Roundtable Discussion: Konduri Looks at Testing and Treatment Options for Patients With RET- and ROS1-Positive Lung Cancer

Kartik Konduri, MD

During a Targeted Oncology^TM Case-Based Roundtable event, Kartik Konduri, MD, hematologist/medical oncologist, Texas Oncology-Baylor Charles A. Sammons Cancer Center, discussed the case of a 59-year-old patient with stage IVA adenocarcinoma of the lung.

MAZHARUDDIN: [Protocol at my hospital is to] order a whole next-generation sequencing (NGS)] panel on every patient with metastatic lung pattern carcinoma. Is PD-L1 reflex? Yes, absolutely. Various testing? Yes again.

Honestly, I’ve run into a lot of insufficient tissue quality, so I’ve been sending for concurrent liquid NGS as well.

KONDURI: Will you do all blood and tissue tests at the same time?

MOSCOL: I do order both tests at the same time, but if I get enough viable sample in tissue, then I can just cancel [the blood test]. Otherwise, I would say about 20% of patients have either necrosis or not enough cells to run the solid part, and that is kind of challenging. So I prefer to run both at the same time.

KOVOOR: I’ve been having issues where I order both, and insurance won’t approve [the tests].

What I’ve been doing is if it’s an FNA [fine-needle aspirate], and that’s my only source, I just do liquid biopsy because I haven’t been having much success with getting a full panel sequence. Baylor [Genetics] has that one sequence that takes 3 or 4 weeks to come back, but I’ve been doing Caris [Life Sciences] when I can now [because] it takes 2 or 3 weeks to get back.

KONDURI: It takes a long...time for some of these tests to come back. Sometimes the blood tests come back a little faster, but there are a lot of colleagues that I’ve talked to that want to do both at the same time. Many people do it together just to get quick readouts, potentially picking up an actionable mutation if one is missing on one side or the other. If you have a bone-based biopsy or if you have a tissue, which is an FNA, it’s somewhat difficult to get NGS, let alone a PD-L1 panel.

So what about PD-L1? Do you do PD-L1 standard reflex, where everybody gets it?

SOLANKI: In the days when we didn’t have NGS, we used to prioritize the most common ones first and then follow up with putting everything together, and that is what is taking up a lot of time.

For example, if [you] get an EGFR and ALK first, and perhaps ROS1, you’ve covered almost 30% of the mutations you’re likely to find in an appropriate patient who is [a] young, nonsmoker, and so on. I’m not always as excited about this NGS and a 2-page panel that comes back because it takes a lot of time. I don’t think they prioritize this because they have to do everything together, I suppose.

REDDY: If it is the bronchoscopy, are you going to get only PD-L1 on that and get everything else on the liquid biopsy? On the pleural effusion on the cytology those couple of times [I sent it], they said they could not do PD-L1, at least the company we sent [the samples to].

That is the only thing I wanted on the pleural effusion cytology. Is it true that you cannot get a PD-L1 at all on the malignant cells?

KONDURI: I’m not aware. The only place that I’m aware it interferes in is...bone decalcified tissue [because] the decalcification process affects it. I have had PD-L1 results come back on pleural cytology. The only caveat is if you don’t have adequate cellularity, then you may not pick up the results. But otherwise, it’s not been an issue for me.

KONDURI: The question is: How do we do a biopsy that easily helps? And this is always a problem because in lung cancer, it’s not always easy to get the type of tissue [and] the amount of tissue you want—especially if you’re doing an endobronchial ultrasound–guided FNA. It becomes a little bit of an issue. So are you all doing peripheral blood at the same time?

ARJUNAN: I tend to do both at the same time. Just because bringing people back and forth just to talk about, “Oh, we got this test, but this was insufficient”—wasting time visit after visit—becomes kind of burdensome.

One of the things I’ve done is up front when talking to the proceduralist is just to make sure that you get sufficient tissue [and that you talk] to them about performing core biopsy over FNA. Also, [regarding] sending off sufficient fluid, often [you realize] they’re only thinking of sending off about 20 mL of fluid for the cytology for a pleural effusion, so that could be the problem.

KONDURI: Have you been helped by doing blood and saying, “Oh, you know what, I’m glad I did it because tissue didn’t give me an answer”?

ARJUNAN: Yes, that’s happened several times but especially with necrotic tumors or when I’ve biopsied a bone lesion; that’s been the circumstances I’ve typically run into with that.

NGUYEN: I tend to do liquid biopsy when I don’t have enough tissue [to biopsy or when I have experienced a delay as a] result of tissue biopsy.

