Summary: There is a special interest group of MBBS students pan India who nurture topics in immuno hemat oncology and they recently had a journal club on the efficacy of certain check point inhibitors following which they even wrote a letter to the editor. During this process , while one of the faculty did ask the meta AI LLM lurking in the group to provide it's inputs pasting the entire article on text for the LLM, it appeared to have been too overwhelming for the LLM and it remained a bystander while the students went ahead with the rest of their dissection of the article. All of that is archived below in their group discussion conversational transcripts. The full text links for the article discussed along with many other references are available in the conversations as well as the letter to editor.
The above summary is human generated and there are no key words as it's hoped that next gen AI systems will be able to tag them automatically.
Conversational Transcripts:
[11/02, 22:16] UG ma: ```Research Snippet 11th February 2025
```
Today’s study reports 5-year efficacy and safety outcomes from the CheckMate 9LA trial, which compared nivolumab plus ipilimumab with chemotherapy to chemotherapy alone in patients with metastatic non-small cell lung cancer (mNSCLC).
*Key Findings*
1. *Improved Overall Survival (OS)*: Patients receiving nivolumab plus ipilimumab with chemotherapy had a 5-year OS rate of 18% vs. 11% for those receiving chemotherapy alone.
2. *Durable Response*: 5-year duration of response (DOR) rates were 19% vs. 8% in favor of the combination therapy.
3. *Consistent Benefit Across Subgroups*: The combination therapy showed consistent benefit regardless of tumor PD-L1 expression, histology, or presence of baseline brain metastases.
4. *Long-term Safety*: No new safety signals were observed in 5-year survivors.
*Conclusion*
The study supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy over chemotherapy in patients with mNSCLC.
[12/02, 06:03] ug an: Is this a study of which, results was now being?
I mean has the randomization method, sample size calculation already been discussed in a previous version of this article?
[12/02, 10:03]cm: Not sure but we can discuss again the results by asking @Meta AI to share it in a PICO format taking care so that it doesn't share relative percentages but carefully shares the absolute values in terms of number of patients, days etc that the study has chosen to share it's outcomes.
Again I'm not sure if meta AI can process the entire article if we paste it here. If not then perhaps one of you could help me to provide it the prompts bit by bit in text here:
European Journal of Cancer
Volume 211, November 2024, 114296
Original research
Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial
Author links open overlay panel
Martin Reck a 1
,
Tudor-Eliade Ciuleanu b
,
Michael Schenker c
,
Stephanie Bordenave d
,
Manuel Cobo e
,
Oscar Juan-Vidal f
,
Niels Reinmuth g
,
Eduardo Richardet h
,
Enriqueta Felip i
,
Juliana Menezes j
,
Ying Cheng k
,
Hideaki Mizutani l
,
Bogdan Zurawski m
,
Aurelia Alexandru n
,
David P. Carbone o
,
Shun Lu p
,
Thomas John q
,
Takekazu Aoyama r
,
Diederik J. Grootendorst r
,
Nan Hu r
…
Luis G. Paz-Ares s
Snipped however available full text at the article link shared above.
[12/02, 10:03] Meta AI: There was a problem generating a response. Please try again later.
[12/02, 10:04] cm: @Meta AI guessed so. @UG ma we'll need to give the data in text to meta AI here in smaller bits of the outcome results
[12/02, 10:04] Meta AI: Sounds like we'll be working with a large dataset. Please go ahead and share the smaller bits of the outcome results, and I'll assist you in analyzing and summarizing the data. I'm ready when you are!
[12/02, 10:30 UG ma: Sure sir
[12/02, 10:34]ug ma: https://ars.els-cdn.com/
[12/02, 10:36]ug ma: @~✨️🐕 please check this out too..
[12/02, 10:38]ug ma: https://www.sciencedirect.com/
[12/02, 10:39]ug ma: The referenced study.
[12/02, 10:47] ug an: Ok surely!
[12/02, 10:50]ug ma: https://sci-hub.se/downloads/
[12/02, 10:50]ug ma: This is the entire article..
[12/02, 10:53]ug ma: It might not be accessible earlier..therefore for your reference I downloaded from external source👍
[12/02, 10:54] ug ma: Sir I will get back with this by evening and send it here!
[12/02, 11:13] v: Even the link would work
[12/02, 11:15] v : I tried to extract data from a study. By giving the Google link to meta AI yesterday.
