Guideline: Appropriate patients with advanced NSCLC that do not harbour an activating EGFR mutation or ALK rearrangement or who are not appropriate candidates for therapies targeting these mutations or who have progressed on or after targeted therapies should receive 4 to 6 cycles of platin-based combination chemotherapy.
Level of Evidence: I
There are currently no established actionable molecular targets for the palliative systemic therapy of squamous cell carcinoma or nonsquamous NSCLC without an EFGR mutation or ALK rearrangement. Chemotherapy, therefore, remains the mainstay of treatment. Chemotherapy modestly improves median and one year survival in patients with distant metastatic NSCLC compared with best supportive care, but is not curative. The results of three published meta-analyses indicate that cisplatin-based chemotherapy yields an improvement in median survival of approximately 6 to 8 weeks in stage IV disease. One year survival improves from 10-15% to 25-35%.18 Newer generation trials, as discussed below, have shown median OS beyond 12 months.
Palliative chemotherapy patients should ideally have a performance status of ECOG 0, 1, or 2. The implications of decreased performance status will be reviewed separately. Extensive previous radiotherapy is associated with increased chemotherapy toxicity and symptomatic disease within a previous radiotherapy volume may be less chemosensitive. Renal, hematologic and hepatic function must be adequate. Nutritional status must be adequate.
First-Line Combination Chemotherapy
Of the chemotherapeutic agents with activity against NSCLC, the platins cisplatin and carboplatin, historically have been considered the most effective and remain the "backbone" of current chemotherapy. It is recognized that doublet therapy, with a second agent added to a platin, provides the best balance of benefit and toxicity in comparison to single agent or triplet chemotherapy. Multiple trials have established that platin combinations with vinorelbine, gemcitabine, docetaxel, paclitaxel are essentially equivalent with respect to response rate and survival benefit.19-22Histology may have a role to play in selecting chemotherapy combinations as some data suggests pemetrexed containing regimens may be more effective than gemcitabine containing regimens for adenocarcinoma while the reverse may be true for squamous cell carcinoma. Other data fail to show any trends for superior outcomes for pemetrexed containing regimens.23-24 Appropriate patients with advanced NSCLC without actionable driver mutations should therefore be offered first line platin-based doublet chemotherapy containing a second agent consisting of vinorelbine, gemcitabine, paclitaxel, pemetrexed or docetaxel. Trials have failed to consistently identify a regimen with superior efficacy.
Comparisons of the two commonly used platin agents in NSCLC, cisplatin and carboplatin, have been undertaken. A meta-analysis found that cisplatin plus a newer second agent yielded 11% longer survival than the same carboplatin doublet.25 When older chemotherapeutic regimens were included, the survival benefit was not statistically significant. Toxicity was noted to be lower with carboplatin-based chemotherapy. Subsequently, the CISCA meta-analysis looked at individual patient data and found an improvement in response rate with cisplatin over carboplatin. However, the survival benefit was not statistically significant (HR for death, carboplatin vs cisplatin 1.07 p=0.101).26 Again, carboplatin was better tolerated. For patients with good performance status and limited co-morbidities, cisplatin is the preferred agent for palliative chemotherapy but carboplatin remains an appropriate agent for patients with metastatic NSCLC in whom cisplatin is likely be poorly tolerated.
Non-platin third-generation regimens including various combinations of gemcitabine, docetaxel, paclitaxel, vinorelbine, pemetrexed have been compared to platin doublets in the phase II and III setting. Meta-analyses suggest that outcomes are similar for both groups with cisplatin doublets faring a little better and carboplatin-doublets faring a little worse that non-platin doublets, but the toxicity profiles differ depending on the combination.27-28 Platin doublets remain the mainstay of first-line systemic therapy for advanced NSCLC in appropriate patients.
Targeted Therapy Plus Chemotherapy
Over the years several biological targeting drugs have been added to first line platin-doublet chemotherapy to improve the modest results. The most studied have been those targeting the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EFGR).
