Reviewing Initial Therapy and Maintenance in NSCLC

The NCCN Annual Meeting included a dinner symposium on “Maintenance Therapy for Non—small cell Lung Cancer (NSCLC).” Supported by an educational grant from Lily USA, the session featured speakers Mark G. Kris, MD, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York; and George R. Simon, MD, director of the Thoracic Oncology Program at Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Kris began the session by discussing progress in chemotherapy for NSCLC and described how maintenance therapy essentially emerged from studies of combination regimens and different treatment durations. “If you want to read one really good paper that puts everything you need to know about chemotherapy in NSCLC,” Kris advised, “It's Stinchcombe and Socinski, Journal of Thoracic Oncology, February 2009.”

Kris said the review article showed “No matter what drug you gave or what question you asked, there was always—with a very rare exception—a benefit to the added treatment, the longer treatment, or a continuing treatment,” supporting the premise of maintenance therapy in NSCLC.

Getting Off to the Right Start

Kris emphasized the importance of pairing appropriate agents with the cancer’s histology and testing for mutations like EGFR and KRAS before selecting treatment. “Choosing the best therapy on day 1 for an individual patient does matter for tolerability and survival,” he said. To illustrate, Kris said after one study showed pemetrexed (Alimta) inferior in squamous cell lung cancer but superior in adenocarcinoma and large cell lung cancer, the FDA “unapproved” pemetrexed for squamous cell and approved it instead as a second-line therapy in the histologies in which it demonstrated efficacy.

Whenever possible, MSKCC analyzes a patient’s tumor tissue for all known mutations in NSCLC, including EGFR, KRAS, and BRAF. “We also look at the rare mutations,” he said. “We have an organized program to identify these mutations and we try to use that data.”

Kris pointed out that several trials and a meta-analysis showed that in patients without an EGFR mutation, initial therapy with cisplatin was slightly more effective than carboplatin at improving overall survival (OS). He acknowledged cisplatin has its downsides in terms of toxicity, but said, “If a patient is symptomatic or you're going for cure in adjuvant setting, cisplatin is better.”

He said patients with EGFR mutations at MSKCC receive erlotinib (Tarceva). He suggested gefitinib (Iressa) as another option for such patients, where available. Gefitinib is not approved for use outside of clinical trials in the United States. “Giving erlotinib second-line for patients who are EGFR positive doesn’t make sense,” he said. “It should be given in the first-line.”

Simon agreed with Kris that the most important principle is to “get it right the first time.” He said more than three-quarters of patients are smokers and lack EGFR or other known mutations, making them ineligible for targeted therapies, however. For these patients, he suggested tailoring chemotherapy to expression of excision repair cross-complementation enzyme and RNA recognition motif (ERCC-1 and RRM-1).

How you use ERCC-1 and RRM-1 depends on the stage of disease, Simon explained. In early stage disease, high expression of ERCC-1 or RRM-1 suggests a more indolent phenotype and is prognostic for better OS than low expression. In patients with low ERCC-1, cisplatin increases expression and, in a Moffit study, improved survival even after therapy was discontinued. Conversely, in advanced disease, high RRM-1 predicts resistance to gemcitabine and worse survival. As an added bonus, Simon said, it only costs approximately $500 to test for ERCC-1.

Maintenance Regimens Improve Survival

Bevacizumab (Avastin) had become a very important therapeutic option in treating NSCLC, said Kris. The ECOG 4599 phase III trial demonstrated that adding bevacizumab to carboplatin and paclitaxel improved survival by more than 2 months compared with carboplatin and paclitaxel alone (P = .007). While some might consider this small improvement, Kris said, “2 months is what we do in this disease, and 2 months is a significant difference and I think most of us changed our practice based on this trial.” Kris emphasized that this trial and others demonstrate the importance of continuing bevacizumab until progression.

Although many questions remain on optimal maintenance therapy, Simon said it seems clear that “continuing therapy is better” because it improves progression-free survival and OS. The advantage of maintaining the patient on some form of treatment after initial therapy, he said, is that you ensure “the patient actually gets the drug.”

Kris told Oncology & Biotech News that it did not make sense to let therapy lapse after induction and restart only after signs of progression unless the patient was unable to tolerate continued treatment. He said stopping increased the possibility that the patient might never get second-line therapy and he would advise against it.

Selecting a Drug for Maintenance

Both physicians weighed in on whether it was better to continue the patient on one of the drugs used in the initial regimen or switch to a new drug immediately after induction. Simon said one metaanalysis suggested switching may be better but the evidence was not conclusive. Kris agreed, saying, “Switching to pemetrexed, docetaxel, or erlotinib [for EGFR-positive patients] while in remission does lengthen survival…but the strength of that recommendation is not great.”

Like the an induction regimen, Kris said selecting the right maintenance drug depends on histology and whether the patient has any mutation contraindicated a particular drug. He outlined his preferred regimens:

•For adenocarcinoma patients whose EGFR status is negative or unknown, Kris recommended pemetrexed, bevacizumab, and cisplatin, continuing at a minimum bevacizumab and pemetrexed until progression, if tolerated. Gefitinib (Iressa) can worsen survival for patients without an EGFR mutation, Kris said, and should not be used in patients with unknown EGFR status.

•For squamous cell cancer, use cisplatin with docetaxel or gemcitabine (Gemzar) until progression or as tolerated.

•For EGFR-positive patients, start with erlotinib or gefitinib (Iressa) followed by pemetrexed plus bevacizumab and erlotinib or gefitinib until progression.

Kris said he is not wholly convinced stopping therapy at progression is the right thing to do for patients with EGFR mutations, however, based on results of an MSKCC study he helped conduct. Investigators stopped gefitinib for 3 weeks at progression, conducted computed tomography (CT) scanning, restarted gefitinib for 3 weeks, and then took another CT scan. They found 7 out of 10 patients who progressed on the drug experienced worse symptoms after discontinuing. “When [we] restarted gefitinib, all these symptoms stabilized or got better.”

Simon said more studies are needed in maintenance therapy, particularly studies that compare one maintenance regimen with another. Kris agreed, saying, “I think CMS, with the National Cancer Institute, should do those trials…since they are paying for most of [the therapy].”

Looking Ahead in NSCLC

At the same time, Kris said the money might be better spent on looking for treatments with greater survival potential or even curative. “As good as maintenance appears to be,” he said, “We’re talking lungs here…it’s not enough. Those people still progress and die.”

Kris suggested looking for more targets. “Most of our patients do not have a driver mutation for which we have a very specific, relatively nontoxic therapy.” He pointed to the development of treatments for chronic myeloid leukemia. “When you find that molecular target, it’s pretty damned easy to find a drug.”

Kris said he also thinks drugs targeting ALK mutations will be “the next big thing in lung cancer.” ALK mutations, he said are mutually exclusive with EGFR mutations and drive the disease in 20% of adenocarcinoma patients.