riely said. He added that more information will be gleaned from a larger, randomized study to be conducted by the drug’s developer, Merck.
Suresh S. Ramalingam, MD
Ganetespib prevents heat shock protein 90 (HSP90) from binding to—and thus activating—oncoproteins associated with lung cancer. The drug has demonstrated activity in patients with certain driver mutations, and a phase III study of the compound versus single-agent docetaxel is being planned, according to Suresh Ramalingam, MD, chief of Thoracic Oncology and director of Medical Oncology at Emory University’s Winship Cancer Institute in Atlanta, Georgia.
As a monotherapy in a phase II trial (J Clin Oncol. 2011;29 [suppl; abstr 7500]), ganetespib showed an objective response rate of approximately 8% in patients with advanced NSCLC, and was particularly effective in those with ALK rearrangements or KRAS mutations, Ramalingam said. Based on those results and on preclinical evidence of synergistic effects, Ramalingam and colleagues evaluated the combination of ganetespib and docetaxel in a phase I trial and “found the regimen to be well tolerated and to show promising activity.”
Those results led to the phase II GALAXY trial for patients with advanced NSCLC who had progressed on one chemotherapy regimen. Patients were randomized to receive docetaxel with or without ganetespib.
Ramalingam said that an interim analysis presented at the 2012 European Society for Medical Oncology (ESMO) Congress (http://tinyurl.com/br7gnsd) showed that PFS was 4.2 months with the combination versus 2.8 months with docetaxel alone (HR = .782; P = .076). In the experimental and control arms, respectively, the response rate was 16% versus 8%, Ramalingam said, and the benefit of the combination was maintained within all prespecified subsets, including patients with mutated KRAS. The trend in OS in the intent-to-treat population was favorable in the combination arm (HR = 0.688; P = .183). Additionally, the combination was tolerated reasonably well, Ramalingam said.
Chandra P. Belani, MD
Afatinib is an irreversible ErbB family blocker that targets ErbB1 (EGFR), ErbB2 (HER2), and ErbB4. The drug has shown in-vitro activity against EGFR-resistant mutations, said Chandra P. Belani, MD, deputy director of Penn State Hershey Cancer Institute in Pennsylvania.
Tested extensively through the LUX-Lung trial program, the drug has led to improved PFS in patients with adenocarcinoma who have been heavily pretreated or have common EGFR mutations, and has sparked a modest improvement in OS among treatment-naïve patients with the disease, Belani said.
When combined with cetuximab, afatinib may be useful in treating patients with EGFR mutations who have become resistant to erlotinib, added Román Pérez-Soler, MD, Gutman Professor of Medicine and chairman of the Department of Medical Oncology at Montefiore Medical Center in New York City. In a trial, he said, the combination sparked a 30% response rate in such patients (ESMO 2012; abstract 1227O).
“It’s one of the few promising treatments for resistance at this point, and it deserves further study,” Pérez-Soler said.
Still ahead is the LUX-Lung 8 trial, which will randomize patients with SCC to receive oral afatinib versus oral erlotinib in the second-line setting.Targeted Inhibitors
In SCC, there are four classes of targeted drugs being investigated, one for each of the most common driver mutations, according to Belani.
In the laboratory, the compound AZD4547, an FGFR1 tyrosine kinase inhibitor (TKI), led to shrinkage in tumors that expressed FGFR1 amplification (Sci Transl Med. 2010;15:2:62ra93). Now, that compound and another in its class, BGJ398, are being studied in clinical trials, Belani said.
In addition, he said, PIK3CA inhibitors are being used in clinical trials to target PIK3CA mutations. Meanwhile, to target DDR2 mutations, which are seen in approximately 1% to 2% of SCCs, trials are being conducted with dasatinib and nilotinib, TKIs approved for use in chronic myeloid leukemia, Belani said.
Finally, for EGFRvIII mutations, the EGFR TKIs typically used in adenocarcinoma are being applied.
In the area of immunotherapy, two compounds have shown “provocative evidence of activity” in SCC, Belani said.
