Abstract
Background
The study was conducted to compare the effectiveness and safety of pemetrexed/carboplatin or cisplatin/bevacizumab (PemPBev) and paclitaxel/carboplatin/bevacizumab (PacCBev) as first‐line therapy for advanced non‐squamous non‐small cell lung cancer (NS‐NSCLC) patients with wild‐type driver genes in a real‐world setting.
Methods
We retrospectively collected the medical records of advanced NS‐NSCLC patients with wild‐type driver genes administered first‐line PemPBev or PacCBev therapy at Shanghai Chest Hospital between January 2014 and June 2016, and analyzed the differences in survival outcomes, efficacy, and safety between PemPBev and PacCBev treatment.
Results
A total of 390 patients were included in our analysis: 249 in the PemPBev group and 141 in the PacCBev group. Patients administered PemPBev experienced significantly improved progression‐free survival (PFS) and overall survival (OS) compared to those administered PacCBev (PFS 7.5 vs. 6.2 months, hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.53–0.84, P < 0.001; OS:18.6 vs. 16.0 months, HR 0.68, 95% CI 0.52–0.90, P = 0.002). The objective response rate (ORR) and disease control rate (DCR) were similar between the groups (ORR 21.7% vs. 30.5%, P = 0.053; DCR 69.1% vs. 67.4%, P = 0.728). There was no significant difference in the incidence of adverse events between the groups (64.7% vs. 68.8%; P = 0.407), but the incidence of peripheral neuropathy in the PacCBev group was higher than in the PemPBev group (7.8% vs. 2.4%; P = 0.012).
Conclusion
Our study shows that for advanced NS‐NSCLC patients with wild‐type driver genes, first‐line PemPBev might be a better treatment option compared to PacCBev.
Keywords: Bevacizumab, chemotherapy, non‐small cell lung cancer
Introduction
Lung cancer is the leading cause of cancer death in the world.1 Approximately 75% of patients have locally advanced or metastatic disease at the time of diagnosis.2 In recent years, targeted therapeutics and immune checkpoint inhibitors have developed rapidly; however, it is undeniable that approximately a third of advanced non‐small cell lung cancer (NSCLC) patients with wild‐type driver genes do not have the opportunity to undergo appropriate targeted therapy,3 and the number of patients who can gain survival benefits from immunotherapy is limited.4 For these patients, chemotherapy is still the primary choice; therefore, it is important to find an effective and safe regimen for this population.
Many studies have shown that bevacizumab (Bev) in combination with platinum‐based chemotherapy can significantly improve the objective response rate (ORR), progression‐free survival (PFS), and overall survival (OS) compared to platinum‐doublet regimens.5, 6, 7, 8, 9, 10, 11, 12 Moreover, maintenance therapy with Bev could further improve OS.13, 14 PARAMOUNT and AVAPERL proved that pemetrexed (Pem) could also be used as maintenance therapy after platinum + Pem induction treatment.12, 15
Two chemotherapy regimens including Bev are recommended in the current National Comprehensive Cancer Network (NCCN 2018) Guidelines for non‐squamous NSCLC (NS‐NSCLC): paclitaxel/carboplatin/bevacizumab (PacCBev) and pemetrexed/carboplatin or cisplatin/bevacizumab (PemPBev).16 At present, only the PointBreak study has examined the difference between PacCBev and pemetrexed/carboplatin/bevacizumab (PemCarBev) regimens, and showed no difference in the primary endpoint, OS (12.6 vs. 13.4 months; P = 0.949), although slight improvement was observed in PFS (6.0 vs. 5.6 months; P = 0.012).11 However, the PointBreak study did not take driver gene mutation status into account, which may affect treatment efficacy.
In this study, we compared the effectiveness of first‐line PemPBev with PacCBev in Chinese advanced NS‐NSCLC patients with wild‐type driver genes.
Methods
Study design and population
We conducted a retrospective cohort study of advanced NS‐NSCLC patients with wild‐type driver genes administered first‐line therapy with PemPBev or PacCBev.
