Editor’s Note: For more on targeting KRAS-G12C with Dr. Melissa Johnson, listen to this recent episode of IASLC’s podcast Lung Cancer Considered.
CodeBreaK 200 lead investigator Melissa Johnson, MD, director of the Lung Cancer Research Program at Sarah Cannon Research Institute, Nashville, Tennessee, said she believes the data show sotorasib beats docetaxel “hands down,” despite the trial not meeting its secondary overall survival endpoint. Dr. Johnson said she was surprised by the controversy the data sparked after she presented the results in September 2022.
ILCN recently had an opportunity to talk with Dr. Johnson about the CodeBreaK 200 results and what they mean for patients with non-small cell lung cancer with KRAS G12C mutations.
ILCN: As a refresher for readers, tell us a bit about the background for this phase III study? What were the key takeaways from the study results?
Dr. Johnson: The CodeBreaK 200 trial was a randomized, phase III trial for patients with previously treated non-small cell lung cancer who harbored KRAS G12C mutations. Patients were randomized one-to-one to receive sotorasib daily or docetaxel intravenously every 3 weeks. The primary endpoint was progression-free survival (PFS). The results were really promising, with significantly improved PFS at 1 year and an objective response rate around 30%. The stats showed sotorasib beat docetaxel hands down.
It is important to know that as the results of CodeBreaK 100 read out and looked so promising, CodeBreaK 200 was already enrolling. The FDA asked that the CodeBreaK 200 trial be shortened so fewer patients would be randomized to docetaxel. The FDA also asked that crossover from docetaxel to sotorasib be allowed. Those key amendments were made halfway through the trial.
The primary endpoint of PFS was met in patients treated with sotorasib; we observed a 34% reduction in risk of progression with oral sotorasib compared to IV docetaxel, which is super exciting. At a year, 25% of patients treated with sotorasib were still progression-free compared to only 10% in the docetaxel arm.
PFS was also positive across all subgroups regardless of where in the world the patients were enrolled, whether they had had CNS involvement, or whether they had received one or two lines of prior therapy. Everybody had improved PFS. Also, the response rates were higher for patients treated with sotorasib compared to docetaxel. Likewise, the disease control rate was higher with sotorasib as was the duration of response.
The one secondary endpoint that was not met was overall survival (OS). It was the one secondary point that lost its initial power. Was it because the trial was cut in half from 600 patients to 300 patients? When we look at PFS and overall survival, we also look at the number of patients who crossed over from docetaxel to sotorasib as a potential explanation for why OS proved negative. In this case, about 34% of patients crossed over, so a large minority. There was also a sizable group—about 12% of patients randomized to docetaxel— who did not join the trial. Presumably, they went on to seek KRAS G12C inhibitors off trial or enrolled in another trial.
I believe it is worth saying that in this comparison, sotorasib was better tolerated. The most common grade 3, treatment-related adverse events were diarrhea and elevated transaminases. With docetaxel, we saw neutropenia, fatigue, febrile neutropenia, and many other toxicities. And sotorasib, of course, is oral, and it doesn’t make you lose your hair. Likely because of all of this, the patient-reported outcomes favored sotorasib as well. As we seek to find therapies where patients are at the core, patient-reported outcomes (PROs) become increasingly important.
In addition, physical functioning and dyspnea improved more quickly with sotorasib compared to docetaxel, and the time to deterioration was slowed with sotorasib versus docetaxel. Often, quality of life and physical functioning slow down or get worse during treatment; that happened less quickly with sotorasib.
So, in totality, sotorasib proved superior to docetaxel, and in the eyes of many, should be the second-line standard of care for previously treated patients with KRAS G12C mutations.
In January the American Society for Clinical Oncology updated its guidance for advanced non-small cell lung cancer (NSCLC) with driver alterations. The update to ASCO’s guideline, published in the Journal of Clinical Oncology, incorporated data from CodeBreaK 100. The guideline now includes monotherapy with sotorasib as an option for previously treated patients with advanced NSCLC and a KRAS G12C mutation.
Sotorasib was the first KRAS G12C inhibitor, but it remains to be seen which will be the best. In my opinion, this is a great step forward, but not the final answer for patients whose tumors harbor KRAS. There are a lot of combination trials in the second line, and I don’t know that there’s a favorite yet. However, there probably is going to be a combination strategy similar to what we have seen in colon cancer, where the KRAS G12C/EGFR combo is twice as good.
