Ramaswamy Govindan, MD.
RAMASWAMY GOVINDAN, MD, is Co-Director of the Section of Medical Oncology and Professor of Medicine in the Division of Oncology at Washington University School of Medicine in St. Louis.
Research in the systemic therapy of lung cancer continues to progress at a good pace, and the past year was no exception. Although some of the following studies are no doubt already familiar to OT readers from presentations at national and international meetings, I offer here a brief review of the lung cancer papers published in 2013 expected to be most useful for practicing clinicians.
Activating mutations in the epidermal growth factor receptor tyrosine kinase (EGFR TK) are present in 10 to 15 percent of patients with non-small cell lung cancer (NSCLC). Patients with advanced EGFR-mutant NSCLC have higher response rates and longer progression-free survival with reversible EGFR TK inhibitors (gefitinib or erlotinib) compared with patients treated with platinum-based chemotherapy.
The results of the LUX-Lung 3 trial, a randomized Phase III study comparing afatinib with cisplatin and pemetrexed in patients with EGFR-mutant advanced NSCLC were published this year (JCO 2013;31:3327–3334).
Afatinib is an orally available irreversible inhibitor of members of the ErbB family. The median progression-free survival (PFS), the primary endpoint of the study, was 11.1 months for patients receiving afatinib and 6.9 months for those receiving chemotherapy (HR 0.58; 95% CI: 0.43–0.78; p=0.001). The median PFS for those with the two most common EGFR mutations (exon 19 deletion and L858R) was 13.6 months with afatinib and 6.9 months with chemotherapy (HR:0.47; 95% CI: 0.34–0.65, p=0.001).
The most frequently observed side effects were diarrhea, rash/acne, and stomatitis with afatinib; and nausea, fatigue, and decreased appetite with chemotherapy. Based on these results, afatinib has now been approved for use in the frontline therapy of patients with EGFR-mutant (exon 19 deletion/L858R) NSCLC.
Combined pemetrexed and cisplatin has been shown to be superior to gemcitabine and cisplatin in patients with non-squamous NSCLC. Given the survival benefit seen with the addition of bevacizumab to paclitaxel and carboplatin in patients with non-squamous NSCLC, it is natural to test the combination of bevacizumab with pemetrexed-platinum doublet in this setting.
The PointBreak trial is a Phase III study that randomized patients with stage IIIB or IV non-squamous NSCLC to either the standard ECOG 4599 regimen of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab maintenance or carboplatin, pemetrexed, and bevacizumab followed by maintenance therapy with pemetrexed and bevacizumab (JCO 2013; doi:10.1200/JCO.2012.47.9626).
The study, designed to show the superiority of pemetrexed-based therapy over paclitaxel-based treatment, did not meet its primary endpoint. However, the overall survival was “comparable” in both groups (HR 1.00; 95% CI: 0.86–1.16, p= 0.949), although median PFS was slightly better with the carboplatin, pemetrexed, bevacizumab combination therapy (6.0 vs. 5.6 months; p= 0.012) compared with the control group.
Grade 3 or 4 adverse events were different in the two groups, with anemia, thrombocytopenia, and fatigue occurring more frequently in the carboplatin, pemetrexed, and bevacizumab arm, while carboplatin, paclitaxel, and bevacizumab resulted in more neutropenia, febrile neutropenia, and sensory neuropathy (Full disclosure: I am one of the authors).
The final overall survival results of the PARAMOUNT trial, a Phase III randomized study of maintenance pemetrexed versus placebo after induction therapy with pemetrexed and cisplatin for patients with advanced NSCLC, were published last summer (J Clin Oncol 2013;31:2895–2902).
It has been shown previously that pemetrexed (“switch”) maintenance therapy improves progression-free survival (PFS) and overall survival (OS) in patients with advanced NSCLC who had no evidence of disease progression following induction therapy with a non-pemetrexed containing doublet therapy. PARAMOUNT is the first study to examine the utility of pemetrexed (“continuation”) maintenance therapy in patients with advanced non-squamous NSCLC following induction therapy with pemetrexed and cisplatin. Only patients with good performance status and no evidence of disease progression following induction therapy were randomized to pemetrexed or placebo.
