Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRASG12C mutation: a randomised, open-label, phase 3 trial
ARTICLES| VOLUME 401, ISSUE 10378, P733-746, MARCH 04, 2023 THE LANCET
Summary
<Background>
Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs.
<Methods>
We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries. We recruited patients aged at least 18 years with KRASG12C-mutated advanced NSCLC, who progressed after previous platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor. Key exclusion criteria included new or progressing untreated brain lesions or symptomatic brain lesions, previously identified oncogenic driver mutation other than KRASG12C for which an approved therapy is available (eg EGFR or ALK), previous treatment with docetaxel (neoadjuvant or adjuvant docetaxel was allowed if the tumour did not progress within 6 months after the therapy was terminated), previous treatment with a direct KRASG12C inhibitor, systemic anticancer therapy within 28 days of study day 1, and therapeutic or palliative radiation therapy within 2 weeks of treatment initiation. We randomly assigned (1:1) patients to oral sotorasib (960 mg once daily) or intravenous docetaxel (75 mg/m2 once every 3 weeks) in an open-label manner using interactive response technology. Randomisation was stratified by number of previous lines of therapy in advanced disease (1 vs 2 vs >2), ethnicity (Asian vs non-Asian), and history of CNS metastases (present or absent). Treatment continued until an independent central confirmation of disease progression, intolerance, initiation of another anticancer therapy, withdrawal of consent, or death, whichever occurred first. The primary endpoint was progression-free survival, which was assessed by a blinded, independent central review in the intention-to-treat population. Safety was assessed in all treated patients. This trial is registered at ClinicalTrials.gov, NCT04303780, and is active but no longer recruiting.
<Findings>
Between June 4, 2020, and April 26, 2021, 345 patients were randomly assigned to receive sotorasib (n=171 [50%]) or docetaxel (n=174 [50%]). 169 (99%) patients in the sotorasib group and 151 (87%) in the docetaxel group received at least one dose. After a median follow-up of 17·7 months (IQR 16·4–20·1), the study met its primary endpoint of a statistically significant increase in the progression-free survival for sotorasib, compared with docetaxel (median progression-free survival 5·6 months [95% CI 4·3–7·8] vs 4·5 months [3·0–5·7]; hazard ratio 0·66 [0·51–0·86]; p=0·0017). Sotorasib was well tolerated, with fewer grade 3 or worse (n=56 [33%] vs n=61 [40%]) and serious treatment-related adverse events compared with docetaxel (n=18 [11%] vs n=34 [23%]). For sotorasib, the most common treatment-related adverse events of grade 3 or worse were diarrhoea (n= 20 [12%]), alanine aminotransferase increase (n=13 [8%]), and aspartate aminotransferase increase (n=9 [5%]). For docetaxel, the most common treatment-related adverse events of grade 3 or worse were neutropenia (n=13 [9%]), fatigue (n=9 [6%]), and febrile neutropenia (n=8 [5%]).
<Interpretation>
Sotorasib significantly increased progression-free survival and had a more favourable safety profile, compared with docetaxel, in patients with advanced NSCLC with the KRASG12C mutation and who had been previously treated with other anticancer drugs.
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https://www.obroncology.com/leading-thoughts/codebreak-200-good-result-or-just-good-enough
より
And so, it is a question somewhat in the U.S., and certainly in other parts of the world, about how sotorasib compares head-to-head to docetaxel, because the use of sotorasib in this setting is based on single-arm trial experience that preceded this and our essential cross-trial comparison and experience of one versus another and lack of great enthusiasm for docetaxel here compared to response rate of about 37% in the single-arm earlier experience that we have from the data with sotorasib in this setting.
So, this was a trial that enrolled 345 patients. About 45% were enrolled in the second-line setting and most of the remainder in the third line, a few beyond that. And patients were randomized to single-agent sotorasib at 960 mg orally or the standard docetaxel dose of 75 mg/m2.
