Identifying the Role of Targeted Therapy in KRAS-Mutated NSCLC

Timothy F. Burns, MD, PhD

Associate Professor of Medicine

Department of Medicine

Division of Hematology-Oncology

UPMC Hillman Cancer Center

Pittsburgh, PA

TARGETED ONCOLOGY: What data support the use of the KRAS inhibitors for second-line treatment of non–small cell lung cancer (NSCLC)?

TIMOTHY F. BURNS, MD, PhD: The phase 2 KRYSTAL-1 study [NCT03785249] was looking at adagrasib [Krazati] in KRAS-mutant lung cancer after platinum-based chemotherapy and PD-1/PD-L1 [inhibition]. The primary end point was overall response rate [ORR]. In terms of demographics, it wasn't unusual, with mostly metastatic patients [88.8%].¹ The vast majority of patients had received both chemotherapy and immunotherapy [98.3%]. Adagrasib had an ORR in the study of approximately 42% [48 of 112 patients]. The waterfall plot [showed a high disease control rate]. The progression-free survival [PFS] was 6.5 months, and the overall survival was about 12.6 months.

What types of patients can benefit from adagrasib and sotorasib (Lumakras)?

Essentially, these drugs are good, and they're both [approved] inhibitors in the second-line setting. The response rates that we see with these drugs are not [as high as those of] other targeted therapies, but we do have these data, and they're better than our alternatives at this point [after progression on prior treatment].

These drugs have shown intracranial activity. The [published KRYSTAL-1 data as of October 15, 2021] are not the best data for adagrasib [with brain metastases]; there are better data. For patients who had brain metastases when they entered the trial and were previously treated, 81% had received previous radiation therapy, the majority [59%] received it [within 3 months] before entering the study [for an intracranial objective response rate of 33.3%].¹ So some of the [intracranial] response rate is hard to tell [which is responsible], but there are real data of patients with untreated brain metastases, both with adagrasib and sotorasib, showing a decrease.^2,3 It's not in large numbers, [and so] are hard to interpret. Coming from patients without treated brain metastases, these do seem to be CNS [central nervous system]-active drugs.

I had a patient who was on the Lung-MAP trial [NCT02154490] where they got sotorasib through [the trial]. They took their sotorasib as soon as they progressed. Then a month went by as they're trying to get on trial and now they had new brain metastases. Just like our other targeted therapies, you keep these drugs on until you start a new therapy. Because even if they're not doing enough, [even at] progression they're often doing something. Whether it's on adagrasib or any other targeted therapies, stop it right before you start the new drug. Adagrasib and sotorasib both have some intracranial activity; it's hard to tell exactly how much but there's data for both.

Would you give sotorasib to patients with asymptomatic brain metastases, or would you treat their brain metastases first?

That's an open question at this point. There's a lot of interest in trying to find that out, and there have been a limited [number] of patients who had adagrasib or sotorasib who have responded. If it's a small brain metastasis, less than 1 cm, and the patient doesn't have a lot of edema, I think it's reasonable as long as you're going to get an MRI in 2 months. Sometimes you'll radiate the larger lesion and then leave the smaller one. Both of these drugs have evidence of having CNS activity. If it's a large metastasis, there are [physicians who treat] patients with EGFR mutations [with brain metastases of up to] 4 cm, and they'll start osimertinib [Tagrisso]. I'd be a little scared to do that even with osimertinib, but for smaller brain metastases, it's something to consider, as long as you're going to get the drug in a reasonable amount of time.

Is there any evidence that radiation therapy makes the response to these drugs better?

You can't tell because they're going to respond to the radiation. That’s why I don’t like [the intracranial response data, which were initially presented] as much because some of those responses may be from the radiation therapy. But there are real data of untreated brain metastases that have responded to both adagrasib and sotorasib in small numbers.^2,3

Are there any data to continue giving sotorasib in addition to the next line of therapy as is sometimes done with osimertinib?

I think that is potentially a reasonable thing to do off label. Both adagrasib and sotorasib are being looked at in combinations with chemotherapy and we can probably [use them]. A lot of our targeted therapies sometimes…are able to be combined with chemotherapy. It’s not an unreasonable thing to do, and sometimes when we can't get a patient on a trial, [or] we don't have a better therapy, it's not unreasonable. I've done that a lot for osimertinib…and others, so that is an option, but it is off label.

How do adagrasib and sotorasib compare in terms of toxicity?

Adagrasib is interesting in that in phase 1 data that they pushed their dose. It shows because they have [a group of adverse events] classified as gastrointestinal toxicity.⁴ If you look at the grades with adagrasib, you can see that too with sotorasib, we found patients who couldn't tolerate the diarrhea, [but with adagrasib], nausea and vomiting are much higher, and liver enzymes are also pretty high.^4,5 Adagrasib is a pretty effective drug, but there is some toxicity with it.

They are doing a phase 3 trial [KRYSTAL-12 (NCT04685135)] as has been done for sotorasib [in the CodeBreak 200 trial (NCT04303780)]. They're trying to [compare adagrasib with] docetaxel.

_References:

_{1. Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non-small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619}

_{2. Negrao MV, Spira AI, Heist RS, et al. Intracranial efficacy of adagrasib in patients from the KRYSTAL-1 trial with KRASG12C–mutated non–small-cell lung cancer who have untreated CNS metastases. J Clin Oncol. Published online June 16, 2023. doi:10.1200/JCO.23.00046}

_{3. Lamberti G, Aizer A, Ricciuti B, et al. Incidence of brain metastases and preliminary evidence of intracranial activity with sotorasib in patients with KRASG12C-mutant non-small-cell lung cancer. JCO Precis Oncol. 2023;7:e2200621. doi:10.1200/PO.22.00621}

_{4. Krazati. Prescribing information. Mirati; 2022. Accessed September 26, 2023. https://bit.ly/3NbtOZT}

_{5. Lumakras. Prescribing information. Amgen; 2021. Accessed September 26, 2023. https://bit.ly/41FnGgR}