We collected and reviewed the data of patients who were treated at Shanghai Chest Hospital between January 2014 and June 2016. The inclusion criteria were: (i) patients were confirmed with NS‐NSCLC by pathology and had wild‐type driver genes (refers to common genes in NSCLC: EGFR, ALK, ROS1) confirmed by amplification refractory mutation system (ARMS) and immunochemistry; (ii) patients were confirmed with a diagnosis of stage IIIB or IV (NSCLC staging was performed according to the eighth edition of the Tumor Node Metastasis [TNM] classification);17 (iii) patients were administered PemPBev or PacCBev with or without maintenance therapy as first‐line therapy, and for the PemPBev group, maintenance therapy could be Pem + Bev or Bev alone (the detailed scheme is shown in Table S1). The exclusion criteria were: age > 75 years, administered other concurrent systematic therapy, or lost to follow‐up after one cycle of chemotherapy without a therapeutic evaluation. Baseline clinical characteristics included gender, age at diagnosis, smoking history, histology, metastatic sites, and tumor stage.
The ethics committee of Shanghai Chest Hospital approved this study, and all patients signed informed consent.
Outcome measures
The primary endpoints were PFS and OS, while secondary endpoints were ORR and disease control rate (DCR). PFS was defined as the interval from initiating chemotherapy to disease progression or death; OS was defined as the interval from initiating chemotherapy to death or the last follow‐up, whichever came first. The final follow‐up was conducted in July 2018. Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1: complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).18
Statistical analysis
PFS and OS were assessed using the Kaplan–Meier method. Differences according to treatment regimen were compared using the log‐rank test, and two‐tailed P values < 0.05 were considered significant. The Cox proportional hazards model was used to perform multivariate analysis of PFS and OS, including the following covariates: gender, age, smoking history, histology, and tumor stage. ORR and DCR were analyzed by chi‐square statistics. All statistical analyses were performed using SPSS version 23.
Results
Patient characteristics
From January 2014 to June 2016, a total of 390 patients with wild‐type driver genes met the study inclusion criteria. A total of 249 patients were administered PemPBev (218 PemCarBev and 31 pemetrexed/cisplatin/bevacizumab [PemCisBev]) and 141 were administered PacCBev therapy (Fig 1). The two groups were balanced in terms of baseline characteristics (Table 1). The median number of therapy cycles in all populations was 6 (range: 1–26 cycles) in the PemPBev group and 5 (range: 1–23 cycles) in the PacCBev group (Fig 1). Among the patients who experienced disease progression (204 in PemPBev and 126 in PacCBev), the proportions of patients who continued to receive subsequent lines of anticancer therapies were 53.4% (109/204) and 48.4% (61/126), respectively (P = 0.375). The subsequent therapy details of the two groups are shown in Table S2.
Figure 1.
Final study population. Car, carboplatin; Cis, cisplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; NS‐NSCLC, non‐squamous non‐small cell lung cancer; Pac, paclitaxel; PacCBev, paclitaxel/carboplatin/bevacizumab; Pem, pemetrexed; PemPBev, pemetrexed/carboplatin or cisplatin/bevacizumab.
Table 1.
Patient and disease characteristics at baseline
| All patients (n = 390) | |||
|---|---|---|---|
| Characteristics | PemPBev (n = 249) | PacCBev (n = 141) | P |
| Gender | 0.401 | ||
| Male | 170 (68.3%) | 102 (72.3%) | |
| Female | 79 (31.7%) | 39 (27.7%) | |
| Age (years) | 0.195 | ||
| < 60 | 151 (60.6%) | 76 (53.9%) | |
| ≥ 60 | 98 (39.4%) | 65 (46.1%) | |
| Smoking history | 0.171 | ||
| Never‐smoker | 131 (52.6%) | 64 (45.4%) | |
| Former smoker | 118 (47.5%) | 77 (54.6%) | |
| Histology | 0.134 | ||
| Adenocarcinoma | 228 (91.6%) | 120 (85.1%) | |
| Large cell | 8 (3.2%) | 9 (6.4%) | |
| Not otherwise specified | 13 (5.2%) | 12 (8.5) | |
| Sites of metastases | |||
| Lung | 96 (38.6%) | 49 (34.8%) | 0.455 |
| Pleural | 83 (33.3%) | 58 (41.1%) | 0.123 |
| Distant lymph nodes | 19 (7.6%) | 14 (9.9%) | 0.433 |
| Bone | 92 (36.9%) | 58 (41.1%) | 0.414 |
| Brain | 57 (22.9%) | 22 (15.6%) | 0.085 |
| Liver | 19 (7.6%) | 14 (9.9%) | 0.433 |
| Adrenal gland | 13 (5.2%) | 11 (7.8%) | 0.308 |
| Other | 9 (3.6%) | 11 (7.8%) | 0.072 |
| Tumor stage | 0.393 | ||
| IIIB | 26 (10.4%) | 11 (7.8%) | |
| IV | 223 (89.6%) | 130 (92.2%) | |
Comparisons of categorical variables were performed using χ2 test. PacCBev, paclitaxel/carboplatin/bevacizumab; PemPBev, pemetrexed/carboplatin or cisplatin/bevacizumab.
