Repotrectinib in ROS1 Fusion–Positive Non–Small-Cell Lung Cancer

N Engl J Med. 2024 Jan 11;390(2):118-131.

BACKGROUND
The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the
treatment of ROS1 fusion–positive non–small-cell lung cancer (NSCLC) have antitumor
activity, but resistance develops in tumors, and intracranial activity is suboptimal.
Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion–positive cancers, including those with resistance mutations such as ROS1 G2032R.
METHODS
In this registrational phase 1–2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion–positive NSCLC.
The primary efficacy end point in the phase 2 trial was confirmed objective response;
efficacy analyses included patients from phase 1 and phase 2. Duration of response,
progression-free survival, and safety were secondary end points in phase 2.
RESULTS
On the basis of results from the phase 1 trial, the recommended phase 2 dose of
repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response
occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with
ROS1 fusion–positive NSCLC who had not previously received a ROS1 TKI; the median
duration of response was 34.1 months (95% CI, 25.6 to could not be estimated),
and median progression-free survival was 35.7 months (95% CI, 27.4 to could not
be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52)
with ROS1 fusion–positive NSCLC who had previously received one ROS1 TKI and
had never received chemotherapy; the median duration of response was 14.8 months
(95% CI, 7.6 to could not be estimated), and median progression-free survival was
9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82)
with the ROS1 G2032R mutation had a response. A total of 426 patients received
the phase 2 dose; the most common treatment-related adverse events were dizziness
(in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3%
discontinued repotrectinib owing to treatment-related adverse events.
CONCLUSIONS
Repotrectinib had durable clinical activity in patients with ROS1 fusion–positive
NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse
events were mainly of low grade and compatible with long-term administration.
(Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers
Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.)

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・ROS1-TKI既治療の患者のうち、ROS1 G2032R耐性変異陽性の患者17人ではmedian PFSが9.2か月だったのに対し、ROS1 G2032R耐性が陰性、あるいは未検出の患者83人ではmedian PFSは5.5か月にとどまっていた。

・ROS1-TKI治療歴なしとありのコホートについて、無増悪生存曲線を並べてみると、ほぼダブルスコアであることが分かります。

・ROS1-TKI治療歴なしでrepotrectinibを使用した際の無増悪生存期間中央値は約36ヶ月。クリゾチニブやエヌトレクチニブの無増悪生存期間中央値が約16ヶ月。そこからreporectinibを使用して上乗せされる無増悪生存期間中央値が9ヶ月ですから、併せて約25ヶ月。ほぼ1年間の開きがありますので、最初からrepotrectinibを使用した方が良さそうです。

・脳転移

FLAURA：Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC

<BACKGROUND>
Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. A phase 3 trial compared first-line osimertinib with other EGFR-TKIs in patients with EGFR mutation–positive advanced non–small-cell lung cancer (NSCLC). The trial showed longer progression-free survival with osimertinib than with the comparator EGFR-TKIs (hazard ratio for disease progression or death, 0.46). Data from the final analysis of overall survival have not been reported.

<METHODS>
In this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with an EGFR mutation (exon 19 deletion or L858R allele) in a 1:1 ratio to receive either osimertinib (80 mg once daily) or one of two other EGFR-TKIs (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily, with patients receiving these drugs combined in a single comparator group). Overall survival was a secondary end point.

<RESULTS>
The median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P=0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.

<CONCLUSIONS>
Among patients with previously untreated advanced NSCLC with an EGFR mutation, those who received osimertinib had longer overall survival than those who received a comparator EGFR-TKI. The safety profile for osimertinib was similar to that of the comparator EGFR-TKIs, despite a longer duration of exposure in the osimertinib group. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125. opens in new tab.)

To the Editor: In the FLAURA trial update, Ramalingam and colleagues (Jan. 2 issue)1 present data regarding overall survival with first-line osimertinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), as compared with one of two other EGFR-TKIs (gefitinib and erlotinib), in patients with mutation–positive advanced non–small-cell lung cancer (NSCLC), regardless of T790M mutational status. The median overall survival was 38.6 months in the osimertinib group and 31.8 months in the comparator group.