But the entire thing was fabricated. May be there was a problem with the prompts I provided.
[12/02, 16:37] cm: Used to work earlier when that feature was initially launched. Later now it doesn't work probably currently hiding behind a paywall
[12/02, 18:03]v: I gave a quick peek, searching for keywords like sample size
I found the mentioned number of patients reqd under Statistical Analysis.
Please correct me if I'm wrong, but I couldn't verify the sample size calculation personally, because of the following:
1. Accrual time not mentioned.
2. Total study duration or follow-up time not mentioned.
I spent some more time on the sample size calculation based on logrank tests.
I felt these are essential in order to calculate sample size or power (used PASS for the analysis).
[12/02, 18:04] v: Please tell me if any details was missed by me.
[12/02, 18:27]ug ma: For the 2021 article or 2024?
[12/02, 18:33] ug an: This
Entire one
[12/02, 18:33]ug ma: Okay!
[12/02, 18:34]ug ma: Will go through this and get back to you..
[12/02, 18:37] ug an: Thank you!
Please lemme know if I missed anything
[12/02, 18:43] cm : 👆the entire full text is available in the link here
[12/02, 18:44] cm: 👆Is this the same as the one available in the link!
[12/02, 18:46] ug aks: No sir….The study which they’ve referenced is the previous one
[12/02, 19:18] ug ma: PICO format -
The PICO format (Population, Intervention, Comparison, Outcome) for the study titled "Five-year outcomes with first-line nivolumab plus ipilimumab with 2 cycles of chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic non-small cell lung cancer in the randomized CheckMate 9LA trial" can be structured as follows:
**Population (P):**
Adults with stage IV or recurrent non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK alterations. A total of 719 patients were randomized, with 361 receiving nivolumab plus ipilimumab with chemotherapy and 358 receiving chemotherapy alone.
**Intervention (I):**
Nivolumab plus ipilimumab combined with 2 cycles of chemotherapy.
**Comparison (C):**
4 cycles of chemotherapy alone.
**Outcome (O):**
- **Overall Survival (OS):** At a minimum follow-up of 57.3 months, the number of patients alive at 5 years was 65 in the nivolumab plus ipilimumab with chemotherapy group and 39 in the chemotherapy group.
- **Duration of Response (DOR):** In the nivolumab plus ipilimumab with chemotherapy group, 19% of responders maintained their response at 5 years, translating to approximately 69 patients, compared to 8% in the chemotherapy group, which corresponds to approximately 29 patients.
- **Progression-Free Survival (PFS):** The number of patients with 5-year PFS in the nivolumab plus ipilimumab with chemotherapy group was 27, while in the chemotherapy group, it was 14.
- **Treatment-Related Adverse Events (TRAEs):** Among patients who discontinued treatment due to TRAEs, 22% were alive and treatment-free at 5 years, which corresponds to approximately 13 patients in the nivolumab plus ipilimumab with chemotherapy group.
This structured format provides a clear overview of the study's design and outcomes without referencing relative percentages, focusing instead on absolute values as requested.
---
[12/02, 19:19]ug ma: @cm sir..
[12/02, 19:28] ug ma: In the CheckMate 9LA study, the accrual time spanned from August 24, 2017, to January 30, 2019, during which a total of 1,150 patients were enrolled. The follow-up period for the primary endpoint of overall survival included a median follow-up of 9.7 months at the time of the pre-planned interim analysis, with an additional follow-up resulting in a median of 13.2 months at the time of the exploratory database lock on March 9, 2020 [page 6]
[12/02, 19:28] ug ma: The sample size for the CheckMate 9LA trial was calculated to ensure sufficient power to detect a significant difference in overall survival between the treatment groups. Specifically, the hypothesis was that a sample of approximately 700 randomly assigned patients and 402 deaths would provide more than 80% power to detect an average hazard ratio (HR) of 0.75 for the experimental group (nivolumab plus ipilimumab combined with chemotherapy) compared to the control group (chemotherapy alone), with a two-sided type 1 error of 0.05.
Randomisation was performed using an interactive web response system, with patients randomly assigned in a 1:1 ratio to either the experimental group or the control group. The randomisation was stratified by tumour histology (squamous vs. non-squamous), sex (male vs. female), and tumour PD-L1 expression level (<1% vs. ≥1%). This stratification ensured that these important prognostic factors were balanced between the treatment groups, thereby enhancing the validity of the trial results (see details on randomisation on [page 4].
