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Spotlight

This roundtable series provides context on the growing number of options for patients with non–small cell lung cancer and 

 G12C mutations, as discussed by key opinion leaders and participants at virtual live events.

Targeted Therapy Options for Patients With KRAS-Mutated NSCLC

A 63-year-old woman presented with dyspnea on exertion, fatigue, anorexia and a 5-lb weight loss​. She had prior medically controlled diabetes mellitus and takes an over-the-counter gastric acid reducing agent pyrrolnitrin for a “sensitive” stomach​. She is a former smoker who quit 13 years prior, with 30 pack years. ​She appeared thin on physical examination. Laboratory results were within normal limits.

A chest x-ray showed 2 right lower lobe masses, and a chest/abdomen/pelvic CT scan confirmed 2 masses (4.7 cm and 7.4 cm) in right lower lobe of lung and 2 liver lesions​. PET scan showed activity in the right lower lobe and liver masses, and a brain MRI was negative. ​Bronchoscopy with transbronchial biopsy of the right lower lobe confirmed lung adenocarcinoma; her PD-L1 expression was less than 1%​. The disease staging was IVB adenocarcinoma; ECOG performance status was 1.

Tumor next-generation sequencing showed she was negative for 

but was positive for a KRAS G12C mutation. PD-L1 expression was 20% by SP263 assay​.

She received carboplatin and pemetrexed (Alimta) plus pembrolizumab (Keytruda), achieved a partial response at completion of 4 cycles of chemotherapy, and continued on pembrolizumab maintenance.

Fourteen months later, while on pembrolizumab, the patient is reporting worsening back pain and shortness of breath. A CT scan shows progression in primary tumor and a new adrenal metastasis. Repeat MRI of the brain was negative​.

 mutation status was unknown at the time of progression on/after first-line therapy, would you retest? ​

Can you think of any scenarios where you would make a second-line treatment decision without knowing the status of all of the actionable molecular biomarkers?​

 mutation status was unknown at the time that they progressed, and she has progression on the KEYNOTE-189 [NCT02578680] regimen, would you retest? Who would retest looking for an alteration? How many of you would try to rebiopsy? She has progression in the primary [tumor] and in the adrenal gland. How many of you would use ctDNA [circulating tumor DNA]?

Can you think of any situation where you would make a decision about second-line treatment without testing? When you don’t have biomarker results, nothing came back at diagnosis, nothing came back from ctDNA. You retest for ctDNA, nothing comes back. Would you keep trying or would you just treat and why?

 [I would] just treat them. I’d say if the mutation is not detected, how many times are we going to keep testing?

 If you don’t get it off of ctDNA, you give them second-line therapy of docetaxel/ramucirumab [Cyramza], and they progress again, would you test again?

 I don’t know if insurance will allow us to keep testing these things.

 Typically they do, but you have to show that they progressed on treatment and that they did not receive [optimal therapy].

 Is the site of progression readily amenable to a safe biopsy? And was it progressive disease or it was responsive disease followed by progression? If the patient responded for 4 months and then progressed, it would be natural history for a second-line treatment. I would not biopsy again unless this is a readily biopsiable adrenal mass.

 I would agree with Dr Rajan. In practice, patients are very hesitant about repeated biopsies unless it makes a huge impact on the treatment decision. But yes, if clinically the patient is within the expected median progression time, I would treat. I’m not aware of the benefit of subsequent repeated testing.

 I usually insist more about testing if I think the patient has a mutation that I might be missing, like an 

 mutation if the clinical picture is suggestive of that, because you can easily miss 

. With repeated testing you increase the chances that you’re going to get positive results. I had a patient who tested 

 negative, but the history was very typical for 

 positive. When I tested him again, using a different technique, it came back positive. That’s probably the only scenario I would insist on a rebiopsy.

 What would you do, [Dr Tsao]? When people progress and if money is not an issue, everybody should probably get some [kind of] biopsy. But if money is an issue, do physicians at your center do molecular testing every time they change the therapy when patients progress?