And I mentioned that progression-free survival was the primary endpoint, and it met that endpoint. It was a positive trial with a hazard ratio of 0.66 favoring sotorasib, and the one-year PFS was about 4% with sotorasib compared to 10% for docetaxel. The response rates were also a little more than double with the sotorasib, where it was, I believe, 28% compared to 13% for docetaxel.
So importantly, docetaxel did not underperform here. This was about what we would expect, really, right in line with our expectations. And sotorasib did beat it in these measures. However, it failed to beat it for overall survival, and not just barely failing and a trend in the right direction. The numeric results were a little more favorable, actually, with docetaxel, for overall survival.
The argument could be made that the trial was not powered for survival, and we do know that they allowed crossover, so the patients who were assigned to docetaxel could get sotorasib, but in fact only 34% did get that. So, pretty much two-thirds did not. And then, there’s the toxicity profile.
We have a long history with docetaxel. We know it’s not the easiest to give or receive. No surprises in how that was, but we did find that while sotorasib on balance did better, more than a third of patients had diarrhea and a lot of those patients had grade 3 or higher diarrhea, and then about 10% of patients on sotorasib developed AST or ALT elevations, and most of those were grade 3 or higher.
So, it’s a positive study, but I would just question how this impacts you personally in your practice, and your impressions of sotorasib and the whole field… So, maybe I can start with you, Devika. What did this trial lead you to think about the results?
Dr. Das: So, I found the results a little bit disappointing because I was expecting an overall survival benefit, and not seeing that was a little bit disappointing. That being said, it doesn’t take away from the fact that sotorasib is still a very good second-line option for our patients once they’ve progressed on frontline therapy.
Where I have a little bit of pause is the presence of the grade 3 diarrhea, which again, one of the things in picking a second-line drug option is quality of life for our patients. So, this higher incidence of grade 3 diarrhea and ELT/AST elevations and not entirely understanding the sequencing from if the patient got prior checkpoint inhibitor, am I going to make that worse by giving them sotorasib in the second line? Would they be better off getting docetaxel?
We don’t know the answer to that, but it does lead me to question that. I will still be using it in a second line, but I will be extremely careful about patient selection and making sure patients who have good baseline liver function and maybe having some space from previous checkpoint inhibitor, not really a washout period, but if they’ve been stable for a while and off therapy for a little bit, I would feel a little bit more comfortable giving them sotorasib in the second line. I’d be following them very closely.
The other place where I thought, I know they also presented some data on the brain metastases, which is another way a lot of these patients progress with CNS metastases, I was disappointed that the duration of response between the two arms was not significantly different. So, the patients who got sotorasib was about nine months and was 6.8 months for the docetaxel arm. They did have a better response rate of 28% versus 13%. But again, not what I wanted to see with sotorasib. I was hoping to see better data in terms of picking that second-line option for patients with CNS mets.
Dr. West: And Charu, what did you think? I mean it’s a positive trial, but did this win, not just against docetaxel but against your expectations?
Dr. Aggarwal: Yeah, so I think Jack, you said this very well that docetaxel didn’t underperform, right, but I think it’s important to call out that docetaxel didn’t overperform either. So, this was not a selection bias that the right kind of performance status patients were doing well with docetaxel and that’s why maybe the results were a wash and the overall survival. And you pointed this out, that the crossover rate was not very high. Thirty-four percent of the patients did end up receiving sotorasib on the docetaxel arm. So, is the survival difference really because of the crossover, or is it because, you know, that there really would not be any difference? I tend to think it’s the latter. I think docetaxel performed as it could have, and we don’t have such a high rate of crossover that we can say that maybe the effect is just getting diluted.
I don’t think that’s the reason. But having said that, and recognizing the fact that we are all surprised, I think this is not going to change our practice. I think we’ve been using sotorasib since the accelerated or, sort of, early approval by the FDA in the second-line setting. We have increased awareness for testing for KRAS G12C. We have increased awareness that G12C is different from G12D or G12V. So, I’m happy about that. That we are trying to really distinguish the correct patient to give this to. But is this a win in the long term? Probably not.