In 2017, the AURA3 trial showed superior progression-free survival for osimertinib over platinum-based therapy (10.1 months vs. 4.4 months) in patients with T790M mutations who had disease progression after first-line treatment with EGFR-TKIs.2 Previously, Maemondo et al.3 found that the use of the first-generation EGFR-TKI gefitinib resulted in longer overall survival than chemotherapy (30.5 months vs. 23.6 months) in previously untreated patients with EGFR-mutated cancers. Therefore, given the survival benefits shown in these two trials, patients in whom T790M mutations develop while they are receiving first-generation EGFR-TKIs theoretically could have an overall survival of more than 40 months with second-line osimertinib if the therapies were sequenced correctly. Furthermore, whether the survival benefit of first-line osimertinib relates to T790M mutational status is still unknown. It is unclear whether patients who participated in the FLAURA trial were tested for the presence of the T790M mutation during enrollment. Also, there was no subgroup analysis of overall survival in the 47% of patients in the comparator group who crossed over to receive osimertinib, results that could have been masked by a different second subsequent therapy.

The question of the most effective sequencing of available therapies is paramount to oncologists. It seems possible that first-line osimertinib may disadvantage the approximately 50% of patients in whom T790M mutations develop and who would benefit more from sequential osimertinib.4

Kelvin Yan, M.D.
University of Oxford, Oxford, United Kingdom

To the Editor: The recent trial by Ramalingam et al. showed the superior efficacy of the EGFR-TKI osimertinib over comparator EGFR-TKIs for the treatment of NSCLC. Similar results were reported earlier for the progression-free survival of these patients.1 However, despite the better responses, a high percentage of patients with this type of cancer die or have disease progression.

In the subgroup analyses, the authors describe notable differences in the response to osimertinib between Asian and non-Asian patients, with more pronounced effects of osimertinib among non-Asian patients.1 The effect of EGFR polymorphisms on EGFR-TKI efficacy has been described previously,2 and it is likely that differences in genetic polymorphisms in various ethnic groups will influence EGFR-TKI efficacy. A recent network meta-analysis also suggested that interethnic differences in genetic polymorphisms may influence the efficacy of osimertinib.3 Differences in allele frequencies and linkage disequilibrium between Asian and non-Asian patients are present in the EGFR locus, and additional polymorphisms can further influence the efficacy of EGFR-TKI treatment. Furthermore, such interethnic differences have been shown to correlate with the EGFR mutational pattern.4 In future studies, it will be important to focus on population-associated genetic determinants that affect the efficacy of current EGFR-TKI treatments.

To the Editor: Despite an initial period of good response, most EGFR-mutated pulmonary adenocarcinomas progress with time. The poor penetrability of older drugs into the central nervous system (CNS) often means that a substantial proportion of failures happen in the CNS.1 Even before the publication of the results of the FLAURA trial,2 osimertinib has been noted because of its more extensive CNS penetration than either gefitinib or erlotinib.

It would be of immense clinical value if Ramalingam et al. could provide us with the following information: First, what was the CNS failure rate among patients without previous CNS metastases in the osimertinib group and in the comparator group? Second, was the between-group separation in the curves for progression-free survival among the patients with CNS metastases greater than the separation in the general population? And third, what was the overall survival for patients with brain metastases in the two treatment groups?

