Current therapies for advanced NSCLC: The role of maintenance therapy in an immunotherapy world
Double-agent, platinum-based chemotherapy has been a standard treatment for metastatic non-small-cell lung cancer (NSCLC) for decades. Trials investigated the optimal duration and schedule of platinum-based therapy, revealing that four cycles is the optimal duration, since many patients experience unacceptable toxicity with longer treatment. However, there remained a need to prevent or delay cancer progression or slow cancer growth. This led to a focus on maintenance therapy, which is further treatment following induction therapy that aims to maintain disease control whilst reducing the toxicity associated with the initial therapy.
Single-agent maintenance chemotherapy
One approach trialed was single-agent maintenance chemotherapy, which reduces the toxicity by discontinuing the platinum agent. Two phase III trials demonstrated a survival improvement with maintenance pemetrexed in patients with non-squamous histology after four cycles of platinum–pemetrexed or a platinum doublet without pemetrexed. Bevacizumab has also been investigated in the maintenance setting, and a phase III trial demonstrated an improvement in overall survival (OS) with carboplatin, paclitaxel, and bevacizumab followed by bevacizumab maintenance therapy compared with carboplatin and paclitaxel in patients with non-squamous histology. However, it was unclear if the survival benefit was from the combination of bevacizumab with chemotherapy, bevacizumab maintenance therapy, or both. The selection of patients for maintenance therapy was based on clinical factors such as performance status, and the patient’s tolerance for therapy.
Further questions: double-agent?
The next series of trials focused on pemetrexed and bevacizumab as part of both the initial and maintenance therapies, and addressed the question of whether single- or double-agent maintenance therapy is superior. A phase III trial compared a regimen of carboplatin, pemetrexed, and bevacizumab, followed by pemetrexed and bevacizumab maintenance therapy, with a combination of carboplatin, paclitaxel, and bevacizumab, followed by bevacizumab maintenance therapy, and revealed a similar OS. A randomized phase II trial revealed a longer progression-free survival (PFS) with maintenance pemetrexed and bevacizumab compared with bevacizumab alone.
Phase III trials investigating double-agent maintenance compared with single-agent maintenance therapy were presented at the 2019 ASCO Annual Meeting. One of these, the Japanese Phase III COMPASS trial, used an initial treatment of carboplatin, paclitaxel, and bevacizumab, and patients without disease progression (PD) were randomized to bevacizumab, pemetrexed, or a combination of both. The combination did not improve OS and was associated with a higher rate of grade 3 or 4 adverse events. The ECOG-ACRIN 5508 trial, on the other hand, used carboplatin, pemetrexed, and bevacizumab as initial treatment, and patients without PD were randomized either to bevacizumab or bevacizumab and pemetrexed. The combination did not improve OS and was associated with a higher rate of neutropenia. PFS, a secondary endpoint, was longer with the combination arm in both trials, but the benefit was modest.
A changing treatment paradigm
The aforementioned trials illustrate how much the treatment of NSCLC has changed in a relatively short time. The identification of subgroups of patients with EGFR-activating mutations and ALK rearrangements, as well as the superiority of therapies specifically targeting these mutations compared with chemotherapy, has changed the treatment paradigm for these patient populations.
More recently, immunotherapy has become another option for certain patient subgroups. For example, the KEYNOTE-024 trial demonstrated the superiority of pembrolizumab compared with chemotherapy in patients with a PD-L1 tumor proportion score of 50% or above. Consequently, a significant number of patients with advanced NSCLC now have a non-chemotherapy option.
A comeback for chemotherapy
Because of the increasing array of alternative treatment options for metastatic NSCLC, the prevailing belief was that chemotherapy was becoming obsolete and would soon be a historical footnote. However, chemotherapy has made something of a comeback, in combinations with immunotherapy. For example, phase III trials of chemotherapy and pembrolizumab versus chemotherapy alone in squamous (KEYNOTE-407) and nonsquamous NSCLC (KEYNOTE-189) have demonstrated a survival benefit in the intent-to-treat patient population that was regardless of the PD-L1 score. Moreover, a phase III trial demonstrated a survival benefit of carboplatin, paclitaxel, bevacizumab, and atezolizumab compared with carboplatin, paclitaxel, and bevacizumab. Thus, the majority of patients will now receive platinum-based chemotherapy with immunotherapy.
The phase III trial in patients with squamous NSCLC compared carboplatin and a taxane, with or without pembrolizumab, and patients without PD continued single-agent pembrolizumab. Given the relatively low toxicity of this drug, the absence of any standard maintenance therapy for patients with squamous histology, and the duration of treatment in single-agent immunotherapy trials, maintenance pembrolizumab makes sense. In the trial of carboplatin, pemetrexed, and pembrolizumab, patients without PD continued with pemetrexed and pembrolizumab maintenance while in the carboplatin, paclitaxel, bevacizumab, and atezolizumab trial, patients continued bevacizumab and atezolizumab as maintenance therapy.
Translating data into my practice
I tend to use the carboplatin, pemetrexed and pembrolizumab combination since I find the pemetrexed toxicities easier to manage than the paclitaxel toxicities, and I do not have to worry about the contraindications related to bevacizumab.
If patients are experiencing pemetrexed-associated toxicities (eg, anemia, neutropenia, fatigue, and loss of appetite) in the maintenance phase with pemetrexed and pembrolizumab, I generally discontinue the pemetrexed or extend the treatment interval. I believe the majority of the long-term benefit is from the pembrolizumab and I only discontinue pembrolizumab if there is a severe immune-related toxicity.
With atezolizumab and bevacizumab, if a patient is experiencing bevacizumab-associated toxicities (eg, proteinuria, hypertension, and bleeding), I feel very comfortable stopping the bevacizumab since the activity of single-agent maintenance bevacizumab is not established. With the greater efficacy of immunotherapy combinations, patients are staying on therapy for a longer duration, and cumulative toxicities will become more common.
Maintenance therapy: debate over?
Current chemotherapy and immunotherapy combinations have incorporated maintenance therapy, which has reduced the debate about the relative benefits and toxicities of maintenance therapy. The current focus of thoracic oncology is developing biomarkers of immunotherapy benefit and treatments for patients with progressive disease with immunotherapy. I do not see any future trials specifically evaluating the role of maintenance therapy, and the two trials presented at the 2019 ASCO Annual Meeting represent the end of an era.
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