I like the fact that the response rate is higher, that the progression-free survival is higher, but the reason why this drug is winning or why we are choosing it is because it’s oral versus IV. I don’t know if the toxicities are that much better. And the docetaxel at attenuated doses and also with significant growth factor support is actually not terrible.
I mean we all don’t like it, but it’s something that we do manage to administer. And I would just pose a question that let’s say tomorrow the Trop2 ADC data comes out against docetaxel. If it looks the same, I don’t think we’ll be more likely to use the Trop2, right, because it’s IV versus IV, or it’s more similar toxicity in terms of mucositis and chemotherapy-related toxicity. So, I do think that the win here is oral versus IV, rather than targeted therapy versus not, or rather than toxicity versus not. But having said this, again, underwhelmed by the data, but unfortunately it’s not going to change practice until we can improve upon the standard or come in with a more CNS-penetrant drug.
Dr. West: So, on balance I would say, even though it is disappointing, I think these results to all of us are somewhat disappointing, and I’d say it saddens me that we are settling for progression-free survival as a primary endpoint. I think that they get away with it here in part because it may not be that good, but it’s good enough in this situation, and the real question is, are they just a placeholder until something better comes along? Does this have any implications to you about your compulsion or eagerness to move this into an earlier setting in some form? Or, in other words, does this lower your enthusiasm for sotorasib overall beyond this particular setting? Devika, if I can start with you.
Dr. Das: I don’t think it does. Again, outside of a clinical trial setting, I would not be wanting to use this drug, either in combination with checkpoint inhibitor or the frontline, based on these results and results of certain other phase 1 studies, CodeBreak 100/101, that was presented at the same meeting. Because again, toxicity in the second line is an important factor in addition to just the progression-free survival. So, I want to make sure I’m giving my patients something that helps them live longer but also live better. So, it does make me pause.
And Charu brought up a good point, we’re thinking of all of these toxicities and we’re really just picking sotorasib because it’s an oral agent versus IV, but financial toxicity is a real issue, and I’m certain this drug is coming at a much higher cost. So, for a lot of physicians who practice in the community or with underserved populations who can’t afford this drug, I think it’s a little bit of a... for now, I would feel OK about giving them docetaxel plus or minus ramucirumab, because I don’t think they’re missing out a lot by not getting the oral sotorasib, based on the data that I’ve seen with CodeBreaK 200. So that is one way to look at this data of how it would inform practices.
Dr. West: I think that’s a great point and something that did come up is like, “Yeah, OK, this wins at 10 times the cost.” It didn’t do 10 times as well, that’s for sure. Charu, what are your thoughts about implications for where to go from here with sotorasib or the relative merits to sotorasib compared to other potential agents against KRAS?
Dr. Aggarwal: Yeah, so I think that’s a great question. I do think that we need to have a CNS-penetrant drug. So, I think if we go into the KRAS G12C development arena in the second-line setting, I think having a drug with good CNS control I think is a major unmet need. I certainly have patients that have very good control of disease extracranially but unfortunately succumb to LMD, or leptomeningeal disease.
So, I do think that’s one of the big areas. And then, I think we don’t know whether any of these combinations that are being explored with KRAS G12C inhibitors in clinical trials right now, such as SHIP2 inhibitors, EGFR inhibitors, chemotherapy. You know, how those are going to fit into our sequencing paradigm. Am I going to be more likely to choose a SHIP inhibitor in patients with certain mutations, or is that going to be more at the time of resistance? I think we just don’t know. And some of the approaches for clinical trial development for these drugs have been quite empiric, and I wish there was a more streamlined approach in terms of understanding the biology and then really trying to attack it.
They have been sort of like, “OK, what drugs do we have? Let’s mix them. Let’s see what happens.” But I would definitely like to understand a little bit more about how to come in with combinations, when to come in with combinations, based on actual biology.
Dr. West: Well, I really appreciate your perspective on this question, and of course the recent meetings have given us data for a bunch of other trials that we’re going to talk about in some other settings. So, I’ll look forward to continuing the conversation with you in another edition.
Dr. Aggarwal: Thank you so much, Jack. This was a great discussion.
Dr. Das: Thank you.