The ligand of the VEGFR is expressed in NSCLC. Over-expression is associated with poor prognosis. Bevacizumab is a humanized monoclonal antibody that binds the VEGF and therefore prevents binding with its receptor. This results in inhibited tumour revascularization and/or neovascularization which are critical for tumour growth. Several trials have looked at the addition of bevacizumab to first line platin-based doublet chemotherapy. A phase II trial found unacceptable rates of fatal hemoptysis in patients with predominantly squamous cell carcinoma.29 As a result, the first phase III trial, Eastern Cooperative Oncology Group E4599, randomized 878 patients with nonsquamous NSCLC and absence of significant bleeding to 6 cycles of carboplatin and paclitaxel alone or the same chemotherapy with bevacizumab at a dose of 15mg/kg every 3 weeks. The bevacizumab continued until disease progression or unacceptable toxicity. The chemotherapy plus bevacizumab arm was superior to the chemotherapy alone arm with respect to RR (35% versus 15%; p<0.001), mPFS (6.2 months versus 4.5 months; HR 0.66 p<0.001) as well as mOS (12.3 months versus 10.3 months; HR 0.79 p=0.003). There were still significantly more fatal bleeding events in the bevacizumab arm than in the chemotherapy alone arm.30 The subsequent AVAiL study looked at the addition of bevacizumab to the European standard of cisplatin and gemcitabine as well as 2 different doses of bevacizumab in a similar group of patients. 1043 patients were randomized to 3 arms: cisplatin and gemcitabine plus placebo versus cisplatin and gemcitabine plus bevacizumab 7.5mg/kg versus cisplatin and gemcitabine plus bevacizumab 15mg/kg. In all 3 arms patients received up to 6 cycles of chemotherapy and then continued on “maintenance” bevacizumab until PD or unacceptable toxicity. The primary endpoint of mPFS was significantly better with both bevacizumab groups than placebo (6.7 months for low-dose and 6.5 months for high dose bevacizumab versus 6.1 months for placebo; HR 0.75 [95% CI 0.64-0.87 p=0.0003] and 0.85 [95% CI 0.73-1.00 p=.0.456] respectively). The mOS was just over 13 months for all groups despite the fact that post study therapies were similar in all arms and <1% of those on the placebo arm received subsequent bevacizumab. As with ECOG 4599, the number of fatal pulmonary events was significantly higher in both bevacizumab groups.31-32 A meta-analysis based on the data from these and other trials showed that bevacizumab only modestly improved PFS and OS compared to chemotherapy alone (a smaller absolute benefit than other interventions adopted as standard of care) but it also showed that grade 3 toxicities were significantly greater when bevacizumab was added to chemotherapy.33 In another meta-analysis of RCTs, bevacizumab in combination with chemotherapy or biological therapy, compared with chemotherapy alone , was associated with increased-related mortality34.Lastly, the cost-effectiveness of bevacizumab is likely unfavourable in a typical NSCLC population.35 Because of these factors current practice at the BCCA does not incorporate bevacizumab in standard systemic therapy. In fact no provincial funding agency in Canada has approved bevacizumab in combination with chemotherapy as standard of care.
Cetuximab is a monoclonal antibody that binds to the extracellular domain of the EGFR to interfere with downstream signalling of this pathway. Two studies combined cetuximab with platin-based chemotherapy. The FLEX trial randomized 1125 patients to cisplatin plus vinorelbine or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered while the cetuximab was maintained until PD or unacceptable toxicity. The mPFS was 4.8 months in both groups but the RR (36% versus 29%) and mOS (11.3 months versus 10.1 months HR 0.87 95% CI 0.762-0.996, p=0.996) favoured the cetuximab group. Toxicities including rash, diarrhea and febrile neutropenia were worse in the cetuximab arm however.36 The BMS-099 study randomized 676 patients to carboplatin plus either docetaxel or paclitaxel or the same chemotherapy plus cetuximab. Up to 6 cycles of chemotherapy was delivered and, again, the cetuximab was continued as maintenance. When assessed by independent radiologic review the mPFS was similar in both groups (4.2 months versus 4.4 months for the cetuximab arm). The mOS was 9.7 months in the cetuximab group and 8.4 months in the chemotherapy alone group but this was not statistically significant (HR 0.89, 95% CI 0.75-1.05, p=0.169).37 Because of the inconsistent OS benefit in clinical trials and unfavourable cost-effectiveness current practice at the BCCA does not incorporate cetuximab into standard therapy.
Several large randomized studies in patients unselected for EGFR mutations showed no benefit to the addition of a first-generation EFGR TKI to platin-doublet chemotherapy.
