Low-dose chemotherapy combined with delayed immunotherapy in the neoadjuvant treatment of non-small cell lung cancer and dynamic monitoring of the drug response in peripheral blood
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eLife Assessment
Liang et al. have conducted a small pilot study investigating the feasibility and tolerability of a regimen of neoadjuvant chemo-immunotherapy for non-small cell lung cancer; with lower cumulative dose of chemotherapy and with the immunotherapy delivered on D8 of each cycle. The clinical data are interesting and novel, and overall the findings of the study are valuable. However, the translational data and analyses are incomplete and do not support key claims in the title.
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Abstract
Background: Despite chemo-immunotherapy has been applied to the neoadjuvant treatment of non-small cell lung cancer (NSCLC), the impacts of dosage and the order of medication on treatment efficacy and safety remain largely unexplored. We originally designed an exploratory study to investigate the efficacy and safety of reduced-dose chemotherapy combined with delayed immunotherapy as well as the dynamic changes of circulating tumor DNA (ctDNA) and T cell receptor (TCR) during the therapy. Methods: Patients with clinical stage IIA to IIIA resectable NSCLC were treated with 2 cycles of reduced-dose platinum-based chemotherapy on day 1 combined with immunotherapy on day 5. The same postoperative modified adjuvant therapy regimen was administered for 2 cycles. Plasma samples at different time-points were collected and performed with T cell receptor (TCR) and circulating tumor DNA (ctDNA) sequencing. Results: 38 patients received modified chemo-immunotherapy. The proportion of patients exhibiting complete response and partial response was 5.3% and 68.4%, respectively. The confirmed objective response rate was 73.7%. Radiological downstaging was achieved in 39.5%. Major pathologic response and complete pathologic response were observed in 47.4% and 31.6% of patients, respectively. Only one patient experienced grade 3 adverse event. Further analyses revealed that this modified chemo-immunotherapy led to the expansion of predominant TCR clones and reduction of tumor burden after the first cycle of chemotherapy. Conclusion: The promising clinical efficacy and low side effects of modified neoadjuvant chemo-immunotherapy position it as a prospective and innovative strategy for NSCLC.
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eLife Assessment
Liang et al. have conducted a small pilot study investigating the feasibility and tolerability of a regimen of neoadjuvant chemo-immunotherapy for non-small cell lung cancer; with lower cumulative dose of chemotherapy and with the immunotherapy delivered on D8 of each cycle. The clinical data are interesting and novel, and overall the findings of the study are valuable. However, the translational data and analyses are incomplete and do not support key claims in the title.
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Reviewer #1 (Public review):
Liang et al. have conducted a small-scale pilot study focusing on the feasibility and tolerability of Low-dose chemotherapy combined with delayed immunotherapy in the neoadjuvant treatment of non-small cell lung cancer. The design of delayed immunotherapy after chemotherapy is relatively novel, while the reduced chemotherapy, although somewhat lacking in innovation, still serves as an early clue for exploring future feasible strategies. Also, the dynamic ctDNA and TCR profiles could give some important hints of intrinsic tumor reaction.
However, as the author mentioned in the limitation part, due to the small sample size and lack of a control group, we cannot fully understand the advantages and disadvantages of this approach compared to standard treatment. Compared to standard immunotherapy, the treatment …
Reviewer #1 (Public review):
Liang et al. have conducted a small-scale pilot study focusing on the feasibility and tolerability of Low-dose chemotherapy combined with delayed immunotherapy in the neoadjuvant treatment of non-small cell lung cancer. The design of delayed immunotherapy after chemotherapy is relatively novel, while the reduced chemotherapy, although somewhat lacking in innovation, still serves as an early clue for exploring future feasible strategies. Also, the dynamic ctDNA and TCR profiles could give some important hints of intrinsic tumor reaction.
