Physicians Compare Platinum Rechallenge With Other Second-Line Options in ES-SCLC

Jason Porter, MD (MODERATOR)

Director, Lung Cancer Disease Research Group

West Cancer Center and Research Institute

Memphis, TN

CASE SUMMARY

A 58-year-old moderately active man presented with worsening shortness of breath, persistent dry cough, and fatigue. He was a smoker with a 30 pack-year history. His ECOG performance status was 1.

A chest x-ray showed opacity in the left lung, and a chest CT showed a hilar mass, with invasion of the left pulmonary artery and 3 contralateral lung nodules present. A brain MRI was negative. Bronchoscopy with transbronchial biopsy/pathology confirmed a diagnosis of extensive-stage small cell lung cancer (ES-SCLC).

He received 4 cycles of carboplatin and etoposide plus atezolizumab (Tecentriq), and he initially achieved a partial response.

DISCUSSION QUESTION

• What is your plan after 4 cycles of carboplatin plus etoposide for a patient like this?

EVENT REGION California, Nevada, and Arizona

PARTICIPANT LIST Marnin A. Merrick, MD | Goetz Kloecker, MD | Michel Bidros, MD | Wail Alnas, MD | Carl Tahn, MD | Mohamad Khasawneh, MD | Sohail Minhas, MD | David Chism, MD

PORTER: For most of these patients, if they are responding, we are going to continue to maintenance. I have a clinical trial [IMforte; NCT05091567] that is offering maintenance therapy with lurbinectedin [Zepzelca]. They get chemotherapy maintenance on top of the immune checkpoint inhibitor [ICI] maintenance. We are going to see if that maintenance chemotherapy is going to improve their outcomes.

CASE UPDATE

Seven months after the patient’s last cycle of platinum chemotherapy, shortness of breath returned, with right upper quadrant pain and midback pain. A CT scan of the chest, abdomen, and pelvis showed recurrence of the left upper lobe mass. He was still negative for brain metastases, and laboratory results were within normal limits, with no change in ECOG performance status.

DISCUSSION QUESTION

• How do we define platinum-sensitive vs platinum-resistant SCLC?

MERRICK: [I define it based on a disease-free interval (DFI) of] 6 months.

PORTER: Does anybody use a 90-day cutoff?

KLOECKER: That’s a big discrepancy. Europeans use 6 months, and Americans use 90 days.

BIDROS: I use 6 months only if the patient received 4 cycles. If the patient received 6 cycles, I would feel very hesitant to recycle the chemotherapy.

DISCUSSION QUESTION

• What are some recommended second-line regimens for ES-SCLC?

PORTER: The NCCN [National Comprehensive Cancer Network] guidelines recommend subsequent therapies for SCLC. Back in 1996, topotecan [Hycamtin] was approved for patients with platinum-sensitive disease who progressed at least 60 days after first-line therapy. In June 2020, lurbinectedin got accelerated approval for adults with metastatic SCLC with disease progression on or after a platinum-based regimen. The preferred NCCN regimen is a platinum doublet rechallenge with original or similar regimen if the DFI was 6 months or greater.1

I’ve used lurbinectedin even in patients after 6 months or more of treatment. It is not the same thing to say chemotherapy-free interval (CTFI) vs platinum-free interval. Sometimes, if I want a platinum-free interval and I am at 6 or 7 months, I may go on to lurbinectedin and then come back to platinum after whatever benefit I’m going to get from lurbinectedin because I may not have increased their CTFI, but I have increased their platinum-free interval. If they are still doing well, I will come back and rechallenge with the platinum in a third round. It’s clearly not standard, but it is what I do for a lot of my patients.

DISCUSSION QUESTIONS

• In your experience, what are the outcomes for your patients who got platinum rechallenge if they had a CTFI of at least 6 months?
• What factors would influence you to use or not use each therapeutic option as second-line therapy? Platinum-free interval?
  • Tolerance to prior therapy?
  • Performance status/frailty?
  • Comorbidities?

ALNAS: Tolerance is a major issue. It is always much more difficult the second time around.

TAHN: I’m not a fan of rechallenging. There must be a good reason. I would have to have a wonderful response for more than 6 months because you worry about the same issues as before, like renal toxicities, neuropathy, neural toxicities, and so forth. I tend to favor going to a second-line agent rather than rechallenging.

KHASAWNEH: I agree with my colleagues. Toxicities seem to be cumulative. Tolerance would be much less with second-line platinum doublets, especially with the availability of lurbinectedin for the last 2.5 to 3 years for SCLC. I just moved to lurbinectedin.

MINHAS: When you rechallenge with platinum, would you add immunotherapy?

PORTER: It depends on if the patient was on immunotherapy and stable until that progression, and we got to 7 to 8 months. I will often try to continue immunotherapy. But sometimes the payers won’t allow you to continue. In that case, I discontinue immunotherapy and just initiate the platinum. But, wherever I can, I try to leave my ICI in place. I feel like the disease is heterogeneous and some of it may be responding to ICI therapy, whereas some of it is only going to respond to chemotherapy. By withdrawing that immune surveillance, you may cause that disease [to progress] even while your platinum-sensitive disease goes back down. So if I can continue immunotherapy, I will, but sometimes the payers won’t let me.