KONDURI: Do you do it sequentially, or do you do it together?

NGUYEN: I would do it sequentially. If I don’t have a complete answer from tissue biopsy or if I don’t have enough tissue, then I would go to the liquid biopsy.

SAEZ: In the case that you presented, the main goal is to avoid chemotherapy in a patient that doesn’t need it. So I think that is the main reason why I do both tests at the same time. I want to know as soon as I can whether that patient has the targetable mutation that I can treat and avoid chemotherapy up front.

Certainly, you have to do the tissue for the PD-L1. I had a recent case where I did blood and it was negative, and the tissue showed an EGFR mutation. Once in a while, you get the opposite. So it’s a good idea to do them both.

KONDURI: Fair enough. The only thing that I would add... is nowadays we have such effective treatments for some of these rarer mutations...even though, you’re right, [some of] those mutations or gene rearrangements [are rarer] in comparison to EGFR and ALK and even ROS1 if you take those into consideration. Suppose by chance you pick up an NTRK or something like that. You have a chance [at] long-term control in terms of these circumstances where you can potentially use a PD-L1, and that’s the major benefit.

The question becomes: What is comprehensive NGS? Do you need 100 or 350 gene panels? I mean if you are doing the research, biorepository...probably...has become a norm to consider doing—at least [for] all those genes where we are acting. And in the past, we didn’t have good treatment options, and now we do.

SAEZ: What is adding time that it takes 3 weeks now?

KONDURI: In my experience, it’s maybe around 2 weeks and likely over 2 weeks. The sequencing platform takes time, and it takes time to get the DNA extracted and run it through.

Now if you are doing a multiplex PCR [polymerase chain reaction], it’s obviously faster, but a comprehensive DNA analysis, where you are going through the exome sequencing, takes time.

That’s part of what the problem is. For example, if you do a particular fusion or if you miss a particular mutation, that’s one of the biggest problems with multiplex PCR because it’s just technically looking and hitting 1 or 2 areas, right?

There are people who will do focused sequencing—like only some amplicons and some areas are being evaluated and sequenced—and that can be a consideration. But what has been seen is, especially like things in NTRK and all that, if you don’t go through that properly, you might miss some of the circumstances.

Now, admittedly you’re right. Most of them will be all these, and our turnaround used to be a little faster, even when the technology was a little primitive.

So [in] nonsquamous non–small cell lung cancer [NSCLC], there’s not a whole lot of debate here [for testing]. As I was talking about, all these should be considered as a part of our testing panel: [EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, KRAS, and PD-L1 testing].

This is what the National Comprehensive Cancer Network [NCCN] recommends at this time—all those mutations and gene arrangements that you know of.1 KRAS was recently added because of an actionable therapeutic target–based treatment that we now have available.

KOVOOR: I have. [The patient] was a nonsmoker, had just over 20 lesions in the lung, and [it] was right when a winter storm hit when they sent off for sequencing. [It] came back with RET-positive disease. I put him on, I think, maybe the once-a-day dosing treatment.

He did very well, and within 1 week, his cough went away. His follow-up CAT scan showed [the] lesions are still there, but they decreased in number and [size]. He’s going on vacation and doing all that stuff now.

KONDURI: What about intercranial disease? Do you know?

KOVOOR: He didn’t have any intercranial disease.

KONDURI: [Brain metastasis is] not a common malignancy seen by a lot of people. So I wanted to know if other people have seen cases in therapy, even if you have not treated them but have observed those cases passing through. Have you seen a lot of brain metastases in circumstances like this?

CHALLAGALLA: Yes, but in general, for asymptomatic patients, I do not routinely do MRIs. However, in patients who have actionable targets, I’ve seen a lot of them have asymptomatic brain metastases. In those patients, I do not use any radiation or anything, and they respond well with any of the targetable agents that we use. So, if a patient presents with symptoms, like someone shows up the in [emergency department] with seizures or a brain bleed, and that’s when we see them, then yes, while we wait for all of our testing to come back, if they’re symptomatic I have used stereotactic body radiotherapy [SBRT] if there are less than 4 or 5 brain metastases.

KONDURI: What about the circumstance for patients who do not have an activating mutation? Did I hear you say that you don’t necessarily check an MRI of the brain for a baseline for all of them?

CHALLAGALLA: No, unless they have headache. In those folks with widespread metastatic disease in every organ, I generally tend to do a brain MRI. But in asymptomatic patients, I’m not doing a brain MRI routinely.