ILCN: Did these results meet your expectations? Why or why not?
Dr. Johnson: Well, I have high expectations. I’ll say that after seeing the CodeBreaK 100 data, many of us thought we would see improved overall survival. So the one disappointment in the CodeBreaK 200 data is the lack of an overall survival advantage. However, it’s worth noting that the populations were different. In the phase I, the study population was largely in the US. In CodeBreaK 200, the population was largely enrolled in Europe and Asia. We had minor enrollment in the US because it was already approved, so patients were able to access the agent off trial. Similar things happened with immune therapy as well in the past. The more options that were available, the worse the data in the randomized trials.
So that was the main surprise to me, but the other surprise—and I should not have been surprised by this—was how controversial the data were. There are a lot of trials where we haven’t seen an overall survival advantage. We use those drugs without question. Look at the EGFR inhibitors in the trials versus chemotherapy in the front line setting; there was no overall survival advantage, largely due to crossover. And KRAS mutated NSCLC is a more recalcitrant tumor to treat. This is a mutation for which we have no other options except chemotherapy. So, I expected thoracic oncologists to be a little bit more forgiving.
ILCN: Is a progression-free survival benefit in the absence of an overall survival benefit in the second-line setting in metastatic non-small cell lung cancer sufficient to justify drug approval?
Dr. Johnson: I believe so. It’s a nuanced question, and the data gave us a nuanced answer. There are many ways the patients benefitted with sotorasib compared to docetaxel in this trial. If I’m a patient, during the time I have left, if my quality of life can be better, I’m going to choose sotorasib every day of the week and not lose my hair. While the bar is high, we should be careful not to be short-sighted about the time patients have. It’s not just about survival.
ILCN: Can you comment on studies attempting to export sotorasib to the front-line setting?
Dr. Johnson: That’s a tough one. I think we all thought that is where we were going, that the next trial would be based on that, because, with a median PFS of 5 to 6 months, that puts you in the same ballpark as chemotherapy or immunotherapy. The question is what is the combination partner.
There has been a lot of talk about combining sotorasib with IOs and whether that’s possible. If so, how do you do that? Combining TKIs and IOs have proven challenging in some disease settings. I think the trials that are ongoing in the front line are showing us that the answer may be in separating patients by PD-L1 level. It may be that patients with KRAS G12C mutation (+) and PD-L1 low tumors benefit enough to get sotorasib first. Or it may be that patients with PD-L1 high tumors who get sotorasib in combination with pembrolizumab or another PD-1/PD-L1 inhibitor benefit enough that chemotherapy is not necessary.
I think assessing tolerability and finding an effective partner are the key questions.
ILCN: What are your expectations for sotorasib going forward?
Dr. Johnson: Well, I think the front-line question is the big one. I do believe there’s some question about whether sotorasib can be combined safely and effectively with immunotherapy. If it can be, great. If it can’t be, then it’s relegated to the second line. However, adagrasib is making a strong run in the front line, and it does appear to combine with immunotherapy. So, if the KRYSTAL-7 trial of adagrasib is positive, then I think things go differently, and adagrasib could end up being used in front-line setting.
ILCN: What are your thoughts about adagrasib and other agents in this class?
Dr. Johnson: In the recent past, I think what we’ve learned from the dilemma about the equivalent efficacy of PD-1 and PD-L1 inhibitors is that where it matters the most is the front line setting. When you are treating patients who are newly diagnosed, you know those drugs are pretty similar.
When it comes to targeted therapies like KRAS G12C inhibitors, there is an abundance. Revolution Medicines has a KRAS G12C inhibitor. Genentech has a KRAS G12C inhibitor. Lily has one. There are many others. Maybe, the story will emerge like the PD-1/PD-L1 inhibitors in that you have to have one in the combination, whatever that is, but the actual drug itself doesn’t matter so much.
The challenge is that there are only so many patients with KRAS G12C mutations—about 13% of non-small cell lung cancer. We also know that less than 5% of American cancer patients join clinical trials each year. How can we work together to examine these strategies clinically in a way that doesn’t dilute the patient population, but rather unites them and unites the field? It’s challenging and will require some innovative thinking, but I think it’s vital.