Abstract
Aim: This study compared the results of nivolumab treatment in patients with pulmonary adenocarcinomas based upon previous chemotherapeutic regimens. Patients and Methods: The data source for this retrospective study was the Czech VILP registry of patients with nivolumab-treated adenocarcinomas in second and higher lines of treatment. In relation to objective response rate, progression-free interval, and overall survival, three comparisons of patient were made: A: Those treated in first line with cisplatin and pemetrexed versus carboplatin with paclitaxel or vinorelbine; B: treatment with cisplatin and pemetrexed versus carboplatin with paclitaxel/vinorelbine and bevacizumab; and C: treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) versus treatment with taxane (first-line carboplatin and paclitaxel only plus those treated with second-line docetaxel). Results: We observed no differences in objective response rate or progression-free survival between patients treated with the stated chemotherapeutic regimens. We observed a trend towards better overall survival for patients treated with carboplatin plus taxanes or vinorelbine with/without bevacizumab. Conclusion: From our overall survival data, a chemotherapeutic regimen of carboplatin plus taxanes or vinorelbine with/without bevacizumab might be a better partner for immunotherapy than a cisplatin and pemetrexed-based one.
Nivolumab is one of the second-line treatment options for patients with non-small cell lung cancer (NSCLC) (1). As previous chemotherapy, a platinum doublet is usually chosen. These treatment combinations have similar efficacy (only pemetrexed has shown slightly better results for non-squamous cell carcinomas) but differ in part in their toxicity and mechanism of action (2, 3). Due to the fact that the levels of neutrophils, lymphocytes and platelets, as well as their ratios (neutrophil-to-lymphocyte ratio, NLR; platelet-to-lymphocyte ratio, PLR), may affect the efficacy of chemotherapy, the question arises as to whether previous chemotherapy which may affect blood counts might also influence the efficacy of nivolumab (4–6). Meta-analyses have shown more significant thrombocytopenia with the use of carboplatin compared with cisplatin. Conversely, no difference has been found in the incidence of neutropenia (7–10). The use of taxanes and vinorelbine leads to neutropenia more often than their use with pemetrexed (11–13). In addition, a study using atezolizumab in combination with chemotherapy and bevacizumab in first-line NSCLC treatment suggests a benefit to the anti-tumour immune response from adding bevacizumab (14). Thanks to the Highly Innovative Medicines Program (VILP), which included nivolumab in the Czech Republic for some time after registration, we also obtained data on previous treatments before its use – including the chemotherapy used. The aim of this study was therefore to evaluate the possible effect of the chemotherapeutic combination of cisplatin with pemetrexed versus carboplatin with taxanes or vinorelbine with/without bevacizumab on the efficacy of nivolumab treatment in higher NSCLC treatment lines.
Patients and Methods
Group of patients. Clinical data of patients with cytologically or histologically confirmed, locally advanced or advanced (stage IIIB/C or stage IV) NSCLC of adenocarcinoma type that had been assigned to the Czech VILP registry for nivolumab were retrospectively analysed. The Czech VILP register for nivolumab is a non-interventional post-registration database of epidemiological and clinical data of patients with lung adenocarcinoma treated with nivolumab in the Czech Republic. The data of 246 patients from the VILP registry were derived from 15 (pneumo-)oncology departments in the Czech Republic between 2018 and 2020. All patients had given their informed consent to be included in this database and for use of these data for scientific purposes.
Three comparisons of patients were made: A) Patients treated in the first line with cisplatin and pemetrexed (CiPe) versus those treated with carboplatin and paclitaxel or vinorelbine (CaPaVi) (allowed with bevacizumab: CaPaViB); B: CiPe group versus CaPaViB group; and C) treatment in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) (CiPe2Pe) versus treatment in previous lines with taxane (in first line with carboplatin with paclitaxel, not vinorelbine, plus those treated in second line with docetaxel) (CaPa2Do). The effectiveness of nivolumab treatment in the second or third lines of treatment was subsequently examined.