However, as the author mentioned in the limitation part, due to the small sample size and lack of a control group, we cannot fully understand the advantages and disadvantages of this approach compared to standard treatment. Compared to standard immunotherapy, the treatment group in this study has three differences: (1) reduced chemotherapy, (2) the use of cisplatin instead of the commonly used carboplatin in neoadjuvant therapy trials, and (3) delayed immunotherapy. Generally, in the exploration of updated treatment strategies, the design should follow the principle of "controlling variables." If there are too many differences at once, it becomes difficult to determine which variable is responsible for the effects, leading to confusion in the interpretation of the results. Moreover, the therapeutic strategy may lack practical clinical operability due to the long treatment duration.
Furthermore, in the exploration of biomarkers, the authors emphasized the procedure of whole RNA sequencing in tumor tissues in the method section, and this was also noted in the flowchart in Figure 1. However, I didn't find any mention of RNA-related analyses in the Results section, which raises some concerns about the quality of this paper for me. If the authors have inadvertently omitted some results, they should supplement the RNA-related analyses so that I can re-evaluate the paper.
To sum up, this article exhibited a certain degree of innovation to some extent, However, due to its intrinsic design defects and data omissions, the quality of the research warranted further improvement.
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Reviewer #2 (Public review):
Summary:
In this single center, single arm, open label non-randomised study the authors tested the use of paclitaxel at 180-220 mg/m2 and cisplatin at 60mg/m2 in patients with squamous NSCLC and pemetrexed at 500mg/m2 and cisplatin at 60mg/m2 in adenocarcinoma of lung origin in the neoadjuvant setting. The chemotherapy appears to have been given at a relatively standard dose; though the platin dose at 60mg/m2 is somewhat lower than has been used in the checkmate 816 trial (75mg/m2/dose), this is a well-established dose for NSCLC.
Key differences to currently approved neoadjuvant chemo-ICI treatment is that anti-PD1 antibody sintilimab (at 200mg/dose) was given on day 5 and that only 2 cycles of chemotherapy were given pre surgery, but then repeated on two occasions post surgery. Between May/2020 and Nov/2023 …
Reviewer #2 (Public review):
Summary:
In this single center, single arm, open label non-randomised study the authors tested the use of paclitaxel at 180-220 mg/m2 and cisplatin at 60mg/m2 in patients with squamous NSCLC and pemetrexed at 500mg/m2 and cisplatin at 60mg/m2 in adenocarcinoma of lung origin in the neoadjuvant setting. The chemotherapy appears to have been given at a relatively standard dose; though the platin dose at 60mg/m2 is somewhat lower than has been used in the checkmate 816 trial (75mg/m2/dose), this is a well-established dose for NSCLC.
Key differences to currently approved neoadjuvant chemo-ICI treatment is that anti-PD1 antibody sintilimab (at 200mg/dose) was given on day 5 and that only 2 cycles of chemotherapy were given pre surgery, but then repeated on two occasions post surgery. Between May/2020 and Nov/2023 50 patients were screened, 38 went on to have this schedule of tx, 31 (~82%) went on to have surgery and 27 had the adjuvant treatment. The rate of surgery is entirely consistent with the checkmate 816 data.
Question to the authors:
It would be very helpful to understand why 7 (~18% of the population) patients did not make it to surgery and whether this is related to disease progression, toxicity or other reasons for withdrawal.
The key clinical endpoints were pCR and mPR rates. 2/38 patients are reported to have achieved a radiological pCR but only 31 patients underwent surgery with histological verification. Supp table2 suggests that 10/31 patients achieved a pCR, 6/31 additional patients achieved a major pathological response and that 13/31 did not achieve a major pathological response
It would be really helpful for understanding the clinical outcome to present the histopathological findings in the text in a bit more detail and to refer the outcome to the radiological findings. I note that the reference for pathological responses incorrectly is 38 patients as only 31 patients underwent surgery and were evaluated histologically.
