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Individualized Maintenance Therapy for NSCLC

Cheryl Zigrand
Published Online: Feb 26,2014
Corey J. Langer, MD

Corey J. Langer, MD

Advances in the treatment of non-small cell lung cancer (NSCLC) have resulted in some positive outcomes in recent years, adding choices to the treatment armamentarium. Once a patient with NSCLC responds to treatment, clinicians must then decide on an appropriate regimen that might continue the progress. The initial treatment may be continued in an attempt to prolong the benefit, or it may be switched to another regimen in an attempt to both attack the malignancy and avoid resistance. These strategies, collectively known as maintenance therapy, have become more common, but they have also fostered considerable debate in the oncology community about their role in NSCLC.

Pemetrexed for Maintenance Therapy

Two agents, the cytotoxic therapy pemetrexed and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, are currently approved as maintenance therapy in NSCLC, expanding options for patients who respond to induction therapy. In the JMEN trial, pemetrexed was compared with best supportive care after frontline platinum-based chemotherapy.1 According to Corey J. Langer, MD, professor of Medicine, Abramson Cancer Center, University of Pennsylvania, this trial “yielded one of the most striking survival advantages we’ve seen in NSCLC. The overall improvement in the adenocarcinoma group was 5.3 months.1 That alone has fueled a willingness to consider maintenance.” Langer stated. “I think [maintenance therapy] has changed the therapeutic paradigm, and I think it has changed outcomes for a sizable minority of patients,” he said. In particular, some of his patients have seen lengthy maintenance periods. “I have seen dozens of patients who stayed on maintenance not just a year, but even 2 years or more.”

Despite positive results, Edward Garon, MD, assistant professor, David Geffen School of Medicine, and director of the Thoracic Oncology Program, UCLA, pointed out that pemetrexed trials were not designed to show superiority, “The recent PointBreak study2 did not show superiority of pemetrexed as an agent; however, it is possible that there are differences in its safety profile that have made it a more appealing option in maintenance therapy. Also, it has been able to achieve statistically significant overall survival (OS) advantages both in a switch-maintenance and a continuation-maintenance setting,” Garon said. He added this qualification: “The overall magnitude of the survival benefit seen so far with some maintenance therapies is modest.”

The Controversy Over Maintenance Therapy

A proponent of maintenance therapy, Langer said that while it “may be able to offer a chance of improved outcomes to a number of patients,” other clinicians are not convinced. One reason for the disagreement may be related to a flaw in trial design. “The studies (JMEN, PARAMOUNT, SATURN, etc)1,3,4 never featured mandatory crossover in the control arm at the time of progression,” Langer admitted. Also, patients can be worn out after chemotherapy, so that “even though they’re doing well radiographically, let’s give them time to recuperate from their toxicity,” Langer said, summarizing the argument of clinicians who are hesitant about maintenance therapy.

A treatment holiday raises other questions about treatment course that require further study. Langer said, “The Fidias trial suggested with docetaxel that if you give patients a break, you could find an equivalent outcome between immediate docetaxel and ‘delayed’ treatment, as long as you are able to institute second-line therapy at a propitious time in the control arm.5 The problem is that 40% or more of those who are being followed expectantly after completing first-line treatment never make it to second line.” These results have yet to be shown with pemetrexed or erlotinib. In the end, though, Langer said, “My main argument for maintenance is that, while patients are doing well and tolerating treatment, at least offer to continue it in some way; this way, you know you’ll get a potential survival benefit.”

Additionally, some of the studies of maintenance strategies have shown improvements in progression-free survival (PFS) without an improvement in OS, which complicates the interpretation of the benefit.2,6 For example, according to Jonathan Riess, MD, MS, University of California at Davis Comprehensive Cancer Center, “ATLAS looked at maintenance bevacizumab with or without erlotinib, and that improved PFS but not OS, and the combination has increased toxicity, so that’s not a regimen that’s been widely adopted in clinical practice.” Furthermore, Reiss stated, “The main practice-changing clinical trial for maintenance therapy was maintenance pemetrexed after platinum/pemetrexed, the PARAMOUNT trial, which showed an improvement in OS. But that was done in an ex-US population,” which may not be directly transferable to US practice.3

In terms of erlotinib, because its main purpose is to target EGFR mutation, it would be expected that it would be more effective in patients with this molecular profile; but in the maintenance setting that has not been the case. “An irony of the SATURN trial4 is that erlotinib showed improvement not just in adenocarcinoma, but also in squamous cell carcinoma, even though we don’t think of EGFR TKIs as being particularly efficacious in squamous carcinoma,” Langer said.

