More Advances Anticipated in Fast-Moving Lung Adenocarcinoma Field

Gregory J. Riely, MD, PhD

After a decade of advances in the diagnosis and treatment of patients with adenocarcinoma non—small cell lung cancer (NSCLC), the prospect for further progress remains bright, according to experts who participated in a recent OncLive Peer Exchange panel.

There are now first- and second-line targeted therapies for both ALK-positive and EGFR-mutant disease. Immunotherapies have been moving closer to the front line, an important development in that most patients with NSCLC do not harbor a currently actionable mutation. And, advances in plasma genotyping give hope that eventually there will be routine clinical use of a predictive molecular proxy of tumor biology derived from a noninvasive test.

Diagnostic Challenges

Molecular Testing

The take-home message from the roundtable, entitled “Treating Adenocarcinoma of the Lung,” is that many studies are underway to further define how best to use targeted therapies and immunotherapies with personalized approaches.Adenocarcinomas represent 40% of all lung cancers and constitute the most dominant histological subgroup in the NSCLC category, according to the American Cancer Society. Accurately diagnosing adenocarcinomas has become more complex, panelists noted.

“In 2016, an accurate diagnosis means you understand the histology well and you have molecular testing done for that tumor because all these things drive what patients are going to get in terms of treatment,” said Gregory J. Riely, MD, PhD. “A fine-needle aspirate, simple one pass needle biopsy is not enough in 2016. We need either multiple passes with a fine needle, multiple passes with a core needle, or even surgical biopsy.”

Riely said it is critical that individual patients are tested for EGFR mutations, ALK status, and ROS1 rearrangements; this testing should be completed within 7 to 10 days. “Randomized clinical trial data has said platinum-based chemotherapy is inferior to targeted therapy for those patients, so we need to know [mutation status] up front,” he said.

John W. Longshore, PhD

Additional testing might include BRAF mutations and MET exon 14 skipping mutations, Riely said.

Tissue Samples

To go beyond the standard FDA-approved tests is to look for ways to make patients eligible for trials and to consider using drugs approved for other indications. Larger gene panel tests may yield information about mutations with no relevance to lung cancer but would make efficient use of tissue samples if priced in the range of single-mutation assays. The panel agreed strongly that once a biopsy has been obtained, testing for markers should be reflexively ordered.The need to obtain sufficient tissue to conduct molecular testing has been a growing topic of discussion, noted John W. Longshore, PhD.

However, he said, “it’s not really the quantity of tissue that’s important but it’s the quantity of tumor that is important. Making sure we get a good biopsy that has sufficient tumor content really is what drives the biomarker testing landscape.” It is essential that clinicians and pathologists communicate well, noted Mark A. Socinski, MD, who served as moderator for the Peer Exchange panel. Oncologists should give the pathologist a tentative diagnosis, so he does not conduct stains to rule out a pancreatic or colon primary tumor.

Mark A. Socinski, MD

Communication is particularly important in the community setting where physicians do not have the ready access to tumor boards, Longshore said. This includes communicating with radiologists and pulmonologists. Even in the community setting, multidisciplinary tumor conferences can be conducted via Skype or another platform.

A major change in practice now emerging involves rebiopsying at progression, Longshore said. This is particularly important because of new therapies directed at the EGFR T790M resistance mutation and the need to learn a patient’s PD-L1 expression level. These markers can change over time.

“This is a huge paradigm shift for us because we never rebiopsied. We were always happy with the first biopsy. But I think we have to rebiopsy.,” said Socinski, adding that some of his patients have had four or five biopsies over time. Plasma-based testing for biomarkers, often called a liquid biopsy, already is approved in Europe and hopefully will be introduced soon in the United States, noted Longshore. Such tests are not quite as sensitive or specific as a tissue-based diagnostic but institutions are using plasma-based testing for circulating DNA for initial screening and, if a negative result appears, perhaps going to a tissue biopsy.

Chemotherapy Considerations

However, that entails a delay, Thomas E. Stinchcombe, MD, pointed out. Liquid biopsies are clearly the way of the future but relatively little validation has been completed and there is poor standardization among the several available platforms, panelists said.Chemotherapy remains an important therapeutic tool in the treatment of NSCLC. It is the first-line option for patients without mutations and even patients with targetable mutations will receive chemotherapy at some point.

Jared Weiss, MD

For patients without mutations, Stinchcombe first looks at performance status and comorbidities and then talks extensively with the patient about preferences and care goals. He typically starts patients with performance status scores of 0-1 with either carboplatin/pemetrexed or carboplatin/ paclitaxel and bevacizumab.

He gives the bevacizumab component to approximately 20% of patients, however. Carboplatin/ pemetrexed is very easy to give and there is not the degree of concern about hypertension or hemoptysis, he said. Notably, there was some disagreement among panel members about the relative efficacy and toxicity profiles of these regimens.

After looking at performance status, patient preferences, and comorbidities, Benjamin Levy, MD, tries to put every patient who reaches second-line therapy or who has progressed on platinum chemotherapy into a clinical trial.

Thomas E. Stinchcombe, MD

Outside of a clinical trial, his default second-line therapy would be a PD-1 checkpoint inhibitor, with nivolumab (Opdivo) as his leading choice. He also will look to docetaxel or docetaxel plus the angiogenesis inhibitor ramucirumab (Cyramza) for very fit patients.