The treatment was very well tolerated with only 1 grade 3 AE reported. The longer term outcome will need to be assessed over time as the cohort is very 'young'. It is not clear what the adjuvant chemo-ICI treatment would add and how this extra treatment would be evaluated for benefit - if all the benefit is in the neoadjuvant treatment then the extra post-operative tx would only add toxicity
Please consider what the two post-operative chemo-ICI cycles might add to the outcome and how the value of these cycles would be assessed. Would there be a case for a randomised assessment in the patients who have NOT achieved a mPR histologically?
While the clinical dataset identifies that the proposed reduced chemo-ICI therapy has clinical merit and should be assessed in a randomized study, the translational work is less informative.
The authors suggest that the treatment has a positive impact on T lymphocytes. Blood sampling was done at day 0 and day 5 of each of the four cycle of chemotherapy with an additional sample post cycle 4. The authors state that data were analysed at each stage.
The data in Figure 3B are reported for three sets of pairs: baseline to pre day 5 in cycle 1, day 5 to day 21 in cycle 1, baseline of cycle to to day 5. It remains unclear whether the datasets contain the same top 20 clones and it would be very helpful to show kinetic change for the individual 'top 20 clones' throughout the events in individual patients; as it stands the 'top20 clones' may vary widely from timepoint to timepoint. Of note, the figures do not demonstrate that the top 20 TCR clones were 'continuously increased'.
Instead, the data suggest that there are fluctuations in the relative distributions over time but that may simply be a reflection of shifts in T cell populations following chemotherapy rather than of immunological effects in the cancer tissue.
Consistent with this the authors conclude (line 304/5): "No significant difference was observed in the diversity, evenness, and clonality of TCR clones across the whole treatment procedure" and this seems to be a more persuasive conclusion than the statement 'that a positive effect on T lymphocytes was observed' - where it is also not clear what 'positive' means.The text needs a more balanced representation of the data: only a small subset of four patients appear to have been evaluated to generate the data for figure 3B and only three patients (P5, P6, P7) can have contributed to figure 3C if the sample collection is represented accurately in Figure 3A.
The text refers to flow cytometric results in SF3. However, no information is given on the flow cytometry in M&M, markers or gating strategy.
Please consider changing the terminology of the 'phases' into something that is easier to understand. One option would be to use a reference to a more standard unit (cycle 1-4 of chemotherapy and then d0/d5/d21).
Please make it explicit in the text that molecular analyses were undertaken for some patients only, and how many patients contribute to the data in figures 3B-F. Figure 3A suggests paired mRNA data were obtained in 2 patients (P2 and P5) but I cannot find the results on these analyses; four individual blood samples to assess TCR changes int PH1/PH2/PH3and PH4 were only available in four patients (P4,P5,P7,P9). Only three patients seem to have the right samples collected to allow the analysis for 'C3' in figure 3C.
Please display for each of the 'top 20 clones' at any one timepoint how these clones evolve throughout the study; I expect that a clone that is 'top 20' at a given timepoint may not be among the 'top twenty' at all timepoints.
Please also assess if the expanded clonotypes are present (and expanded) in the cancer tissue at resection, to link the effect in blood to the tumour. Given that tissue was collected for 31 patients, mRNA sequencing to generate TCR data should be possible to add to the blood analyses in the 12 patients in Figure 3A. Without this data no clear link can be made to events in the cancer.
Please provide in M&M the missing information on the flow cytometry methodology (instrument, antibody clones, gating strategy) and what markers were used to define T cell subsets (naïve, memory, central memory, effector memory).
The authors also describe that ctDNA reduces after chemo-ICI treatment. This is well documented in their data but ultimately irrelevant: if the cancer volume is reduced to the degree of a radiological or pathological response /complete response then the quantity of circulating DNA from the cancer cells must reduce. More interesting would be the question whether early changes predict clinical outcome and whether recurrent ct DNA elevations herald recurrence.
Please probe whether the molecular data identify good radiological or pathological outcomes before cycle 2 is started and whether the ctDNA levels identify patients who will have a poor response and/or who relapse early.
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