Survival outcomes
In all populations, median PFS (mPFS) was significantly better in the PemPBev group (7.5 months, 95% confidence interval [CI] 6.6–8.5 months) than in the PacCBev group (6.2 months, 95% CI 5.4–7.1 months, hazard ratio [HR] 0.66 [95% CI 0.53–0.84]; P < 0.001) (Fig 2a). Median OS (mOS) was also longer in the PemPBev group (18.6 months, 95% CI 16.4–20.7 months) than in the PacCBev group (16.0 months, 95% CI 15.3–16.7 months, HR 0.68 [95% CI 0.52–0.90]; P = 0.002) (Fig 2b). Multivariate analyses of PFS and OS showed that PemPBev therapy was superior (Fig 3).
Figure 2.
Kaplan–Meier curves of survival of (a) progression‐free survival (PFS) and (b) overall survival (OS) of all 390 patients administered pemetrexed/carboplatin or cisplatin/bevacizumab (PemPBev), or paclitaxel/carboplatin/bevacizumab (PacCBev) chemotherapy. (
) PemPBev (n = 249) and (
) PacCBev (n = 141), hazard ratio (HR) (95% confidence interval [CI]).
Figure 3.
Subgroup analysis of (a) progression‐free survival and (b) overall survival of all 390 patients administered pemetrexed/carboplatin or cisplatin/bevacizumab (PemPBev), or paclitaxel/carboplatin/bevacizumab (PacCBev) chemotherapy. CI, confidence interval; HR, hazard ratio.
A total of 161 (64.7%) patients in the PemPBev group and 84 (59.6%) patients in the PacCBev group were administered maintenance therapy, but there was no difference in the proportion of maintenance therapy administered (P = 0.318). In the maintenance population, the mPFS and OS in the PemPBev group were longer than in the PacCBev group (mPFS 10.8 vs. 8.7 months, HR 0.53, 95% CI 0.39–0.73, P < 0.001; HR 0.61, 95% CI 0.41–0.91, P = 0.007, respectively) (Fig S1).
Among the 161 patients administered maintenance therapy in the PemPBev group, 120 (74.5%) patients received Pem + Bev and 41 (25.5%) received Bev. The mPFS of two populations were 11.4 (95% CI 10.0–8.7) and 8.7 (95% CI 6.9–10.5) months, and there were no significant differences (HR 0.74, 95% CI 0.49–1.12; P = 0.106). OS was similar between the groups (HR 0.87, 95% CI 0.52–1.46; P = 0.504). The mPFS of patients administered Bev maintenance therapy was the same in both groups (8.7 months, HR 0.64, 95% CI 0.41–1.00; P = 0.141). The OS of patients administered Bev maintenance therapy in the PemPBev group is immature, thus follow‐up continues.
In the PemPBev group, a total of 218 and 31 patients received PemCarBev and PemCisBev therapy, respectively. The mPFS of both groups was 7.5 months (P = 0.985), while the mOS was 18.5 (95% CI 18.5–20.9) months in the PemCarBev and 22.5 (95% CI 15.3–29.8) months in the PemCisBev group; the difference was not statistically significant (P = 0.488) (Fig S2).
Efficacy
None of the patients achieved CR. The ORR of all populations in the PemPBev group was lower than in the PacCBev group (21.7% vs. 30.5%). However, there were no significant differences between the groups (P = 0.053). Similar results for DCR were observed, and there were also no statistically significant differences between the PemPBev and PacCBev groups (69.1% vs. 67.4%; P = 0.728).