Nivolumab was administered intravenously at the approved dose of 240 mg every 2 weeks. The treatment was administered until disease progression or unacceptable toxicity for a maximum of 2 years. In cases of treatment-related toxicity, corticosteroid use with/without interruption of nivolumab were recommended. Clinical follow-up including physical examination, chest X-ray, and routine laboratory tests were performed at least every 4 weeks. Computed tomography or positron-emission tomography–computed tomography was performed at regular intervals according to the standard practice of the given centre or when progression was suspected based upon clinical or chest X-ray examination. Previous chemotherapy was given as recommended in the Modra kniha Czech national guidelines (https://www.linkos.cz/lekar-a-multidisciplinarni-tym/personalizovana-onkologie/modra-kniha-cos/).
Statistical methods. Data are described by absolute and relative frequencies. Groups of patients were compared using chi-square test. Responses to therapies were defined according to Response Evaluation Criteria for Solid Tumors 1.1 criteria (15). The objective rate of response (ORR) to nivolumab treatment was defined as the sum of complete treatment responses and partial responses to treatment. Overall survival (OS) was defined as the time from initiation of treatment with nivolumab to the date of death from any cause. Progression-free survival (PFS) was defined as the time from treatment initiation of nivolumab to the date of radiological progression (defined according to Response Evaluation Criteria for Solid Tumors 1.1) or death from any cause (whichever occurred first). OS and PFS were plotted using Kaplan–Meier methodology. The log rank test was used to estimate statistical significance of the difference between the curves. The Cox proportional hazards model was utilized to explore the association of risk factors (sex, age, smoking status, performance status and previous treatment lines) with OS of nivolumab treatment. The effects of all potential prognostic factors were assessed in the multivariate model.
p-Values of less than 0.05 were considered statistically significant (all tests were two-sided). Analysis was performed in SPSS software (IBM SPSS Statistics for Windows, Version 25.0, released 2017; IBM Corp., Armonk, NY, USA) and software R version 3.5.0 (www.r-project.org).
Results
Patient characteristics. Comparison A (first-line treatment with CiPe vs. CaPaVi before nivolumab in second line): In total, 121 patients were evaluated. Their mean age was 65.2 years. Patient characteristics are summarized in Table I.
Characteristics of patients treated with first-line cisplatin and pemetrexed (CiPe) compared with those treated with carboplatin and paclitaxel or vinorelbine (CaPaVi) with/without bevacizumab before receiving nivolumab (comparison A).
Comparison B (first-line treatment with CiPe versus CaPaViB before nivolumab in second line): In total, 77 patients were evaluated. Their mean age was 65.2 years. Patient characteristics are summarized in Table II.
Characteristics of patients treated with first-line cisplatin and pemetrexed (CiPe) compared with those treated with carboplatin and paclitaxel or vinorelbine with bevacizumab (CaPaViB) before receiving nivolumab (comparison B).
Comparison C (CiPe2Pe versus CaPa2Do before nivolumab in second or third line): In total, 118 patients were evaluated. Their mean age was 64.8 years. Patient characteristics are summarized in Table III.
Characteristics of patients treated in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) (CiPe2Pe) versus those treated in previous lines with taxane (in first line with carboplatin with paclitaxel, not vinorelbine, as well as those treated in second line with docetaxel) (CaPa2Do) before receiving nivolumab (comparison C).
Rate of response to nivolumab therapy. In no comparison did we observe significant differences in ORR to nivolumab therapy based on previous treatment lines. In comparison A, ORR to nivolumab was 10.2% (6/59 patients) after CaPaVi versus 16.1% (10/62 patients) for CiPe (p=0.333). In comparison B, ORR was 6.7% (1/15 patients) for CaPaViB versus 16.1% (10/62 patients) for CiPe (p=0.347). In comparison C, the ORR was 7.4% (2/27 patients) for CaPa2Do versus 16.5% (15/91 patients) for CiPe2Pe (p=0.238).
PFS and OS after nivolumab therapy in the univariate model. We observed no statistically or clinically significant differences in PFS in any of our examined patient comparisons. In comparison A, the median PFS was 3.4 [95% confidence interval (CI)=1.1-5.7] months for the CiPe group versus 3.5 (95% CI=1.1-5.9) months for the CaPaVi group (p=0.562), with an associated hazard ratio (HR) of 1.15 (95% CI=0.71-1.87). For comparison B, the median PFS was 3.4 (95% CI=1.1-5.7) months for the CiPe group versus 2.8 (95% CI=1.3-4.3) months for the CaPaViB group (p=0.792), with an HR of 0.91 (95% CI=0.44-1.89). In comparison C, the median PFS was 3.2 (95% CI=2.4-4.1) months for the CiPe2Pe group versus 3.5 (95% CI=1.3-4.3) months for the CaPa2Do group (p=0.526), with an HR of 1.19 (95% CI=0.69-2.06). Kaplan–Meier curves for PFS are shown in Figure 1.