ALNAS: Not sometimes. [In my experience], all the time they won’t let you.

PORTER: Sometimes I can get a peer-to-peer discussion, and I can justify it and keep it going. That’s not in a lot of patients because often that disease is either going to [have progressed in] less than 6 months, or in the ones who get out that far, they are going to do well anyway. [I don’t have to] make that argument [ for a whole lot of patients]. But there have been cases in the past. Obviously, frailty and comorbidities affect our ability to even give these therapies in the second line or at the time of progression. That platinum-free interval that I talked about does speak to me and some of my patients, especially in my younger patients where I am not worried about comorbidities and frailties. I have one patient who worked straight through 2 separate platinum doublet rounds, about 13 months apart. Sometimes they can tolerate it, and it’s worth it, but having options like lurbinectedin, as was pointed out, are very important.

DISCUSSION QUESTIONS

• If you have used lurbinectedin, what types of patients did you use it for?
• How do you consider it for patients who are platinum sensitive?

PORTER: Does anyone have any reactions to the lurbinectedin data, whether you were using 90 or 180 days of a CTFI and platinum rechallenge?

KHASAWNEH: I use it regardless of the platinum interval. I use it as second-line therapy to avoid the use of topotecan, which is a tough drug to manage, especially its cytopenia adverse effects [AEs]. It is a stagnant field in SCLC. Lurbinectedin filled a big gap in the care of those patients. I no longer take platinum sensitivity into account. I just moved to lurbinectedin as second-line therapy. My experience as far as adverse reactions is very low grade 3 to 4 AEs. [There is] some fatigue, some GI [gastrointestinal] effects, and some myelosuppression. But other than that, it is a well-tolerated drug. It is convenient at a once-every- 3-weeks dosing. Unfortunately, almost all of these patients ultimately will succumb to [the] disease.

ALNAS: It is a well-tolerated drug, but it has limited activity. But it is easier than topotecan. Now there is a drug [trilaciclib (Cosela)] we can add to topotecan to help with neutropenia, so I wonder if that makes a difference too.

PORTER: I’ve even convinced myself in those patients who are 6 months out that I am going to look more at lurbinectedin as opposed to the platinum rechallenge. I was already doing that with some patients, and then saving that for later and coming back in the third line and doing a platinum rechallenge. It is something I would think about.

DISCUSSION QUESTIONS

• Would your approach for the next lines of therapy differ if this patient had brain metastasis?
• What is your approach to follow-up for patients on the second line or later lines of therapy?

PORTER: If I am able, I will get a platinum rechallenge for a patient with brain metastasis. What are you all doing for your patients with brain metastasis? Does it change what you do in the second line? What do you do beyond lurbinectedin in the second line? Are your patients still able to tolerate treatment? Do you just tell them you don’t have anything else—go to hospice? Do you go on to single-agent chemotherapy?

TAHN: I go to single-agent chemotherapy. Either a taxane or one of the others.

PORTER: For a few of my patients with cytopenia or other chemotherapy AEs, I’ve even used a carboplatin/paclitaxel combination as my platinum rechallenge in the third line. If they get in trouble [with AEs, this is] one approach I’ve used beyond the second line.

ALNAS: Irinotecan [Camptosar] is good with brain metastasis, right? I don’t use it too much.

TAHN: Yes. I have used irinotecan.

PORTER: Yes, but then we run into that same diarrhea scenario.

PORTER: I try to get patients to 3 lines of therapy, but sometimes we don’t. Some patients go on to hospice after a couple of lines. But for young, robust patients in their 50s who can tolerate another line, I try to keep pushing them to go for clinical trials. There are not a lot [of trials] going on, but we do look for them.

DISCUSSION QUESTIONS

• In the small proportion of patients who do receive a third line, how do you view the following sequence options:
  • A second-line mechanism-of-action switch followed by a third-line platinum rechallenge?
  • A second-line platinum rechallenge followed by a third-line mechanism-of-action switch?

PORTER: Does anybody favor one of these vs the other? Most of us would use lurbinectedin. But I don’t think many patients do the platinum rechallenge at the third line. I would feel guilty if I pushed them to try. Does anyone feel strongly about one of these vs the other?

KLOECKER: You can’t generalize. You must judge case by case.

PORTER: Yes, you judge case by case.

DISCUSSION QUESTIONS

• What do you view as the most critical unmet needs for these patients?
• Which emerging data or ongoing studies in ES-SCLC are you most interested in?

CHISM: I think we need to know how to treat brain metastasis and get more understanding on which treatments have the best outcomes. Also [we need to understand] chemotherapies and potential biomarkers [and] understand these treatments and the inflammatory responses to immunotherapy. Separating patients who may benefit from other drugs earlier on might be key to the second line, teasing out who are more likely to react to which type of treatments.

PORTER: The biomarkers are [the unmet need] for me. That would be a huge experience in SCLC, as well as squamous cell carcinoma, because we just don’t have enough. There has been a lot of work done in adenocarcinoma. Sequencing patients with SCLC, I have reason to look for trends, things besides TP53 and RB mutations, and to try to identify some biomarkers.

_REFERENCE

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 3.2023. Accessed June 12, 2023. https://tinyurl.com/9tvae44j}