This paper reports the final overall survival (secondary endpoint) data from the PARAMOUNT study. The median overall survival was 13.9 months with pemetrexed and 11.0 months with placebo (HR: 0.78; 95% CI: 0.64–0.96, p=0.0195). The one-year and two-year survival rates were longer with pemetrexed (58% and 32%, respectively) than with placebo (45% and 21%). The updated results confirmed the previous observations that pemetrexed was superior to placebo, with a median PFS (the primary efficacy endpoint) of 4.4 months vs. 2.8 months, respectively (HR 0.60; 95% CI: 0.50–0.73, p<0.001).
The median number of cycles of pemetrexed administered in the PARAMOUNT study was 7.9 (range: 1–44). No new safety issues were identified with a longer follow up.
These data are fairly similar to the benefits observed with pemetrexed switch maintenance therapy. Clearly, maintenance pemetrexed is an option for patients with advanced non-squamous NSCLC who have a good performance status and have no evidence of disease progression after platinum-based induction therapy.
Maintenance therapy with pemetrexed is not appropriate for patients who have a poor performance status following induction therapy. While pemetrexed is generally well tolerated, cumulative fatigue and limb edema are the two most common problems I see in my own practice. Other issues to keep in mind include an increase in serum creatinine and excessive tearing.
The maintenance therapy options for patients with advanced squamous cell NSCLC are more limited. Maintenance pemetrexed is not an option for these patients. While some have advocated gemcitabine, docetaxel, or erlotinib, I am personally not convinced that maintenance therapy with any of the existing agents is useful in patients with metastatic squamous NSCLC. The role of molecularly targeted agents and immunotherapy with checkpoint inhibitors in the maintenance setting will be explored in the coming years.
For all the advances and excitement surrounding targeted therapies in NSCLC, it is somewhat sobering to realize that we have not had any progress in the treatment of the most common molecular subgroup—KRAS-mutant NSCLC.
KRAS, a member of the RAS superfamily of oncogenes, encodes small GTPases involved in activation of several pathways regulating cellular proliferation, differentiation, and survival. Previous strategies to inhibit RAS function by using farnesyl transferase inhibitors did not work in the clinic despite some promising findings in the laboratory. It has been harder to develop small molecular inhibitors (like gefitinib or erlotinib) given the high affinity of RAS proteins to bind nucleotides.
MEK is a protein downstream of activated RAS. MEK inhibitors are currently in development for the treatment of a variety of cancers. Results of a Phase II randomized trial of the MEK inhibitor selumetinib or placebo in combination with docetaxel (75 mg/m2 every three weeks) in KRAS-mutant NSCLC were published in January 2013 (Lancet Oncol 2013;14:38–47).
Patients who received selumetinib had better outcomes compared with those who received only placebo, with higher response rates (37% vs. 0%, p<0.0001), better median PFS (5.3 months vs. 2.1 months, HR 0.58; 80% CI: 0.42–0.79, one sided p= 0.014), and improved median overall survival (9.4 months vs. 5.2 months, HR 0.8; 80% CI: 0.56–1.14, one-sided p=0.21).
Unfortunately, combination of selumetinib and docetaxel produced higher rates of febrile neutropenia compared with docetaxel and placebo (18% vs. 0%). Although the study did not meet its primary endpoint of improving overall survival with the addition of selumetinib, the higher response rates and better PFS are very encouraging in this molecular subset.
Clearly the control arm of docetaxel alone did relatively poorly compared with many other studies with docetaxel in the second-line setting. Nevertheless it is likely that a subgroup of KRAS mutants may benefit from MEK inhibitors. Whether it is related to specific genotype (G12C, G12D etc.) or the presence or absence of additional genomic alterations (p53 mutation status, for example) is unknown. Several other approaches are being pursued at the moment to target this very important molecular subset of NSCLC.
Another paper worth mentioning in this context is the report from four trials of adjuvant chemotherapy examining the prognostic and predictive effects of KRAS mutational status in patients with early-stage resected NSCLC (JCO 2013;31:2173–2181).
There have been several conflicting reports regarding the prognostic value of KRAS mutation in patients with NSCLC. Among 1,543 patients with NSCLC, 300 had KRAS mutations (codon 12, n=275; codon 13, n=24, codon 14, n=1). KRAS mutation status had no prognostic value. Interestingly, those with codon 13 mutations did poorly with adjuvant therapy (HR 5.78, P<0.001; interaction p=0.002).
These results have to be interpreted with caution since the number of patients with KRAS mutations involving codon 13 was quite small. In this study, patients with KRAS mutations who were enrolled in the observation arm (but not those treated with chemotherapy) had a higher risk of developing second primary cancers (HR 2.76, 95% CI: 1.34–5.70, p=0.005).