Safety
A total of 258 (66.2%) patients reported grade 1–4 adverse effects (AEs); none of the patients reported grade 5 AEs or discontinued therapy because of an AE. There was no significant difference in the incidence of AEs between the PemPBev and PacCBev groups (64.7% vs. 68.8%; P = 0.407), and the incidence of grade 3 or 4 AEs was also similar (31.7% vs. 35.5%; P = 0.451). The most common AEs were neutropenia, thrombocytopenia, anemia, and asthenia in the groups.
Table 2 summarizes the grade 3–4 AEs that occurred in all patients. The incidence of grade 3–4 peripheral neuropathy in the PacCBev group was higher than in the PemPBev group (7.8% vs. 2.4%; P = 0.012), while the incidence of other grade 3 or 4 AEs was similar between the groups.
Table 2.
Toxicity profile in all treatment courses
| PemPBev (n = 249) | PacCBev (n = 141) | |||
|---|---|---|---|---|
| Grade 3–4 adverse events | N | % | N | % |
| Neutropenia | 68 | 27.3 | 47 | 33.3 |
| Thrombocytopenia | 47 | 18.9 | 23 | 16.3 |
| Anemia | 31 | 12.4 | 20 | 14.2 |
| Asthenia | 14 | 5.6 | 12 | 8.5 |
| Proteinuria | 17 | 6.8 | 11 | 7.8 |
| Peripheral neuropathy | 6 | 2.4 | 11 | 7.8 |
| Vomiting | 14 | 5.6 | 9 | 6.3 |
| ALT/AST increased | 9 | 3.6 | 5 | 3.5 |
| Diarrhea | 4 | 1.6 | 5 | 3.5 |
| Thromboembolic | 5 | 2.0 | 4 | 2.8 |
| Bleeding | 3 | 1.2 | 2 | 1.4 |
| GI perforation | 3 | 1.2 | 2 | 1.4 |
ALT, alanine transaminase; AST, aspartate transaminase; GI, gastrointestinal; PacCBev, paclitaxel/carboplatin/bevacizumab; PemPBev, pemetrexed/carboplatin or cisplatin/bevacizumab.
Discussion
This study shows that first‐line PemPBev could achieve PFS and OS benefits comparable to a PacCBev regimen in advanced NS‐NSCLC patients with wild‐type driver genes.
The results of our study show that the PFS in the PemPBev group was longer than that in the PacCBev group (7.5 vs. 6.2 months; P < 0.001), and a similar outcome was observed in the maintenance populations (10.8 vs. 8.7 months; P < 0.001). These results are consistent with the results of the PointBreak study (PFS of all populations: 6.0 vs. 5.6 months, P = 0.012; PFS of maintenance populations: 8.6 vs. 6.9 months).11
After a series of prospective studies, Pem and Pac were approved for the first‐line treatment of NSCLC patients.19, 20, 21, 22 However, no head‐to‐head Pem and Pax‐based prospective study has been conducted until now.23, 24 A few small retrospective studies have shown that platinum + Pem seems to achieve longer PFS and OS than platinum + Pac.25, 26 Shah et al. found that the PFS of patients treated with platinum + Pem was longer than those treated with Car + Pac (134 vs. 106 days; P < 0.001).25 Bittoni et al. found that Car + Pem treatment was related to a higher survival probability from 18 to 63 months than Car + Pac.26 In our study, however, the mPFS of patients with Bev alone maintenance therapy was 8.7 months in both groups; only 41 patients were treated with Bev maintenance in the PemPBev group and 33 experienced disease progression. Therefore it remains unknown whether Pem or Pac is the better treatment choice; Pem induction therapy was no worse than Pac.
In the PemPBev group, the ORR was just 21.7%, lower than the ORR in the PacCBev group (30.5%, P = 0.053). Nevertheless, the PFS and OS rates in the PemPBev group were both longer than in the PacCBev group. We compared the PFS of patients in the PemPBev group who achieved PR with those that had SD, and similar mPFS rates were observed (11.3 vs. 9.4 months; P = 0.346). Further analysis showed that the DCRs in the PemPBev and PacCBev groups were also similar (69.1% vs. 67.4%; P = 0.728); in other words, although some patients in the PemPBev group did not achieve PR, their disease was stabilized, which may have contributed to the better survival rates in the PemPBev group.