Bevacizumab

Although it is not technically indicated for use as maintenance therapy, the mechanism of action of the anti-angiogenic agent bevacizumab makes for an attractive potential strategy in NSCLC. Langer explained, “There’s this notion that angiogenesis as a target never really goes away. Angiogenesis would be a putative target throughout the lifespan of the malignancy.” Therefore, if it is always a target, then continuing the treatment indefinitely may be a promising option. However, he cautioned, “We have no prospective, dedicated, randomized, phase III trials isolating the role of bevacizumab maintenance in NSCLC.”

What we do know about bevacizumab as a possible maintenance tool is that, “If you’re going to give bevacizumab, all the trials were done with continuation maintenance,2,6-8 so if there are no substantial toxicities that require changes, you should keep going past the four to six cycles of the platinum doublet and continue it until progression,” said Riess. Drawing on his own practice, Langer shared that, “If somebody is on paclitaxel/carboplatin/bevacizumab, I’ll usually continue the bevacizumab, even though we have not one lick of data isolating a role for bevacizumab in the maintenance setting. It’s all by extrapolation. We have the ovarian data, where maintenance therapy demonstrated a benefit, at least for PFS.9 And there was a landmark analysis of the ECOG 4599 study that did show a benefit.”10 In that study, he said, “when you look at the group that completed concurrent chemotherapy and bevacizumab and went onto bevacizumab maintenance compared with those in the chemotherapy group who made it all the way through six cycles of chemotherapy and then were observed (per protocol), there seemed to be a survival benefit.”

Cancer cell As with pemetrexed, some of the bevacizumab data collected to date have been mixed. Langer said, “AvaPERL showed a PFS benefit for pemetrexed and bevacizumab compared with bevacizumab alone, but that didn’t translate into a statistically significant survival benefit, mostly because it was underpowered. If you look at the raw numbers, the curves separate, there’s about a 3.5-month difference in median survival,8 it’s close but no cigar.” Trial design has also been a barrier to meaningful bevacizumab results, as Langer pointed out that, “PointBreak wasn’t really asking a maintenance question, but the investigators provided a landmark analysis, although there were no P values or hazard ratios. When we look at the data for pemetrexed/bevacizumab compared with bevacizumab alone in the maintenance setting, there was about a 2-month difference in PFS and OS.2 I’m staying tuned for the meta-analysis of both AvaPERL and PointBreak that’s going to compare pemetrexed/bevacizumab with bevacizumab alone.”

What Does Maintenance Treatment With Targeted Agents Mean?

Unlike some other cancers, in which the treatment course may be primarily defined by molecular profile due to the availability of targeted agents that have been proven to have superior efficacy in selected populations, in NSCLC, “When it comes to maintenance therapy, decisions are really based on histology and not on molecular characteristics, at least not yet,” said Langer. None of the data so far has shown any conclusive benefit of targeted therapy in selected populations in NSCLC maintenance. “When you look at the SATURN trial and specifically assess the patients with EGFR mutation, there was a whopping PFS benefit, with a hazard ratio of 0.1 or so, but, ironically, that didn’t translate into a survival benefit in this cohort,” added Langer.4

Also, Riess explained, “In a sense, most approved targeted therapies are given as maintenance. Erlotinib in patients with EGFR-activating mutations or crizotinib in patients with Ros1 or ALK gene rearrangements are not given for a set time point and stopped. You keep going until they progress, so, in a sense, those are all continuation maintenance.” As for the new options in this new version of continuation maintenance, Riess said, “I would consider ALK and Ros1 to be the targets with the biggest recent practice-changing clinical trials,” where crizotinib has shown benefit with continuation maintenance.11 However, even though these targets represent advances in treatment possibilities for certain patients, Reiss cautioned that, “The median PFS for a patient going on erlotinib with an EGFR-activating mutation is still on the order of 10 months or so, and for crizotinib in patients with ALK translocation, it’s only 7.7 months, so we haven’t advanced to where we could or should be.”