Kaplan–Meier curves for progression-free survival (PFS, upper panel) and overall survival (OS, lower panel) for comparison of patient groups. A: Patients treated in first line with cisplatin and pemetrexed (CiPe) versus those treated with carboplatin and paclitaxel or vinorelbine (CaPaVi) (allowed with bevacizumab: CaPaViB). B: CiPe group versus CaPaViB group. C: Patients treated in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) (CiPe2Pe) versus those treated in previous lines with taxane (in first line with carboplatin with paclitaxel, not vinorelbine, plus those treated in second line with docetaxel) (CaPa2Do).
Although we observed rather higher OS for patients treated with carboplatin, these differences did not reach statistical significance. In comparison A, the HR for CiPe versus CaPaVi was 2.33 (95% CI=0.93-5.84), p=0.063. In comparison B, the HR for CiPe versus CaPaViB was 6.73 (95% CI=0.79-57.60), p=0.055. In comparison C, the HR for CiPe2P versus CaPa2Do was 3.02 (95% CI=0.90-10.31), p=0.064. Kaplan–Meier curves for OS are shown in Figure 1.
OS after nivolumab therapy in the multivariate model. In comparison A, we observed significantly better OS after nivolumab therapy with higher age. Regarding the effect of previous treatment before nivolumab, we observed a trend only towards better OS after nivolumab therapy in the CaPaVi group (CiPe vs. CaPaVi: HR=1.88, 95% CI=0.74-4.79; p=0.186). Although in comparison B we recorded no significant result in relation to OS after nivolumab therapy, in terms of previous treatment before nivolumab, we observed a trend only towards better OS after nivolumab therapy in patients previously treated with CaPaViB (CiPe vs. CaPaViB: HR=4.85, 95% CI=0.47-50.60; p=0.187). We recorded similar results in comparison C, wherein in terms of previous treatment before nivolumab, we observed a trend towards better OS after nivolumab therapy only in patients previously treated with taxanes (CiPe2Pe vs. CaPa2Do: HR=2.63, 95% CI=0.76-9.10; p=0.127). The results are summarized in Table IV.
Multivariate Cox proportional hazards model for overall survival (OS) in comparisons of treatment groups. Comparison A: Patients treated in first line with cisplatin and pemetrexed (CiPe) versus carboplatin and paclitaxel or vinorelbine (CaPaVi) (allowed with bevacizumab: CaPaViB). B: CiPe group versus CaPaViB group. C: Patients treated in previous lines with pemetrexed (first-line cisplatin and pemetrexed plus those treated in second line with pemetrexed) (CiPe2Pe) versus those treated in previous lines with taxane (in first line with carboplatin with paclitaxel, not vinorelbine, plus those treated in second line with docetaxel) (CaPa2Do).
We also note that in comparison A, we observed no statistically or clinically significant difference in OS after nivolumab between patients previously treated with carboplatin plus paclitaxel and those treated with carboplatin plus vinorelbine (HR=0.81, 95% CI=0.18-3.62; p=0.778).
Discussion
We observed a trend within our cohort towards better OS among patients treated with carboplatin with taxane/vinorelbine-based chemotherapy compared to patients treated with cisplatin with pemetrexed. This trend neared but did not reach statistically significant values, which may be because the patient groups were too small to achieve sufficient statistical power. PFS was also not altered by treatment. This is line with the fact that PFS did not differ significantly between patients with NSCLC treated in second line with nivolumab versus docetaxel in the CheckMate057 trial (16). From our point of view, therefore, OS is a determining indicator for the effectiveness of immunotherapy.
Several theoretical explanations are offered for the better efficacy of the mentioned chemotherapeutic regimens. Firstly, chemotherapeutic regimens, with their different side-effects, may lead to altered NLR or PLR, which in previous studies appeared to be possible predictors of the efficacy of immunotherapy (4, 5). Secondly, different types of chemotherapy probably bring about immunogenic induced cell death (ICD) to different degrees in accordance with how they alter the properties of the tumour microenvironment (17–21).
