Physicians Discuss Rebiopsy Options Before Second-Line NSCLC Therapy

Anne S. Tsao, MD (Moderator)

Professor and Thoracic Section Chief

Department of Thoracic/Head and Neck Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

CASE SUMMARY

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 ALK, EGFR, ROS1, BRAF, NTRK, MET, RET, 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​.

DISCUSSION QUESTIONS

• If this patient’s KRAS 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?​

ANNE TSAO, MD: If this patient’s KRAS 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?

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

TSAO: 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?

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

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

SANDEEP RAJAN, MD: 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.

MOHAMAD KHASAWNEH, MD: 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.

ZUHAIR GHANEM, MD: I usually insist more about testing if I think the patient has a mutation that I might be missing, like an ALK mutation if the clinical picture is suggestive of that, because you can easily miss ALK. With repeated testing you increase the chances that you’re going to get positive results. I had a patient who tested ALK negative, but the history was very typical for ALK 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.

G. GARY TIAN, MD: 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?

TSAO: 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: TP53, random [non-driver] mutations. The odds are they don’t have an oncogenic driver mutation. Those I might do ctDNA for patient convenience.

TIAN: So do you retest them when you change therapy?

TSAO: 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 TP53, I’ll keep hunting for those patients.