A Potential Role for Immunotherapy

Beyond chemotherapy and molecular targeted agents, there is a possibility that immunotherapy, such as inhibition of programmed cell death-1 (PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), may have a place in maintenance treatment in the future, but data are needed. According to Langer, “Immunotherapy is definitely going to make a mark in NSCLC. The problem is, as with everything, there’s probably a core group of 15% to 25% of patients who are really going to benefit, and we have yet to figure out who they are.” The question of the appropriate population arises because, as Langer explained, “Initially, there seemed to be particular hope in the squamous population. The original studies for the checkpoint inhibitors, both PD-1 inhibitors and ipilimumab,12,13 implied perhaps a preferential benefit in squamous carcinoma, although as time went on, there seems to be much less difference between adenocarcinoma and squamous.”

Because pemetrexed, which is used for many continuation maintenance strategies in patients with adenocarcinoma, is contraindicated in squamous cell carcinoma, “Coming up with a maintenance strategy in squamous cell carcinoma is really a major unmet need,” said Langer. But if the ongoing research is fruitful, “Hopefully, immunotherapy drugs, particularly the PD-1 and PD-1 ligand (PDL-1) drugs, will expand the population of patients who can receive a new type of biologic to patients who haven’t benefited as much from targeted therapy, such as patients with squamous cell lung cancer,” said Reiss.

References

  1. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440.
  2. Patel JD, Socinski MA, Garon EB, et al. PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013;31(34):4349-4357.
  3. Paz-Ares LG, de Marinis F, Dediu M, et al. PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non–small-cell lung cancer. J Clin Oncol. 2012;47:1102.
  4. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, Molinier O, Brugger W, Melezínek I, Klingelschmitt G, Klughammer B, Giaccone G, SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010;11(6):521-529.
  5. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27:591-598.
  6. Johnson BE, Kabbinavar F, Fehrenbacher L, et al. ATLAS: randomized, double-blind, placebo-controlled, phase IIIB trial comparing bevacizumab therapy with or without erlotinib, after completion of chemotherapy, with bevacizumab for first-line treatment of advanced non–small-cell lung cancer. J Clin Oncol. 2012;47:3983.
  7. Kim ES, Moon J, Herbst RS, et al. Phase II trial of carboplatin, paclitaxel, cetuximab, and bevacizumab followed by cetuximab and bevacizumab in advanced nonsquamous non-small-cell lung cancer: SWOG S0536. J Thorac Oncol. 2013;8(12):1519-1528.
  8. Barlesi F, Scherpereel A, Rittmeyer A, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol. 2013;31(24):3004-3011.
  9. Penson RT, Dizon DS, Cannistra SA, et al. Phase II study of carboplatin, paclitaxel, and bevacizumab with maintenance bevacizumab as first-line chemotherapy for advanced mullerian tumors. J Clin Oncol. 2010;28(1):154-159.
  10. Lopez-Chavez A, Young T, Fages S, et al. Bevacizumab maintenance in patients with advanced non-small-cell lung cancer, clinical patterns, and outcomes in the Eastern Cooperative Oncology Group 4599 Study: results of an exploratory analysis. J Thorac Oncol. 2012;7(11):1707-1712.
  11. Ou SH, Jänne PA, Bartlett CH, et al. Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. Ann Oncol. 2014;25(2):415-422.
  12. Lynch T, Bondarenko I, Luft A et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in non-small cell lung cancer: analysis by baseline histology in a phase 2 trial. Presented at the 2011 World Congress of Lung Cancer; July 3-7; Amsterdam, Netherlands.
  13. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.



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