In addition, we hypothesized that Pem maintenance therapy in the PemPBev group might contribute to survival. Several studies have shown that Pem can be used as maintenance therapy and achieve a survival benefit.12, 13, 14, 15 AVAPERL showed that PFS in the Pem + Bev maintenance group was longer than in the Bev maintenance alone (mPFS 10.2 vs. 6.6 months; P < 0.001) after induction therapy with Car, Pem and Bev.12 In our study, most of the patients (74.5%, 120/161) administered maintenance therapy in the PemPBev group received Pem + Bev maintenance therapy. In subgroup analysis of the PemPBev group, we observed that the mPFS of patients administered Pem + Bev maintenance was longer than that of Bev maintenance alone (11.4 vs. 8.7 months), although the difference did not reach statistical significance (P = 0.106), which may have been a result of the small sample size. The mPFS in patients administered Bev maintenance in both the PemPBev (n = 41) and PacCBev groups (n = 84) was 8.7 months, strongly suggesting that Pem + Bev maintenance in the PemPBev group may result in longer PFS.
There was a statistically significant difference in mOS between the groups in our sample (18.6 vs. 16.0 months; P = 0.002); however, no significant difference in OS was observed between these two groups in the PointBreak study (12.6 vs. 13.5 months; P = 0.949).11 The reason for the difference in findings may be explained by the fact that more patients in the PemPBev group were administered subsequent lines of anticancer therapies (53.4% vs. 48.4%), although there was no statistically significant difference in the rate of subsequent line therapy between the groups (P = 0.375).
Some studies have reported that when combined with some chemotherapy drugs, such as Pac, docetaxel and gemcitabine, Cis is superior to Car for prolonging survival.27, 28 However, no study has compared the efficacy of Pem combined with Cis or Car. In the PemPBev group in our study, 31 patients were administered PemCisBev therapy and the mOS of this population (22.5 months) was longer than of patients who received PemCarBev therapy (18.5 months), although the difference was not statistically significant (P = 0.488). However, few patients in our sample received PemCisBev therapy; therefore, determining whether PemCarBev therapy in the PemPBev group yielded a survival benefit requires a larger sample.
In our study, the number of grade 1–4 and 3–4 AEs between the groups were similar, indicating that the use of Pem maintenance does not lead to greater toxicity. In contrast, patients in the PacCBev group experienced peripheral neuropathy more frequently than patients in the PemPBev group (7.8% vs. 2.4%, P = 0.012); however, none of the patients were required to discontinue therapy as a result of AEs in this study.
There were several limitations to our study. Firstly, as this was a retrospective study, the choice of treatment regimen might be affected by the subjective wishes of clinicians or patients, which may have affected our results. Secondly, more patients were administered PemPBev than PacCBev, which may be related to the fact that patients in the real world are more likely to be treated with Pem than with Pac because of toxicity risks.
In conclusion, our real‐world study demonstrated that Pem/Car or Cis/Bev could achieve PFS and OS benefits with tolerable toxicity; therefore, PemPBev might be a better therapy regimen than PacCBev for advanced NS‐NSCLC patients with wild‐type driver genes.
Disclosure
No authors report any conflict of interest.
Supporting information
Table S1. Scheme.
Table S2. Subsequent therapy.
Figure S1. Kaplan–Meier curves of survival of maintenance populations
Figure S2. Kaplan–Meier curves of survival of PemPBev populations
Acknowledgments
This study was supported by the Western Medicine Guide Project of Shanghai Committee of Science and Technology (Grant No. 16411964700 and No. 18411968500).
Contributor Information
Jialin Qian, Email: jialin_qian@aliyun.com.
Tianqing Chu, Email: tianqing_chu@126.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1. Scheme.
Table S2. Subsequent therapy.
Figure S1. Kaplan–Meier curves of survival of maintenance populations
Figure S2. Kaplan–Meier curves of survival of PemPBev populations