Cadi-05. Cadi-05, or mycobacterium w, is a pure Th1 response enhancer, a potent TLR2 agonist, and a TLR4E and 9 antagonist. It causes P38 (MAPK) downregulation in normal cells and upregulation in cancer cells, Belani said. The intradermally administered, minimally toxic drug stimulates cells that produce interferon-gamma, IL-2, and Granzyme-B#.
In a phase II trial (J Clin Oncol. 2011;29:15s [suppl; abstract 7501]), the drug was combined with cisplatin and paclitaxel.
“Though there was a benefit overall in all comers, we saw that, in SCC—especially in those who expressed desmocollin—there was a benefit in overall survival,” Belani said.
An ongoing clinical trial is comparing chemotherapy to chemotherapy plus Cadi-05 specifically in SCC patients who express desmocollin, Belani said, with results expected soon.
Ipilimumab. In a phase II trial of ipilimumab (J Clin Oncol. 2012;30:2046-2054. Epub 2012 Apr 30), patients with advanced NSCLC were randomized to receive carboplatin and paclitaxel either concurrently with the immunotherapy; in combination with ipilimumab from the third chemotherapy cycle onward, with the experimental drug then being continued as maintenance therapy; or with placebo.
“If you look just at the squamous cell patients, there was a benefit seen in terms of hazard ratio” for PFS and OS, Belani said. Those results led to a large phase III study with a similar design that is enrolling treatment-naïve patients with SCC, he added.Anti—PD-1 Antibodies
Also in the immunotherapy class, anti—PD-1 antibodies are of interest in lung cancer, Belani said, because they block pathways that would otherwise suppress tumor-infiltrating lymphocytes equipped to fight the disease.
One such compound, BMS-936558, is a fully humanized IgG4 antibody that blocks the binding of PD-L1 and PD-L2, Belani said. With an overall response rate of 27% as a single agent with a 3 mg/kg dose, the drug showed similar levels of activity in both adenocarcinoma and SCC; PFS at 24 weeks was 44% in both subsets, he explained.
An important principle gleaned from that phase I, multidose regimen study, which was presented at ESMO this year (abstract 1237PD), is that immunotherapeutic agents may stimulate cancer flare-ups before they shrink tumors, Belani said.
Enrolling now is a phase III study (NCT01642004) that will compare docetaxel and an anti—PD-1 antibody in advanced/metastatic SCC, with primary endpoints of objective response rate and OS. In addition, two trials of anti–PD-1 antibodies are being conducted in patients who have EGFR-mutated, nonsquamous NSCLC.
A practice that may arise from these trials, Belani said, is the selection of patients for treatment with anti—PD-1 antibodies, based on PD-L1 expression in pretreatment tumor biopsies.
Román Pérez-Soler, MD
Talactoferrin, which is contained in breast milk and stimulates the maturation of dendritic cells, and thus the immune system, looked promising after it was tested as a second- and third-line monotherapy in two randomized phase II studies of patients with advanced NSCLC, Pérez-Soler said.
In those studies (J Clin Oncol. 2011;29 [suppl; abstr 7569]), conducted in India, patients with both squamous and nonsquamous histology experienced prolonged survival while taking the oral drug, noted Pérez-Soler.
The success of those trials led to Fortis-M (http://tinyurl.com/bpvlpzq), a revcently completed, randomized phase III study of the drug as a third-line or later-use monotherapy for previously treated patients with advanced NSCLC.
Surprisingly, Pérez-Soler said, the results reflected “absolutely no difference in survival between patients taking talactoferrin and patients on the placebo arm. Survival was 7.66 months for those on placebo and 7.49 months for those in the talactoferrin arm, and there was no indication that talactoferrin could benefit any subgroup based on clinical characteristics. In terms of PFS, again there was absolutely no difference.”
“The only good news,” Pérez-Soler said, “was that talactoferrin had absolutely no toxicity. I think we can add this to the list of inactive agents in NSCLC.”