Chemotherapy Remains Critical in NSCLC Paradigm

Mark G. Kris, MD

Although targeted therapy and immunotherapy have been well validated, chemotherapy has been and will remain integral to the treatment of patients with non—small cell lung cancer (NSCLC), says Mark G. Kris, MD.

“There's no targeted therapy, no antiangiogenesis therapy, no immune checkpoint blocker that has been shown to improve the chance of cure,” said Kris. “Of all the systemic therapies we have to fight lung cancers, only cytotoxic chemotherapy—particular cisplatin-based chemotherapy—has been shown to improve the chance of cure.”

Ongoing clinical trials are now looking to consolidate the benefits of chemotherapy and targeted agents and/or immunotherapies in combination regimens, Kris explained. Emerging evidence has confirmed the progression-free survival (PFS) and overall survival (OS) benefit of combination chemotherapy and targeted agents.

For example, results of the phase III IMpower150 trial demonstrated that the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel delayed progression or death by 38% versus bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC. The median PFS was 8.3 months versus 6.8 months, respectively (HR, 0.62; 95% CI, 0.52-0.74; P <.0001).

Genentech (Roche), the manufacturer of atezolizumab and bevacizumab, also reported in a press release in March 2018 that the atezolizumab combination had been shown to improve OS in the study, as well.

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In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Kris, William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, discussed the continued significance of chemotherapy in patients with NSCLC in the era of targeted agents and immunotherapy.Kris: My topic of discussion tonight is the use of chemotherapy. By chemotherapy, I mean drugs that target the cell cycle. There is a misconception that chemotherapy is not a targeted treatment, but it actually is. We're not quite as sure about the target as we are perhaps with EGFR tyrosine kinase inhibitors (TKIs), but we know how it works. Chemotherapy does affect cells, particularly cells that have already undergone a neoplastic transformation. Chemotherapy given with radiation, or given before or after surgery can improve the chance of cure. It's really the only treatment today that can do that.

The other extraordinary thing is the emergence of more data showing that giving more targeted agents with cell cycle—targeted chemotherapies improves outcomes above those targeted immune or antiangiogenic therapies. The first example of that would be with bevacizumab. Bevacizumab and now ramucirumab (Cyramza) given with chemotherapy has been shown to improve outcomes over those agents alone. There is much excitement surrounding the recent data on bevacizumab in combination with cell cycle–targeted chemotherapy and atezolizumab.

The other area that is exploding is the use of checkpoint inhibitors. The drugs that physicians now have include pembrolizumab (Keytruda), atezolizumab, nivolumab (Opdivo), and durvalumab (Imfinzi). There’s emerging evidence that when you give drugs with chemotherapy, there are improved outcomes both in terms of PFS and OS. It is going to give a new life to chemotherapy. Giving chemotherapy with checkpoint inhibitors will become the standard of care in virtually every patient with NSCLC. For those who get chemotherapy and then suffer disease progression, a checkpoint inhibitor can be helpful.

The other interesting area is targeted therapies. Any guideline for the treatment of patients with an EGFR-targeted therapy, for example, states that patients who progress on an EGFR TKI require a change in systemic therapy. Chemotherapy is the universal treatment that is both helpful and recommended in the guidelines.

The interesting thing about patients who have an oncogenic target is that giving a chemotherapy drug is more effective than in patients without a target. The 2 clearest examples of that are the use of pemetrexed in patients with ALK-positive NSCLC. There's a randomized trial comparing chemotherapy with crizotinib (Xalkori). In that trial, crizotinib beat chemotherapy in terms of PFS, but the response rates of chemotherapy in ALK-positive patients were much better than you would expect. Pemetrexed was better than docetaxel. The IPASS trial led to the widespread use of upfront gefitinib (Iressa) after showing that response rates with chemotherapy in patients with EGFR mutations were double that of patients without mutations.

What does the safety profile look like in these combinations?

Is there anything else you would like to emphasize?

Chemotherapy can be used after targeted therapy, and you can also expect a better result. As time has gone on, chemotherapy is used more rather than less. It's the standard of care in NSCLC. It's used either with an immune checkpoint blocker, or following an immune checkpoint blocker for adenocarcinomas and squamous cell carcinomas. It’s also used following acquired resistance to many therapies. Chemotherapy is even more effective when coupled with antiangiogenic drugs. It's the only treatment that has been shown to add to the cure rate. It's extremely important and will remain so for all these reasons.Regardless of drug class or therapeutic class, there are more toxicities with combination therapies. Two drugs are always more toxic than 1 drug. However, we have to remember that the adverse events (AEs) are offset by the additive or synergistic benefits. The good thing about adding chemotherapy to other regimens is that while you see more toxicity, you also see more benefit. We have decades of experience in either lessening the AEs of chemotherapy or preventing them altogether. You can virtually eliminate the nausea and vomiting that follow even our most potent chemotherapies, such as cisplatin, by giving the best available drugs. While chemotherapy adds to toxicity, its ability to add benefit far exceeds that. We know how to manage those toxicities. It's very important to speak out against the trend of trying to avoid chemotherapy-containing regimens. The critical thing for patients are survival and cure outcomes. Patients will be willing to accept the AEs if you explain to them that using the treatment will improve their chance of cure and prolongation of survival. It's a disservice to try not to use chemotherapy.

How heavily should physicians rely on the results of IMpower150 and KEYNOTE-021?

For each patient and each situation, you have to use the best drugs you have and do whatever can be done to lessen AEs. You have to use them wisely and in the right sequence or combination. You have to get away from the ideology and knee-jerk reaction of “chemotherapy is too toxic.” You have to give the therapy that is going to be best for the patient. Don't get caught up in what the name of it is or what the AEs are; it's all risk and benefit. It's incumbent on oncologists to make the best choices for patients, lay them out, see what's best for patients in terms of safety, personal goals, and of course your recommendations for the most effective regimens. We've known and accepted that the treatment for patients who have a low PD-L1 expression and other measures of possible sensitivity to immune checkpoint blockers, like tumor mutational burden, is chemotherapy. There is a growing body of knowledge that adding an immune checkpoint blocker to chemotherapy improves response, PFS, and in the data from the IMpower150 trial, OS as well. It does so even in patients with EGFR mutations—a situation where people generally shied away from immune checkpoint blockers.

The increasing body of evidence [suggests] that adding an immune checkpoint blocker to chemotherapy is going to become the standard of care. If you started with an immune checkpoint blocker, then you later received chemotherapy. If you started with chemotherapy, you later received an immune checkpoint blocker. We now have the know-how and the data that allow us to put these agents together, and that is going to make an impact. The vast majority of patients are going to receive both classes of drugs.