The authors reply: In response to the comments by Yan: approximately 30% of patients in the two treatment groups (including those who died) did not receive a second-line therapy after discontinuation of the trial drug. As noted in the Discussion section of our article, the EGFR T790M resistance mutation develops in approximately 50% of the patients who receive an earlier-generation EGFR-TKI, which creates a biologically driven limit to the number of patients who are eligible to benefit from second-line osimertinib. Of the patients in the comparator group who received a second-line therapy, 47% received osimertinib as a T790M-directed therapy. The median overall survival that we observed in the comparator group was among the highest reported for EGFR-mutated NSCLC, which is at least in part attributable to the crossover from the comparator group to receive osimertinib. The use of osimertinib resulted in an overall survival benefit over the comparator EGFR-TKIs despite this crossover. In our trial, de novo T790M mutations were detected in only five patients (four in the osimertinib group) at baseline,1,2 which would not account for the benefit in progression-free survival and overall survival observed with osimertinib. Therefore, osimertinib is the preferred first-line therapy to provide all patients with the opportunity to benefit.

In response to the comments by Staege: progression-free survival is the best direct measure of efficacy, and we have previously reported longer progression-free survival with osimertinib than with a comparator EGFR-TKI (hazard ratio, 0.46; P<0.001), a difference that was also observed across all predefined subgroups, including Asian and non-Asian subgroups.2 Overall survival encompasses subsequent lines of therapy, and multiple factors may influence the margin of improvement, including differences in local clinical practice, ethnic differences in metabolism of EGFR-TKIs, and ethnic sensitivity to subsequent therapies. The suggested analysis of EGFR polymorphisms and their influence on EGFR-TKI efficacy may shed further light on this topic and merits further investigation.

In response to Revannasiddaiah and colleagues: patients in the osimertinib group had a 52% lower risk of CNS progression than the comparator group (hazard ratio, 0.48; P=0.01); CNS response rates were numerically higher with osimertinib.3 We have also reported that among the patients with no known or treated CNS metastases at trial entry, CNS progression occurred in 7 patients (3%) in the osimertinib group and in 15 patients (7%) in the comparator group.2 In our final overall survival analysis, subgroup data show that the hazard ratios for death were similar between patients with CNS metastases at trial entry and those without such metastases.

KEYNOTE-189: Chemotherapy and Pembrolizumab in mNSCLC

Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer

N Engl J Med 2018; 378:2078-2092

Abstract
<BACKGROUND>
First-line therapy for advanced non–small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial.

<METHODS>
In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review.

<RESULTS>
After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.

<CONCLUSIONS>
In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680. opens in new tab.)

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https://www.youtube.com/watch?v=fQKK_1XP5l4

Hossein Borghaei, DO: KEYNOTE-189 is a phase III randomized clinical trial for patients with treatment-naïve nonsquamous non—small cell lung cancer who do not have an activated mutation. The study specifically talked about EGFR and ALK, and those were definitely excluded. Patients also had to have a good performance status, no active brain metastases, and other standard inclusion/exclusion criteria for a clinical trial. Everybody had to have adequate tissue for PD-L1 testing. PD-L1 testing results were not needed for the study randomization, but everybody had to have tissue just so that we could determine the level of the PD-L1 expression. The patients were simply randomized to a combination of carboplatin plus pemetrexed with pemetrexed maintenance, and that was the standard-of-care control arm with this study.

On the other arm, they got the exact same combination plus pembrolizumab. Now, this was built upon the results of KEYNOTE-021g, which was a randomized phase II trial with the exact same combination. Over 600 patients were randomized to these 2 arms of the study, and in the experimental arm, the arm with pembrolizumab, maintenance with pembrolizumab plus pemetrexed was allowed. I think patients were also allowed to cross over from the chemotherapy arm at the time of progression to the more active, or the experimental, arm with pembrolizumab.

Corey J. Langer, MD: KEYNOTE-021g was actually the precursor for the much larger randomized phase III KEYNOTE-189 trial. This was a randomized phase II effort that compared the control regimen of pemetrexed/carboplatin with the combination of pemetrexed/carboplatin with the checkpoint inhibitor pembrolizumab with 4 cycles of combination carboplatin given in both arms. Pemetrexed was continued as maintenance therapy in the absence of disease progression or untoward toxicity. In the investigational arm, pembrolizumab was grafted onto the pemetrexed/carboplatin and continued as maintenance along with pemetrexed for up to 2 years. The unique feature of this trial included crossover in the control arm to pembrolizumab at the time of disease progression, so that lent extra credibility to the trial in light of the results.

