With five-year survival rates of 15%, lung cancer treatment is not, overall, one of oncology's poster children. Partly, that's due to the sheer genomic complexity of the disease. And the disease, like its most frequent cause, smoking, comes with social stigma.
While breast cancer's pink ribbons have become a cottage industry, many of lung cancer's victims—even if they are nonsmokers—are less enthusiastic about being the face of a disease that many people view as, to a degree, self-inflicted. But several presentations at this year's American Society of Clinical Oncology (ASCO) meeting suggested that scientists are beginning to make inroads into the disease, which kills more patients than breast, prostate and colorectal cancer combined.
Much excitement greeted LUX-lung 3, a late-breaking phase 3 trial reporting that in patients with advanced or metastatic lung adenocarcinoma, first-line treatment with Boehringer Ingelheim GmbH's afatinib extended progression-free survival by 4.2 months, or 60%, overall, and doubled it in some subgroups, when compared to a combination treatment with Alimta (pemetrexed, Eli Lilly and Co.) and cisplatin chemotherapy.
EGFR was the target of the first targeted therapies to be approved for the disease: Iressa (gefitinib, AstraZeneca plc) and Tarceva (erlotinib, Astellas Pharma Inc. and Roche AG) were approved in 2003 and 2004, respectively. (See BioWorld Today, May 6, 2003, and Nov. 22, 2004.)
During their development, Tarceva and Iressa were thought to work because they targeted cells with high levels of EGFR expression.
But it soon became clear that the science had not quite caught up with the clinic.
Iressa was withdrawn from the market after a post-accelerated approval study failed to show a benefit of treatment, although later studies have shown benefits of Iressa treatment in prescreened populations. Tarceva, meanwhile, was approved on the basis of a trial that showed a more than 40% survival advantage. (See BioWorld Today, Dec. 20, 2004, and May 29, 2012.)
Additional research made clear that high expression of EGFR was beside the point for EGFR-targeting drugs. Instead what is critical in lung cancer is that there are activating mutations in EGFR. In fact, in another presentation at ASCO, Italian researchers showed that patients treated with docetaxel had higher response rates and longer progression-free survival compared to those treated with Tarceva as second-line treatment in patients with wild-type EGFR.
Afatinib's design was based on that improved understanding of why EGFR-targeting drugs work—and the results of the LUX-lung 3 trial appear to reflect that better understanding. The drug performed best in patients with the two most common mutations in EGFR. In that subgroup, it more than doubled survival time.
KRAS is another frequently mutated gene in lung cancer. But unlike EGFR, which, as a receptor, is relatively straightforward to target, KRAS is a transcription factor, and KRAS mutant cancers have not been successfully targeted to date.
At the meeting, researchers from the Dana-Farber Cancer Institute presented the results of a double-blind randomized phase 2 trial that selumetinib (Array BioPharma Inc. and AstraZeneca plc) plus chemotherapy improved the overall response rate and more than doubled progression-free survival compared to chemotherapy alone as second-line treatment. The trial did not show an effect on overall survival. But presenter Pasi Janne told the audience that the trial is "the first prospective study to demonstrate clinical benefit for patients with KRAS-mutant lung cancer, or even, perhaps, with KRAS-mutant cancer of any kind."
What may turn out to be the biggest game-changer in the long run, though, are results from a study of Bristol Myers-Squibb Co.'s PD-1 blocker BMS-936558. (See BioWorld Today, June 4, 2012.)
PD-1 is an immunotherapy, designed to prevent activated T cells from shutting down. It is early days for BMS-936558—the data presented at ASCO were from a phase 1 trial. And the response rate of 18% was lower than in other tumor types that were responsive to BMS-936558 at all.
But the data mark the first time that any immunotherapy has had an appreciable effect in lung cancer, which has long been impervious to that approach. In fact, study lead Suzanne Topalian told reporters at a press briefing, the response in lung cancer was the "biggest surprise" in the study.
The potential for immunotherapy of lung cancer means the disease could eventually be attacked by a combination of targeted and immunotherapies. The response to targeted therapies is often spectacular, but short-lived. As Benjamin Solomon noted when discussing the results of the LUX-lung 3 study, "As impressive as these results with afatinib may seem. . .all patients still eventually develop resistance."
Immunotherapies, generally speaking, have a lower response rate, but more often lead to durable remissions. Many researchers hope that combining the two will lead to the best of both worlds, that is, a high rate of durable remissions.