 I will only do it in patients whom I suspect have an oncogenic driver mutation. If they have an adenocarcinoma, are a never-smoker, [and/or] a young patient in their 50s or 60s, I will always keep hunting for an alteration until I find it. In the patients who are older, heavy smokers, they have other mutations that come up: 

, random [non-driver] mutations. The odds are they don’t have an oncogenic driver mutation. Those I might do ctDNA for patient convenience.

 So do you retest them when you change therapy?

 Only if I haven’t discovered it and I think that they have an oncogenic driver alteration, and again usually that’s going to be in adenocarcinomas. If it’s a squamous cell carcinoma, large cell carcinoma, or an adenocarcinoma in someone who’s a heavy smoker that has a ton of alterations that are not actionable, those are not ones that I retest. I definitely don’t biopsy them. I might run a ctDNA just for interest to the natural progression of their alterations but that’s rare. In clinical practice I don’t use that information, but if they’re a never-smoker in their 50s or 60s and I never get a single mutation, not even a 

, I’ll keep hunting for those patients.

During a Targeted Oncology™ Case-Based Roundtable™ event, Anne S. Tsao discussed with participants 

Physicians Discuss Rebiopsy Options Before Second-Line NSCLC Therapy

Shirish M. Gadgeel, MD, MBBS, division head for hematology/oncology and associate director for patient experience and clinical care at Henry Ford Health, discusses the results of the KRYSTAL-1 trial (NCT03785249) trial of adagrasib (MRTX849) in patients with 

-positive non–small cell lung cancer (NSCLC).

 G12C, like the approved agent sotorasib (Lumakras), Gadgeel says. In a phase 2 registrational cohort of the trial, 116 patients with NSCLC and confirmed 

 G12C mutations were enrolled to receive adagrasib, 98.3% of whom had previously received chemotherapy and immunotherapy. The primary end point was objective response rate (ORR) assessed by blinded independent central review. Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival, and safety.

At median follow-up of 12.9 months, 48 of 112 evaluable patients had a confirmed response (42.9%). The median DOR was 8.5 months (95% CI, 6.2-13.8) and the median PFS was 6.5 months (95% CI, 4.7-8.4). It also had central nervous system (CNS) penetration, with an intracranial confirmed ORR of 33.3% (95% CI, 18.0-51.8) in 33 patients with treated stable brain metastases.

Adagrasib did show toxicities including nausea and vomiting; however, Gadgeel says it appeared better tolerated after a dose reduction from 600 mg twice daily to 400 mg twice daily, with only 7% of patients discontinuing treatment due to toxicity. The FDA is expected to announce its decision on granting accelerated approval to adagrasib by December 14, 2022.

Adagrasib is also a G12C-specific direct inhibitor similar to sotorasib. In preclinical trials, it showed a long half-life, [meaning] sustained inhibition of 

 G12C, and did show CNS penetration in preclinical models. Updated results from KRYSTAL-1, the phase 1 trial of the drug, were presented by Dr Alex Spira at ASCO [the American Society of Clinical Oncology Annual Meeting] this year. [These were] data on 116 patients. Baseline characteristics were similar to what one would expect in this population with a median age of 64. Almost all patients were current or former smokers, and over 95% of patients had adenocarcinoma histology. Ninety-eight percent of the patients had received both chemotherapy and [an] immune checkpoint inhibitor. And in this study, the drug demonstrated an ORR of 43% with a median PFS of 6.5 months and a median DOR of 8.5 months.

The drug did have some toxicities, in particularly in terms of nausea [and] vomiting. The recommended phase 2 dose based on the phase 1 study [was] 600 mg [twice daily]. But it is important to note that 50% of the patients did require a dose reduction to 400 mg [twice daily], the next-lower dose. And with that dose adjustment, only 7% of the patients discontinued the drug because of toxicity.

Shirish M. Gadgeel, MD, MBBS, discusses the results of the KRYSTAL-1 trial  trial of adagrasib in patients with KRAS-positive non–small cell lung cancer.