For third-line therapy, there is no excellent evidence.

Targeted Therapies

EGFR Mutations

For Jared Weiss, MD, avoiding docetaxel is a central concern, as he sees docetaxel as being one of the most toxic cytotoxic agents in current use. Riely noted that once he has decided to give docetaxel and accept the toxicity profile, however, he will frequently include ramucirumab, as its toxicity profile is modest.The three approved EGFR tyrosine kinase inhibitors (TKI)—gefitinib (Iressa), erlotinib (Tarceva), afatinib (Gilotrif)—have similar mechanisms of action and side-effect profiles, and all have demonstrated improved outcomes compared with chemotherapy, Riely said. At the FDA-approved dose, there is a modest difference in the side-effect profile of the three drugs, however. Gefitinib has a more moderate side-effect profile with lower rates of rash and diarrhea, afatinib the least moderate.

However, the LUX-Lung-7 study demonstrated a statistically and clinically significant difference in progression-free survival (PFS) among 319 patients with EGFR-mutated advanced NSCLC randomized to receive afatinib versus gefitinib as first-line therapy, particularly after approximately 6 months.¹

Benjamin Levy, MD

As a result, Riely is now considering the possibility that afatinib has a greater efficacy than gefitinib in this setting. He also noted that a large analysis of multiple trials demonstrated that patients who had EGFR exon 19 deletions had a better overall survival with afatinib compared with chemotherapy.

Regardless of which EGFR TKI is chosen as frontline therapy, approximately 50% to 60% of patients will develop a second-site EGFR mutation in T790M, said Benjamin Levy, MD. In November 2015, the FDA approved osimertinib (Tagrisso) for this population.

In a phase I study, osimertinib demonstrated a 61% response rate among 127 patients with centrally confirmed EGFR T790M who could be evaluated for response.² The median PFS achieved by mutation- positive patients was 9.6 months, while adverse events (AEs) were very manageable. Osimertinib does not bring the rash and diarrhea seen with first-generation TKIs. As to the use of osimertinib as a first-line agent, Riely said there is insufficient data.

ALK Rearrangements

Immunotherapy

Rociletinib, another highly anticipated third-generation drug aimed at the resistance mutation, faltered in a phase III trial, prompting the company developing the drug to terminate all studies in early May.For patients with ALK-positive disease, crizotinib (Xalkori) has demonstrated better outcomes compared with both first- and second-line standard chemotherapy, Socinski said. Although crizotinib is an extraordinarily useful drug, emerging agents have proved superior as second-line therapy, Riely said. Ceritinib (Zykadia) and alectinib (Alecensa) both achieve very high response rates with durable PFS rates. Yet, how to sequence these agents, which have somewhat different spectrums of activity against particular resistance changes, is unknown, Weiss said. Alectinib seems to be the better tolerated drug, Levy said. Importantly, both agents have CNS activity, and ALK-positive disease frequently involves brain metastases, said Stinchcombe.The PD-1 inhibitors nivolumab and pembrolizumab (Keytruda) are approved for second-line treatment of patients with nonsquamous NSCLC, which includes adenocarcinoma. Nivolumab was approved based on an improvement in overall survival versus docetaxel (12.2 months vs 9.4 months), while pembrolizumab gained approval based on a 41% objective response rate among patients with PD-L1 expression on ≥50% of tumor cells.

Stinchcombe said the efficacy and the toxicity profiles of the two drugs are similar. Nivolumab is administered every 2 weeks, while pembrolizumab is given every 3 weeks. Additionally, PD-L1 testing is currently required with pembrolizumab although that might not necessarily be the case going forward. This class of drugs obviously brings tremendous excitement, but they also bring a challenging AE profile for some patients, Levy said.

Endocrinopathies, thyroid problems, pneumonitis, colitis, and hepatitis may be relevant, and are forcing oncologists to consult pulmonologists, gastroenterologists, and other physicians. Other immune checkpoint blockade agents in development in NSCLC include the PD-L1 inhibitors atezolizumab and durvalumab and the CTLA-4 inhibitor tremelimumab. Although more immunotherapy agents are on the horizon, Riely believes the near-term goal is determining whether the existing agents should move into the first line of therapy. As data about comparative first-line trials are reported, “it’s really going to be exciting because it’s going to transform how we think about first line, if any of them are positive,” said Riely.

Weiss stressed the need for continued gains through clinical trials. “I’ve been dazzled by the acceleration of progress that we’ve had in our clinical trials and how much more promising our clinical trials are than they were even just 5 years ago,” he said. “And so I’ll make a pitch that we should lower our threshold to put patients on clinical trials, including even in first-line for the most promising of these agents.”

References

1. Park K, Tan E, Zhang L, et al. Afatinib (A) vs gefinitib (G) as first-line treatment for patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations: results of the global, randomized, open-label phase IIb trial LUX-Lung 7 (LL7). Presented at: 2015 ESMO Asia Symposium; December 18-21, 2015; Singapore.
2. Jänne PA, Yang JC, Kim DW, et al. AZD9291 in EGFR inhibitor—resistant non-small-cell lung cancer. N Engl J Med. 2015;372(18):1689-1699.