We observed a major improvement in response rates, initially from 28% to 57%. Both arms have inched up somewhat over the past year or so now to 30% and 60%. PFS showed a significant advantage for the pembrolizumab arm, which over time has matured to about 20.0 months versus 8.9 months. What’s remarkable there is the control arm has actually exceeded historic controls.

Initially, survival did not show much difference at 1 year: 75% for pembrolizumab in combination versus 72%. But as time has gone on, we’ve actually seen a major improvement. The median survival has still not been reached in the pembrolizumab arm, now easily exceeding 2 years; whereas it’s about 13 or 14 months in the control group. We have to remember that this was a multi-institutional, academic-oriented trial. Selection bias clearly had some play in the nature of the patients who went on it.

KEYNOTE-189 was the logical follow-up of this trial. It was a randomized phase III trial with 2:1 randomization of platinum, either carboplatin or cisplatin, combined with pemetrexed plus or minus pembrolizumab. It was placebo controlled, a distinct difference from the precursor randomized phase II trial, which did not employ a placebo. Like KEYNOTE-021g, eligibility was restricted to nonsquamous non—small cell in the absence of any activating molecular aberrations: no EGFR mutations, no ALK translocation.

Once more, there was an astounding improvement in overall response rate that was statistically significant and clinically meaningful. We essentially see a doubling in progression-free survival from 4.9 to about 8.9 months and a highly significant—in fact, unprecedently significant&mdash;improvement in overall survival. The hazard ratio here is 0.49. In my entire career of research of advanced non—small cell lung cancer, I have never seen a hazard ratio that good. The patients were evaluated based on their PD-L1 expression. The survival benefit was seen across the board but was even more pronounced in the group that had 50% or higher PD-L1 expression. The hazard ratio there was 0.42, and in that group, the response rate was about 68%, which exceeds the 45% or 46% that was seen with single-agent pembrolizumab in the KEYNOTE-024 study.

This trial was a major game changer. The phase III results validate what we had seen in the randomized phase II trial. It had a conditional approval, and now a formal approval, by the FDA for nonsquamous non—small cell lung cancer in the absence of activating mutations, regardless of PD-L1 status.

KRAS G12C+, Stage IV NSCLC～CodeBreak200

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.

EGFR陽性のケモ・ICIのデータ

<IMpower150>

一次治療における非扁平上皮非小細胞肺癌に対する，CBDCA＋PTX＋ベバシズマブ＋アテゾリズマブ療法とCBDCA＋PTX＋ベバシズマブ療法を比較した第Ⅲ相試験。

EGFR遺伝子変異陽性のサブグループ解析において，OS中央値 未到達vs 18.7カ月（HR 0.61，95％CI：0.29-1.28），PFS中央値10.2カ月vs 6.9カ月（HR 0.61，95％CI：0.36-1.03）とアテゾリズマブ併用群が良好な傾向を示した45）。

さらにEGFR遺伝子感受性変異（エクソン19欠失・L858R変異）のみを対象としたEGFR-TKI治療後の患者におけるOSのアップデート解析では，OS中央値29.4カ月vs 18.1カ月（HR 0.74，95％CI：0.38-1.46）と良好な傾向を示した46）。

しかし，このサブグループ解析はプロトコールであらかじめ予定されていた解析ではなく，EGFR遺伝子変異の有無が割付調整因子に設定されていないなど，解釈には注意が必要である。

<IMpower130>

また，非扁平上皮非小細胞肺癌に対するCBDCA＋nab-PTX＋アテゾリズマブ療法とCBDCA＋nab-PTX療法を比較した第Ⅲ相試験（IMpower130試験）のEGFR遺伝子変異もしくはALK融合遺伝子陽性のサブグループ解析において，PFS中央値7.0カ月vs 6.0カ月（HR 0.75，95％CI：0.36-1.54），OS中央値14.4カ月vs 10.0カ月（HR 0.98，95％CI：0.41-2.31）であった47）。上記試験においてEGFR遺伝子変異陽性では一次治療としてEGFR-TKIの治療歴のある患者が対象とされており，二次治療の患者が登録されている。