Regarding the toxicity of chemotherapy, several meta-analyses have shown significantly higher thrombocytopenia after carboplatin than with cisplatin (7–10). Older meta-analyses also indicated a higher incidence of neutropenia with cisplatin (10), but newer meta-analyses have not confirmed this (7, 8). There are differences in the incidence of neutropenia between the chemotherapeutic partners of platinum derivatives examined in our study. While neutropenia was shown to occur in approximately 23% of patients treated with pemetrexed, it occurred in 57-75% of those receiving taxane/vinorelbine therapy, and the rate of severe neutropenia (grade 3-4) was similarly about 10% in pemetrexed-based as well as in taxane/vinorelbine-based regimens (11–13). These data (more thrombocytopenia in carboplatin versus cisplatin treatment and more neutropenia in taxane/vinorelbine versus pemetrexed treatment) show that PLR and NLR would be more favourable under therapy with carboplatin and taxanes/vinorelbine.
Although cisplatin and carboplatin have the same basic mechanism of action (i.e. by cross-linking DNA), some differences in their action can be found. Higher concentrations of carboplatin are needed to form the same amount of DNA adducts, and other mechanisms are involved in the action of carboplatin (22). For example, carboplatin is a larger oligomerizing agent (i.e., more capable of forming RNA oligomers) than is cisplatin (23). Moreover, due to its different pharmacokinetics, carboplatin has different dose-limiting toxicity from cisplatin, that is to say myelosuppression versus nephrotoxicity (24). Overall, this reflects the different possibilities for cisplatin and carboplatin to support ICD (17). For cisplatin, an increase in expression of programmed death-ligand 1 (PD-L1) has been reported in NSCLC (17). By contrast, carboplatin had no effect on PD-L1 expression on tumour cells (20). Neither carboplatin nor cisplatin appear to affect the expression of PD-L1 on immune cells (20). Carboplatin combines well with immunotherapy, probably increasing antitumor effector CD4+/CD8+ T-cells. Carboplatin reduces immunosuppressive T-regulatory cells and myeloid suppressor cells for the treatment of ovarian cancer (21). In NSCLC, the combination of carboplatin with paclitaxel and bevacizumab has been shown to cause an increase in peripheral blood CD8+ T-cells (25). In ovarian cancer, the combination of carboplatin with paclitaxel has been shown to result in increased dendritic cell function (19). A question arises, however, as to whether these effects are brought about primarily by carboplatin or by taxanes. The fact that taxanes play a greater role than does carboplatin alone is shown by a study wherein docetaxel had a greater ability to induce ICD than did both cisplatin and carboplatin alone, and the combination of docetaxel and carboplatin increased this ability even more (26). Moreover, docetaxel enhanced PD-L1 positivity on tumour-infiltrating immune cells and the density of CD8+ lymphocytes and downregulated PD-1 expression in T-lymphocytes via activation of the signal transducer and activator of transcription 3 signalling pathway (21). Yang et al. even reported that docetaxel is much more potent at inducing PD-L1 gene and protein expression than is cisplatin in bone marrow stromal cell lines (27). Paclitaxel is also known to have immunogenic potential due to its promoting tumour antigen presentation through up-regulation of tumour antigens or major histocompatibility complex class I molecules, increasing cell surface PD-L1 protein expression in human ovarian cancer cell lines, increasing the proportion of tumour-infiltrating effector and cytotoxic CD8+ T-cells in a model of breast cancer, or increasing populations of CD8+ and CD4+ tumour-infiltrating lymphocytes and decreasing the population of PD-1+ TILs at the tumour site (21). On the other hand, pemetrexed also has the ability to induce transcriptional activation of PD-L1 by inactivating thymidylate synthase in NSCLC cells and, in turn, activating T-lymphocytes when combined with the anti-PD-1/PD-L1 therapy (18). According to the literature, vinorelbine can also influence immune processes, inter alia, by affecting the expression of PD-L1 (21). Therefore, more data are needed to accurately compare individual treatment combinations in relation to bringing about ICD.