While these observations need to be confirmed, the important message from the study is this: KRAS mutation status should not be used to select patients for adjuvant chemotherapy following complete resection.
Anaplastic lymphoma kinase (ALK) rearrangements are found in approximately three to five percent of patients with NSCLC. Patients with ALK-positive NSCLC tend to be younger and to respond well to crizotinib. Based on a single-arm study with spectacular responses, crizotinib was approved for use in patients with ALK-positive NSCLC.
The results of the first randomized Phase III study comparing crizotinib with second-line chemotherapy (docetaxel or pemetrexed) in 347 ALK-positive NSCLC were reported in June (NEJM 2013;368:2385–2394). The median progression-free survival, the primary endpoint, was 7.7 months in the crizotinib group compared with only three months in the chemotherapy group (HR: 0.49, 95% CI: 0.37–0.64, p<0.001).
The response rates were predictably higher with crizotinib than with chemotherapy (65% vs. 20%, p<0.001). Overall survival was no different between the two groups—likely secondary to a significant crossover effect (as a part of a separate study). Patients reported greater reductions in symptoms of lung cancer and greater improvement in global qualify of life with crizotinib than with chemotherapy.
Although these results are not surprising, this important study confirms the superiority of crizotinib over conventional chemotherapy. Several ongoing studies are evaluating novel agents in patients with ALK-positive NSCLC who have developed resistance to crizotinib. Early results from these studies are very encouraging. Every effort should be made to enroll patients with ALK-positive NSCLC who progress following crizotinib in one of several ongoing studies.
Adjuvant chemotherapy with cisplatin and vinorelbine has been shown to improve overall survival in patients with completely resected stage II-III NSCLC. An ongoing study is currently evaluating the role of bevacizumab in combination with chemotherapy in this setting. The role of EGFR TKIs in patients with resected NSCLC has not been defined yet.
Several years ago, the National Cancer Institute of Canada (NCI-C) conducted a randomized study of gefitinib, an EGFR TKI, in patients with completely resected stage IB, II, or IIIA (BR19) (JCO 2013;31:3320–3326). This study was developed before the discovery of EGFR TK mutations and the beneficial role of adjuvant chemotherapy in this setting. The study was activated in September 2002 and amended a year later to allow adjuvant chemotherapy. Patients were not selected by EGFR TK mutational status.
Based on the unexpectedly poor results from two other studies, a decision was made to close this study in April 2005. At the time of closure, 503 patients had been enrolled, with 251 assigned to gefitinib and 252 to placebo. Median duration of treatment was 4.8 months (range 1–25 months) with gefitinib. With a median follow-up of 4.7 years (range 0.1–6.3 years), postoperative gefitinib did not improve the overall survival compared with placebo (HR 1.24; 95% CI: 0.94–1.64).
Although these results are disappointing and not entirely unexpected, the critical question really is whether patients with completed resected EGFR-mutant NSCLC would benefit from EGFR TK inhibitors. That there was no benefit in the group of 15 patients with EGFR-mutant NSCLC with either disease-free survival or overall survival can be easily explained by the very small sample size and limited duration of therapy.
The results of the RADIANT study comparing erlotinib or placebo following standard therapy in patients with resected NSCLC are likely to be available this year. Unfortunately, the RADIANT study is not designed specifically to address the role of erlotinib in patients with resected early stage EGFR-mutant NSCLC. Ongoing efforts through the NCI cooperative group system (ALCHEMIST trial) will likely address this issue in the coming years (Full disclosure: I am one of the principal investigators).
The plan is to screen several thousand patients with resected early-stage NSCLC for EGFR mutation and ALK rearrangement to identify patients for specific therapeutic studies (ALCHEMIST EGFR-erlotinib versus placebo; ALCHEMIST ALK-crizotinib versus placebo) and for genomic analyses.
In summary these papers highlight a rapidly changing research landscape over the past 10 years, from empiric approaches to molecularly targeted therapies coupled with scientific studies to fully understand the complex, deranged, and diverse genomic landscape.
Acknowledgment: I thank my dear colleagues Drs. Daniel Morgensztern, Saiama Waqar, Nithya Ramnath, Karen Reckamp, Thomas Stinchcombe, Suresh Ramalingam, and Geoffrey Oxnard for their help in preparing this article.
Links to Studies
Access the hyperlinks (shown in grey) for all the journal studies noted by reading the article on our iPad app, or by reading the pdf of the article on oncology-times.com