肺結節フォローについて

結節性病変の鑑別診断に際して、

6mm以上の肺結節を内部の性状により3つに分類する。
その3つとは、

内部が充実成分のみ(solid nodule)
内部が充実成分＋すりガラス影(part-solid nodule)
内部がすりガラス影のみ(pure GGN)
の3つ

ところですりガラス影とは、「肺の血管が見える程度の吸収値の増大（白さ）」を言います。充実成分の場合は肺野の血管が見えない程度の吸収値が増大します。

結節の内部が充実成分のみの場合、

結節の大きさ(最大径)が6mm以上10mm未満
→ 経過観察(フォロー)を行う。
1,喫煙者の場合：3,6,12,18,24ヶ月後
2,非喫煙者の場合：3,12,24ヶ月後
結節の大きさが10mm以上
→原則として確定診断(生検、手術)を行う。
とサイズで分類されます。

内部が充実成分＋すりガラス影(part-solid nodule)の場合

結節の大きさ(最大径)が15mm以上
→原則として確定診断(生検、手術)を行う。
結節の大きさ(最大径)が15mm未満でかつ、充実部位の最大径が肺野条件で
5mm以上→確定診断を行う。
5mm未満→経過観察を行う。
とサイズで分類されます。

右下葉にpart-solid nodule(mixed type GGN)を認めています。腫瘍の最大径は2.78cmで、充実部位は1.2cm大です。

結節の大きさ(最大径)が15mm未満でかつ、充実部位の最大径が肺野条件で5mm以上ですので、確定診断を行うことになります。

手術にて肺腺癌(腺房型)と診断されました。

内部がすりガラス影のみ(pure GGN)の場合

結節の大きさ(最大径)が15mm以上のまま
→確定診断(生検、手術)を行う。
結節の大きさ(最大径)が15mm未満
→3,12,24ヶ月後、経過観察を行う。
とサイズで分類されます。

※ 24ヶ月後不変であってもその後も年に1回の経過観察は必要です。緩徐に発育する肺腺癌があるためです。

感染症になると低アルブミン血症になるという話

肺炎や尿路感染症といった感染症や慢性関節リウマチや多発筋痛症など慢性疾患などがあると低アルブミン血症になることが知られている。これにはCRP（C反応性タンパク質）が関係している。

CRPとは肝臓で作られるタンパク質であり、炎症や組織細胞の破壊が起こると血液中に増加すると言う特徴がある。よって身体のどこであっても炎症反応が起こればCRPは上昇する。裏を返せば、感染症などになって肝臓で頑張ってCRPを作っているような状況下では同じく肝臓で作られるアルブミンの産生が低下することになる。

具体的にはストレス負荷時に分泌されるIL6やTNF-αなどのサイトカインが貯蔵タンパク質であるアルブミンの分解を促進し、逆に炎症性タンパク質であるCRPやフィブリノーゲンの合成を促進する（炎症時に上昇するこれらのタンパク質を急性期タンパクと呼ぶ）。また、サイトカインの働きによって血管透過性が亢進してアルブミンが血管から濾出してしまうのでより低アルブミン血症が進行する理由になってしまう。

まとめ：感染症時の肝臓ではCRP産生が忙しくてアルブミンなんて作ってる隙がない。本当に低栄養でなければ炎症が落ち着くとアルブミンも徐々に改善する。高齢者の肺炎患者などで「アルブミン低いですし栄養状態悪いですねぇ」とアルブミンだけで栄養状態を判断しないようにしたい所。栄養状態が悪いのではなくCRPが作られてアルブミンを作っていない＋血管の外に漏れているからである。