Duration of First-Line Therapy
There is no evidence that continuing doublet chemotherapy beyond 4 to 6 cycles in responding patients prolongs survival and cumulative treatment toxicity is a concern and should be minimized. Maintenance therapy with single agent chemotherapy or EGFR tyrosine kinase inhibitors may improve outcomes in patients with stable or responding disease after initial doublet chemotherapy and this topic will be discussed separately below.
Second-Line Systemic Therapy and Beyond
Many patients who receive first-line doublet chemotherapy will be willing and able to receive further systemic therapies. The choice of therapies depends on the histologic subtype, prior systemic therapy, genotype, extent of disease and multiple patient factors including age, ECOG PS, comorbidities and patient preference.
For patients with advanced NSCLC without a driver mutation who received initial first line platin-based combination chemotherapy single agent chemotherapy with a non-cross-resistant agent is usually the preferred approach in the second line setting. Pemetrexed and docetaxel are the most commonly prescribed second-line chemotherapy drugs.
Docetaxel was studied in a phase III trial of 104 previously treated patients who were randomized to either 100mg/m2 every 3 weeks or 75mg/m2 every 3 weeks or BSC. The high dose arm proved too toxic but the docetaxel 75mg/m2 arm was superior to BSC in terms of mOS (7.5 versus 4.6 months), pain control and deterioration in QOL.38 Another study demonstrated similar efficacy but better tolerability of weekly docetaxel at a dose of 33.3 mg/m2 for 6 weeks out of 8 weeks.39Second-line docetaxel is approved in BC after progression following first-line platin-doublet chemotherapy that did not contain docetaxel.
Pemetrexed was compared to docetaxel in the second-line setting. 571 patients were randomized to either pemetrexed 500 mg/m2 or docetaxel 75mg/m2 both given every 3 weeks until PD or unacceptable toxicity. The usual folic acid, vitamin B12 and dexamethasone premedications were given with the pemetrexed. In the overall analysis, both drugs were equivalent in terms of RR (9% for both) and mOS (8 months for both). The hematologic toxicity was better with pemetrexed.40 In a subsequent analysis of this and another trial based on histology that mirrors combination studies in the first-line setting, mOS was better with pemetrexed than docetaxel in patients with nonsquamous NSCLC (9.3 months versus 8.0 months, HR 0.78, 95% CI 0.61-1.00) while the reverse was true in squamous cell carcinoma where pemetrexed had a lesser impact on mOS than docetaxel (6.2 months versus 7.4 months, HR 1.56, 95% CI 1.08-2.26).41 It is reasonable to consider second-line docetaxel for those with squamous cell carcinoma who did not receive docetaxel in the first line setting and second-line pemetrexed for those with non-squamous histology who did not receive pemetrexed in the first line setting.
First-generation EGFR TKI erlotinib can also be considered second or third line therapy in EGFRwt NSCLC. The NCIC BR.21 trial randomized patients to erlotinib and BSC or placebo and BSC after first line platin-doublet chemotherapy. Almost half of the patients also received second-line docetaxel before being randomized. In these patients unselected for EGFR mutations the erlotinib significantly improved mOS compared to BSC (6.7 months versus 4.7 months, HR 0.70, 95% CI 0.58-0.85).42 Despite these results single agent chemotherapy is still preferred over EGFR TKIs in EGFRwt NSCLC after first-line platin-doublet chemotherapy, especially for patients who had clinical benefit (PR+SD) from first-line chemotherapy. The TAILOR trial is one of several studies that randomized patients with EGFRwt NSCLC to either chemotherapy or an EGFR TKI. In this trial 222 patients were randomized to erlotinib or docetaxel 75mg/m2 every 3 weeks. Median PFS was superior in the docetaxel arm (2.9 months versus 2.4 months, HR 0.71, 95% CI 0.53-0.95) as was mOS (8.2 months versus 5.4 months, HR 0.73, 95% CI 0.53-1.00). In a planned subgroup analysis those patients with ECOG PS 2 and those who progressed while receiving first-line platin doublet chemotherapy did not have greater benefit from docetaxel with respect to PFS or OS.43 These observations reinforce the concept that patient as well as tumour factors must be considered when deciding on the most appropriate second and third line therapies.