[12/02, 19:31] ug ma: They didn't specifically used PASS..but they calculated sample size based on the hypothesis mentioned above to get more than 80 percent power..
[12/02, 19:51] cm: At a minimum follow-up of 57.3 months, the number of patients alive at 5 years was 65 in the nivolumab plus ipilimumab with chemotherapy group which means 291 died and 39 in the chemotherapy group which means 319 died.
We need to check what was the actual cause of death by meticulously studying the event sequence leading to their death in all these patients if possible blinding the evaluators to the interventions.
That means each and every case report form or detailed EMR data or a sequence of events summary for each patient should have been made available open access in this information age for a global audience critically appraising this work. However we know that most trials haven't yet been able to meet this simple requirement till date
[12/02, 20:08] cm: Similarly what exactly do they mean by 69 patients maintained their response at 5 years in the NI group vs 29 patients in the Chemo group? What exactly was happening to them that could be causally attributed to their interventions? Again we need to study the individual patients detailed sequences of events here
[12/02, 20:11]cm: What was the quality of life in 27 patients with 5-year PFS in the nivolumab plus ipilimumab with chemotherapy group and 14 in the only chemotherapy group?
[12/02, 20:14] cm: What was the sequence of events in 13 patients in the nivolumab plus ipilimumab with chemotherapy group who
discontinued treatment due to TRAEs and yet were alive and treatment-free at 5 years? This hints that treatment was not the cause of their survival?
[12/02, 20:23]ug an: I'll run the analysis again after studying this.
The tool doesn't affect the results in a grand manner.
I just wanted to verify.
[12/02, 21:17] ug ma: Yes sir detailed data is not given in this aspect
[12/02, 21:41 ug ma: Mixed factors could be there. They might have switched to another treatment or immune responses might be different in these patients..(duration of the response to the treatment even after discontinuation)
[12/02, 21:41] ug ma: But detailed sequence is not provided there sir.
[02/03, 00:13] ug ma: I was working on the LTE for this paper and got answers to your earlier queries
[02/03, 00:14] ug ma: At a minimum follow-up of 57.3 months, the number of patients alive at 5 years was 65 in the nivolumab plus ipilimumab with chemotherapy group which means 291 died and 39 in the chemotherapy group which means 319 died.
We need to check what was the actual cause of death by meticulously studying the event sequence leading to their death in all these patients if possible blinding the evaluators to the interventions.
That means each and every case report form or detailed EMR data or a sequence of events summary for each patient should have been made available open access in this information age for a global audience critically appraising this work. However we know that most trials haven't yet been able to meet this simple requirement till date
[02/03, 00:14] ug ma: Similarly what exactly do they mean by 69 patients maintained their response at 5 years in the NI group vs 29 patients in the Chemo group? What exactly was happening to them that could be causally attributed to their interventions? Again we need to study the individual patients detailed sequences of events here
[02/03, 00:14] ug ma: What was the quality of life in 27 patients with 5-year PFS in the nivolumab plus ipilimumab with chemotherapy group and 14 in the only chemotherapy group?
[02/03, 00:14] ug ma: What was the sequence of events in 13 patients in the nivolumab plus ipilimumab with chemotherapy group who
discontinued treatment due to TRAEs and yet were alive and treatment-free at 5 years? This hints that treatment was not the cause of their survival?
[02/03, 00:14]ug ma: These were your questions
[02/03, 07:19] cm: 👆no answer as to the sequence of events?
[02/03, 10:24]ug ma: No sir couldn't find this and quality of life
[02/03, 10:25] ug ma: They've also not mentioned the route of administration of NI..it would have been IV since S/C route was approved in 2025 January..
[03/03, 12:28] ug ma: This is the draft of the letter upon the discussion we had earlier..
[03/03, 12:29] ug ma: https://www.sciencedirect.com/
Drafted letter to editor:
Revisiting the Checkmate 9LA trial
To the editor,
We would like to congratulate the authors of the Checkmate 9LA trial for the success of
outcomes, which would act as a foundation in the treatment regimens of the metastatic
non-small cell lung cancer (mNSCLC) patients.(1)
The trial evidenced improved overall
survival (OS) in mNSCLC patients receiving nivolumab plus ipilimumab with 2 cycles of
chemotherapy (NI) as compared to chemotherapy alone (18% vs 11%) and highlighted the
beneficial response in various subgroups like different metastatic sites, squamous histology
and PD-L1 expression less than 1%, indicating treatment maybe effective in diverse range of
patients.