The presumption of greater immunogenic potential of taxanes vis-à-vis pemetrexed in particular is also supported by some clinical data. In their phase IB study, Kanda et al. demonstrated that the combination of nivolumab with carboplatin, paclitaxel and bevacizumab had the best effect, while nivolumab with cisplatin and pemetrexed achieved poorer results, with median OS not being reached (during follow-up) versus 28.5 months, respectively, and median PFS of 40.7 versus 11.8 months, respectively (28). Similarly, Rizvi et al. demonstrated the best efficacy for the combination of 5 mg/kg nivolumab with carboplatin and paclitaxel, with 2-year OS of 62% versus 33% for the combination of cisplatin with pemetrexed (29). Although direct comparison as to the efficacy of different chemotherapeutic regimens with immunotherapy in phase III studies is lacking, certain trends can be found in the patient subgroups of some studies that report efficacy for different types of chemotherapy. The IMpower132 studies with atezolizumab and pemetrexed with cisplatin/carboplatin (30), as well as the KEYNOTE-189 studies with pembrolizumab with pemetrexed and cisplatin/carboplatin (31) indicate a similar effect of both chemotherapeutic regimens (HR for OS in IMpower 132: 0.84 for carboplatin vs. 0.9 cisplatin; HR for OS in KEYNOTE 189: 0.55 for carboplatin vs. 0.44 for cisplatin). This would support the idea that the inclusion of a platinum partner will play a greater role in the efficacy of chemoimmunotherapy than does the specific type of platinum derivative itself. In the PACIFIC study with durvalumab in consolidation therapy after chemoradiotherapy in stage III NSCLC, the HR was slightly better for treatment with cisplatin than for carboplatin (0.51 vs. 0.61, respectively) (32). If we look at the chemotherapeutic partners of platinum derivatives, however, it is likely that this difference is due to the combination with etoposide, which achieved the best HR (0.49), while the HR for taxanes and vinorelbines did not differ (0.59 vs. 0.60, respectively). In that study for stage III NSCC, the use of radiotherapy may also have played a role compared to metastatic NSCLC treated with only chemoimmunotherapy regimens. For nivolumab, there is a lack of a comparison of different chemotherapeutic regimens for advanced pulmonary adenocarcinomas in phase III studies. The CheckMate 9LA study only showed that in cases of squamous carcinoma using the chemotherapeutic combination of carboplatin with paclitaxel had only a slightly better HR for OS than that for those with adenocarcinoma treated with cisplatin with pemetrexed (HRs of 0.62 and 0.69, respectively). However, we are comparing two histologically different types of NSCLC here and this may not reflect the reality of using these types of treatment in adenocarcinoma itself.
A limitation of our study is its retrospective character, which caused some imbalances to exist between the individual groups examined, and that might have influenced the results. Due to its retrospective origin, we also do not know the expression of PD-L1 nor, for example, the occurrence of KRAS mutations in the study arms. We know that the CheckMate 057 study showed higher expression of PD-L1 and KRAS mutations as being parameters associated with a better prognosis of patients (16). The VILP registry also did not indicate treatment after nivolumab, which might also lead to imbalances between the study arms. In this regard, several studies demonstrated superior efficacy of chemotherapy in patients pretreated with previous immunotherapy (33, 34). It should also be noted that the ORR was evaluated only by the investigators themselves, and not by independent reading of the computed tomography findings, which may have led to some bias in the results.
In conclusion, our study suggests a possible better outcome with carboplatin combined with taxanes/vinorelbine compared to cisplatin with pemetrexed regimen in patients subsequently treated with nivolumab. The question therefore arises as to whether a different chemotherapy regimen would not be better for patients with adenocarcinomas than the usual cisplatin with pemetrexed when transferring immunotherapy to the first line of treatment. In this respect, in our opinion, it is appropriate to carry out a prospective study that might answer this question.
Acknowledgements
This study was supported by the grant of Ministry of Health of the Czech Republic - Conceptual Development of Research Organization (Faculty Hospital in Pilsen - FNPl, 00669806).
Footnotes
Authors’ Contributions
Conceptualization: M. Svaton; Methodology: M. Svaton, JB; Investigation: M. Svaton, JB, PM, LB; Statistical analyses: PM, LB; Writing - original draft preparation: M. Svaton, MB, LK, OF, BM, MH, DD, OB, JK, MD, ZD, JB and M. Stastny; Writing - review & editing: M. Svaton.
Conflicts of Interest
In connection with this article, the Authors declare they have in the past provided consulting services to Bristol Myers Squibb.
- Received January 20, 2022.
- Revision received February 22, 2022.
- Accepted February 25, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