MOSCOL: Even if I was screening and the patient has metastases, I wouldn’t offer treatment unless they’re symptomatic. Usually, they’re small and they have a very high rate of intercranial response—we’re talking 95%, 80%, 85%. So most likely I would rather just allow the systemic therapy to begin and control the disease. I would still treat symptomatic lesions but not small lesions that are widely distributed in the brain.

TIJANI: For all patients with stage IV lung cancer as part of baseline, I think we need to get MRIs of the brain with or without contrast, whether they are symptomatic or not because the incidence of nonsymptomatic disease is high— and in small cell [it’s] almost 80%.

So because of that, I think it’s also recommended by NCCN and all the organizations that as part of staging for lung cancer, everybody for stage IV should have a baseline MRI of the brain.1 If you cannot get an MRI, then a CT with contrast.

CHU LUU: I think for me personally, if there was a patient who had [an] asymptomatic brain metastasis that was—a random number here—2.53 cm, I think I would set them up for SBRT or at least an SBRT evaluation to see what radiation-oncology thinks. But obviously limited data, but, you know, not a perfect response within the CNS.2-4

KONDURI: At least that is a 50% response; it’s not 100%,2-4 and there are some CNS CRs [central nervous system complete responses] in those patients. So pralsetinib [Gavreto] does have intercranial efficacy and activity. Circumstances are going to dictate our anatomical circumstances as well as clinical circumstances as to what you want to consider doing and whether you need to add SBRT in this situation or not. Sometimes these lesions are peppered all over the place, and SBRT is no longer a feasible consideration.

Any other thoughts or comments about the trial?

CHALLAGALLA: I think for the interstitial lung disease [ILD], cessation of the drug kind of resolved it. Or steroids or empiric steroids just because, you know, dose reductions or reinitiations or no reinitiations?2

KONDURI: So there is an academic guidance for these kinds of scenarios where generally you have an ILD scenario like this.1,4 Reinstitution of these drugs is very difficult now. I don’t know the specifics about how they resolved, but many of these patients I’m sure were on steroids.

NGUYEN: There’s a high percentage of patients who have elevated transaminases. So what do you do? Do you adjust the dose?

KONDURI: All these drugs will have a guidance document in the package insert as to how you grade the adverse events based on how high the numbers are or how low the numbers are, depending on what you’re looking at.5 And depending on that situation, you either hold it and then you can resume at a lower dose level, or if it is extremely off and you cannot bring it back down to a certain point... you have to hold it and then discontinue it completely.

SAEZ: I think I’d pick the selpercatinib because it had fewer [adverse] effects.6 I also think the dose reduction wasn’t as high a percentage as it was in the other drug. So I just picked it more for safety component.

NGUYEN: I agree. For this trial there’s 42% of drug interruptions and 31% of dose reductions.7,8

And my other question is for the prolonged QT. What do you normally do? Do you use the baseline [electrocardiogram (ECG)] before you treat these patients? And repeat the [ECG] every cycle?

KONDURI: No, from what I remember...it is primarily to be evaluated for risk factor considerations—if you see something of concern—and you are supposed to do an [ECG] and then follow it up in a serial basis, especially for patients who have increased propensity.

Now sometimes CYP3A4 drugs and all that will have drug interactions and will boost the number and increase the risks. So those [are] things to [keep] in mind. Patients who have family history risks, electrolyte risks, cardiac abnormalities, or prior issues of QT, you need to be worried about that. And so, therefore, those [are] patients who you need to try to reevaluate.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 7.2021. Accessed November 1, 2021. https://bit.ly/3qQ035C}

_{2. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515}

_{3. FDA approves pralsetinib for lung cancer with RET gene fusions. FDA. Updated September 8, 2020. Accessed May 20, 2021. https://bit.ly/3nm0C1I}

_{4. Gavreto. Prescribing information. Genentech; 2021. Accessed November 1, 2021. https://bit.ly/3FAeWgG}

_{5. Drugsa@FDA: FDA-approved drugs. FDA. Accessed November 1, 2021. https://bit.ly/3nA1xz0}

_{6. Goto K, Oxnard GR, Tan, DSW, et al. Selpercatinib (LOXO-292) in patients with RET fusion-positive non-small cell lung cancer. J Clin Oncol. 2020;38(suppl 15):3584. doi:10.1200/JCO.2020.38.15_suppl.3584}

_{7. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653}

_{8. Retevmo. Prescribing information. Eli Lilly and Company; 2021. Accessed November 1, 2021. https://bit.ly/3kRZioX}