The combination therapy was also effective in patients suffering from baseline brain
metastasis who usually have poor prognosis.
While the results of the study show new prospects and hope for treating mNSCLC patients, I
believe there are a few critical points and limitations worth addressing. At a minimum
follow-up of 57.3 months, the number of patients alive at 5 years was 65 in the intervention
group vs 39 in the chemotherapy-only group, implying 291 and 319 patients died in each,
respectively. It is essential to check the actual cause of death by studying the event sequence
leading to their death in all these patients, if possible blinding the evaluators to the
interventions which could be done via a sequence of events summary for each patient.
This
meticulous data provision would also explain possible factors attributing maintaining the
response by 69 patients at 5 years in the NI group vs in the chemotherapy group.
As illustrated by the potential benefits in trials of targeted therapies like EGFR inhibitors, where
sequence data could have elucidated resistance mechanisms and progression patterns, this
information would significantly enhance our understanding of treatment efficacy and inform
clinical decision-making.(2)
Providing such meticulous patient-level data would bridge the
gap between group-level outcomes and tailored therapeutic interventions, ultimately
improving patient care.
Another important consideration is the most effective treatment duration of NI in these
patients. While patients receiving the full two years showed good long-term outcomes, there
was no comparison to shorter durations. Determining if earlier treatment cessation yields
similar survival benefits and reduced treatment-related adverse events (TRAEs) is crucial.
Sung et al.'s evaluation of the correlation between immune-related adverse events (irAEs) and
response from immune checkpoint inhibitors suggests irAE development might correlate with
longer survival in mNSCLC patients. (3) However, the duration of immunotherapy exposure
is a potential confounder; patients discontinuing early due to TRAEs might have better
response rates, leading to better overall survival. The 37% of patients surviving five years
despite early NI discontinuation due to TRAEs could have additional survival factors beyond
the NI regimen. The study also lacked specific follow-up and quality of life details, which
may be affected by long-term TRAEs like pneumonitis. Prospective research should explore
the impact of these TRAEs and the quality of life in these survivors.
It is crucial to have an exploratory evaluation of the quality of life (QoL) of those 27 patients
with 5 years progression-free survival in the NI group and the 14 patients in the
chemotherapy-only group. Cancer patients often have variable treatment priorities like having
a good quality of life for the remaining period, low out-of-pocket expenses, longest possible
survival and having fewer hospital visits, etc.(4) Considering factors like quality of life,
treatment costs, and hospital visits is crucial for patient acceptance of therapy. Therefore,
incorporating patient-reported outcomes and experiences related to these factors as secondary
endpoints in clinical trials is essential. (5)This is further supported by a metastatic prostate
cancer trial, in which mitoxantrone significantly improved patient-reported outcomes like
pain and QoL, despite no survival benefit. These improvements led to regulatory approval,
highlighting the importance of QoL assessments in clinical trials beyond primary survival
endpoints (6,7)
We would also like to focus on the role of the route of nivolumab administration since the
emergence of the subcutaneous (SC) route is more preferred by patients than the intravenous
formulation, which takes more time and logistics than the subcutaneous route. The SC route
not only satisfies patients by decreasing their time spent in hospitals but also decreases the
involvement of oncologists and on-call doctors, allowing them to attend to other patients and
commitments. (8,9)While the authors suggest NI's superiority through indirect comparisons,
direct prospective trials against pembrolizumab and other immunotherapies are needed to
solidify its benefit over chemotherapy, as supported by the CheckMate 9LA trial.
References
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N, Richardet E, Felip E, Menezes J, Cheng Y, Mizutani H, Zurawski B, Alexandru A,
Carbone DP, Lu S, John T, Aoyama T, Grootendorst DJ, Hu N, Eccles LJ, Paz-Ares
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chemotherapy versus 4 cycles of chemotherapy alone in patients with metastatic
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39270380.
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6. Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with
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7. Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al.
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symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with
palliative end points. J Clin Oncol. 1996 Jun;14(6):1756–64.
8. George S, Bourlon MT, Chacon MR, Cutuli H, Lopez Chuken YA, Zurawski B, et al.
Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in
patients with previously treated advanced or metastatic clear cell renal cell carcinoma
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JCO. 2024 Feb;42(4_suppl):LBA360–LBA360.
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from:
CC licence for the image above: https://commons.m.
