As in the years before, presentations related to lung cancer at this year's ASCO Annual Meeting evoked a mixture of feelings in me—hope; caution; intrigue; and at times, frank despair.
It is clear now that the optimal front-line therapy for patients with metastatic non-small cell lung cancer (NSCLC) whose tumor cells harbor mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) involves use of EGFR TK inhibitors such as gefitinib or erlotinib.
The results of LUX-Lung 3 reinforce this view (Abstract LBA7500). Afatinib, an irreversible EGFR TK inhibitor, produced longer progression-free survival (PFS) compared with cisplatin and pemetrexed in the frontline therapy of patients with EGFR-mutant NSCLC (median PFS of 11.9 vs. 6.9 months, hazard ratio of 0.58, p=0.0004). The median PFS for those with the two more common EGFR TK mutations (exon 19 deletions/L858R) was 13.6 months with afatinib compared with only 6.9 months with cisplatin and pemetrexed (HR 0.47, p<0.0001).
The side effect profile reported in this study was typical of what one would expect with an EGFR TK inhibitor or chemotherapy. However, the rate of grade III diarrhea was 14 percent with afatinib, much higher than what is typically reported with gefitinib or erlotinib.
Afatinib has some activity against the so-called “resistant” mutations (T790M, for example). While these results are encouraging, at present no data are available comparing afatinib with gefitinib or erlotinib in this patient population. Afatinib has not yet been approved by the Food and Drug Administration.
Also presented were updated results of the PARAMOUNT study (Abstract LBA7507), which compared pemetrexed maintenance or placebo in patients who have no progressive disease after four cycles of induction therapy with cisplatin and pemetrexed. The previous presentation from PARAMOUNT highlighted the fact that the study met its primary endpoint of PFS. The focus of the new report was on overall survival.
Patients who received pemetrexed maintenance had a median overall survival of 13.9 months compared with 11 months with no maintenance chemotherapy (HR 0.78, p=0.0195). This study provides some reassurance that “continuation” maintenance therapy with pemetrexed is associated with modest but clinically meaningful survival benefit. Of course, this benefit must be weighed against toxicities. Though relatively well tolerated, pemetrexed was associated with grade 3/4 fatigue in five percent of patients.
KRAS is the most frequently mutated oncogene (20%-30%) known (at least as of now) in adenocarcinoma of the lung outside Asia. KRAS mutation has been associated with resistance to chemotherapy and to EGFR inhibitors No specific therapy is available at the present time for those with KRAS-mutant NSCLC.
Selumetinib (AZD6244) is a potent and selective inhibitor of MEK1/2. Preclinical data suggest that selumetinib has activity against BRAF/RAS-mutant cell lines.
In a phase II double-blind randomized placebo-controlled multi-center study, patients with metastatic KRAS-mutant NSCLC had a better median PFS with docetaxel and selumetinib (5.3 months) compared with docetaxel alone (2.1 months, HR= 0.58, p=0.0138) (Abstract 7007). The response rates were strikingly higher with the combination therapy (37%) than with docetaxel alone (0%). Overall survival was better with the combination (9.4 months) than with docetaxel alone (5.2 months, HR 0.80, p=0.2) although it did not reach statistical significance in this small, underpowered study (n=83).
These results certainly raise considerable hope that drugs like selumetinib that target MEK could improve the outcomes in patients with KRAS-mutant NSCLC.
In an unrelated presentation, the investigators leading the efforts of the LACE-BIO team reported intriguing results regarding the prognostic and predictive role of KRAS mutation in patients enrolled in four prospective adjuvant chemotherapy trials (ANITA, JBR 10, IALT, and CALGB 9633) (Abstract 7007). In a large well-defined cohort (1,543 patients), the presence of KRAS mutations did not have any prognostic or predictive value.
Very intriguingly, the presence of KRAS mutation (as opposed to wild type) was associated with increased chances of having a second primary cancer (HR 2.76, p=0.005). If these findings are confirmed, the presence of KRAS mutation may call for a more rigorous follow-up with CT screening in a select group of patients following potentially curative surgical resection.
After many years of painstaking research, there is a great deal of enthusiasm for immune therapy for patients with cancer. The programmed death-1 (PD-1) receptor is an inhibitory T-cell receptor that responds to two ligands, PD-L1 and PD-L2. PD-1 acts as a brake or a checkpoint to avoid immune overactivation.
The results of a multi-center phase I trial with anti-PD-L1 antibody showed that anti-PD-L1 antibody induced durable regression in patients with advanced cancers of various types including lung cancer (Abstract 7509). Of 76 patients with NSCLC treated with this antibody, 18 percent had an objective response, and the progression-free survival rate at 24 weeks was 26 percent. Some of the responses were very durable, and the treatment was well tolerated with common side effects being fatigue, rash, and diarrhea.
Investigators from the American College of Surgeons Oncology Group reported results analyzing the accuracy of FDG-PET scanning in diagnosing NSCLC in patients enrolled in a prospective trial (Z 4031, Abstract 7008). The sensitivity was only 82 percent and specificity was a mere 31 percent. The most common reason for false-positive FDG-PET scan was granuloma. The accuracy was less than 50 percent for lesions less than 2 cm in size.
As with all procedures and tests, one should use clinical judgment and considerable caution while interpreting results of FDG-PET scan.
We continue to have problems in identifying better therapies for patients with small-cell lung cancer. Unfortunately, this frustrating trend continues and no practice changing studies were reported at this meeting. It is unlikely that we will make significant progress in this disease unless we understand the molecular mechanisms governing treatment resistance in SCLC.
The Cancer Genome Atlas (TCGA) is a massive effort to comprehensively study the genomic landscape of more than 20 types of tumors. On behalf of the TCGA investigators, I presented the results of comprehensive genomic characterization of squamous cell lung cancer from 178 patients (Abstract 7006). This ongoing effort clearly reveals that squamous cell lung cancer is replete with potentially actionable targets. Over two-thirds of patients studied had potentially actionable targets. It is likely that we will see, in the coming months, a number of new trials specifically designed for patients with squamous cell lung cancer targeting pathways such as PI3 kinase pathway and fibroblast growth factor receptor.
As we move forward, I remain optimistic that with better understanding of the complex molecular landscape using comprehensive and integrative genomic approaches, we will make considerable progress in the treatment of lung cancer.