Maintenance Therapy
While continuing platin doublet therapy beyond 4 to 6 cycles in those with a response or stable disease can improve PFS, cumulative toxicities can have a negative impact on QOL and survival is not likely impacted. In contrast, single agent maintenance therapy can improve PFS while having a smaller impact on QOL and may also improve OS. The choice of post-doublet systemic therapy depends both on the regimen used in the first line setting as well as patient factors. These include PS, toxicities of the original therapy and philosophy of care i.e. balancing QOL with treatment benefits and toxicities. Close observation with institution of second-line systemic therapy at the time of disease progression is an acceptable alternative for the well-informed patient.
Pemetrexed, docetaxel and gemcitabine have all been shown to improve PFS versus no maintenance therapy. A large RCT of maintenance pemetrexed after a response or stable disease from 4 cycles of one of three platin-containing doublets not including pemetrexed showed significantly improved mPFS (4.3 versus 2.6 months) and mOS (13.4 versus 10.6 months). This trial has been criticized because only 19% of the placebo group received pemetrexed in the second-line setting. The benefit of maintenance pemetrexed was limited to those with non-squamous NSCLC and supports the preference of this drug in this population.44 The more recent PARAMOUNT study in an all non-squamous NSCLC population showed that maintenance pemetrexed after a response or SD from 4 cycles of cisplatin/pemetrexed also significantly improved mPFS (4.1 versus 2.8 months) and mOS (13.9 versus 11.0 months) compared to placebo.45 The PointBreak study, however, is not supportive of maintenance pemetrexed or the concept that nonsquamous NSCLC are better treated with pemetrexed versus other platin-companion drugs. In this study exclusively nonsquamous NSCLC patients were randomized to either carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab or carboplatin/paclitaxel/bevacizumab followed by bevacizumab. The pemetrexed arm was superior in terms of mPFS (6.0 versus 5.6 months) but not mOS (12.6 versus 13.4 months).46 Cost-effectiveness of maintenance pemetrexed has also not been well established. Overall, however, the data are supportive of maintenance pemetrexed as an option for suitable patients with non-squamous NSCLC who have had SD or a response from 4 to 6 cycles of platin-based doublet chemotherapy and is approved at the BC Cancer Agency for patients who did not receive pemetrexed as part of their induction regimen.
Maintenance docetaxel was studied in a population of patients who had not progressed after 4 cycles of carboplatin/gemcitabine. Those randomized to receive up to 6 cycles of immediate docetaxel had significantly improved mPFS compared to those who were randomized to observation and second-line docetaxel at disease progression (5.7 versus 2.7 months) but there was only a trend to improved mOS (12.3 versus 9.7 months, p=0.09) in the maintenance group. Like other maintenance studies this one was criticized because only 63% of the delayed group received second-line docetaxel. Those who did had similar outcomes compared to those who received immediate docetaxel.47 Maintenance gemcitabine has also been shown in a large RCT to improve mPFS after first line platin-doublet chemotherapy without a significant improvement in mOS compared to placebo.48 Maintenance docetaxel and gemcitabine are not as well supported as maintenance pemetrexed and are not approved at the BC Cancer Agency.
Several trials have explored the value of maintenance EGFR TK inhibitors in unselected patients with NSCLC with a response or SD after first line doublet chemotherapy. The two most robust trials demonstrated significantly improved mPFS with maintenance erlotinib versus placebo but no improvement in mOS. The SATURN trial demonstrated significantly improved mPFS (12.3 versus 11.1 weeks) but not mOS (12.0 versus 11.0 months).49 The PFS advantage was preserved in the 89% with EGFR wild type cancers when tissue samples were subsequently reanalyzed.50 The ATLAS study showed similar results in a population of patients who received bevacizumab in combination with platin-doublet chemotherapy. Those randomized to maintenance bevacizumab/erlotinib had significantly improved mPFS (4.8 versus 3.7 months) but not mOS (14.4 versus 13.2 months) compared to those who received bevacizumab and placebo.51 EGFR status was determined in 45% and both mPFS and mOS were significantly improved in those with an EGFR mutation. The significance of these results and the value of maintenance EGFR TKIs in patients with known EGFR mutations are unclear with the availability of first line EGFR TKIs in EGFRm+ NSCLC. The comparative value of maintenance pemetrexed versus maintenance erlotinib in EGFRwt NSCLC is also unclear.
