Jared Weiss, MD

 We have an unmet need. What are the future directions that we can consider, and what advice can I offer for community oncologists treating extensive-stage small cell lung cancer? This is a bit of a tough question, because the greatest unmet need is that our treatments don’t last and they’re toxic. After a long time without improvements in survival, we have had legitimate gains in recent years. The addition of PD-L1 inhibition to chemotherapy improves survival of it. Trilaciclib decreases the toxicity of standard-of-care chemotherapy: carboplatin-etoposide; carboplatin, etoposide, and atezolizumab; or topotecan. It’s an unmet need to study it together with lurbinectedin. Lurbinectedin adds to our treatment armamentarium. In the combination comparative study it may not have improved survival, but I hope we can improve total patient outcomes by having an additional active drug in our armamentarium.

Frankly, community oncologists know how to care for extensive-stage small cell lung cancer. They’ve already integrated PD-L1 inhibition into their care, and they’re actively integrating trilaciclib. I don’t believe that community oncologists are the gap. The gap, or the unmet need, really falls on those of us in research. Where are we? TCGA [The Cancer Genome Atlas] transcription subtyping has shown us the diverse biology of small cell lung cancer, and I’m hopeful that it may ultimately lead to differential treatments. SLFN11 may prove to be our first biomarker. Multiple preserved neoantigens are being studied for BiTE [bispecific T-cell engager] and cellular therapeutics, most prominently DLL3 and GD2.

If I had to add 1 piece of advice for my community colleagues, it might be to consider trials for their patients. Small cell is a rough disease, and standard treatments don’t offer as much as we’d like for our patients. The limitations of our current standard therapies should lower the bar for offering trials to every patient. Thank you for your kind attention.

Case: A 64-Year-Old Woman with Small-Cell Lung Cancer

A 64-year-old woman presented with a persistent cough, chest discomfort, fatigue and unintended weight loss

PMH: osteoporosis, hysterectomy at age 60, prediabetic managed with diet and exercise

SH: 45-pack year smoking history; drinks alcohol 1-2/month socially

PE: Decreased breath sounds in left lung, wheezing on auscultation, axillary lymph node enlargement

Labs: serum Na 132 mEq/L; ALT 54 IU/L; AST 58 IU/L; all others WNL

Axillary lymph node biopsy revealed small cell carcinoma

Chest/abdomen/pelvic CT showed a 7.2 cm mass above the diaphragm, a small contralateral lung nodule and evidence of invasion into the left side of the pericardium

PET scan showed activity in the left lung above the diaphragm, mediastinum and small hypermetabolic activity in the surrounding area

Contrast‐enhanced MRI of the head was negative for brain metastases

Stage IV small-cell lung cancer; ECOG PS 0



Initiated carboplatin + etoposide + atezolizumab for 4 cycles; followed with atezolizumab as maintenance therapy

7 months after starting treatment she complained of fatigue, shortness of breath, right upper quadrant pain and back pain

CT scan showed hematogenous metastases in the liver

Initiated lurbinectedin 3.2 mg/m2 IV q21 days

Videos

Jared Weiss, MD, shares insight into current unmet needs in extensive-stage small cell lung cancer and provides advice to researchers about the importance of clinical trials studying differential treatments and biomarkers.

Unmet Needs and Future Directions in ES-SCLC

 Let’s turn our attention now to the ATLANTIS study. ATLANTIS was a randomized study of lurbinectedin in combination with doxorubicin in relapsed small cell lung cancer. This combination was compared in randomized fashion with the standard of care, defined as dealer’s choice of CAV [cyclophosphamide, doxorubicin, vincristine] or topotecan. The dose of lurbinectedin in this combination trial was 2.3 mg/m². The combination with doxorubicin left many doctors, myself included, scratching our heads from a clinical perspective. Adriamycin [doxorubicin] is a fairly hated drug, sometimes nicknamed the red devil, but there were preclinical data to support this combination. Unfortunately, the combination of doxorubicin and lurbinectedin at a dose of 2.3 mg/m² failed to improve survival compared with CAV [cyclophosphamide, doxorubicin, vincristine] or topotecan. Why did this happen? One possibility is dosage. The dose in the combination was 2.3 mg/m². In the basket trial, it was 3.2 mg/m².

In evaluating this possibility, the companies put out a poster [at the International Association for the Study of Lung Cancer World Conference on Lung Cancer] that looked at the relationship between AUC [area under the curve] dose exposure and both response rate and toxicity. It showed that when the exposure was ideal, the response rate was quite a bit better and the toxicity more limited. That argues that the dose really might have mattered. Unfortunately, the AUC exposure was fairly broad at that 3.2 mg/m² dosing in the basket trial. Still, it does make common sense that if the patients are at 3.2 mg instead of 2.3 mg, you’re going to have more patients at an adequate dose. Where does that leave us? Unless the FDA says otherwise, lurbinectedin remains a second-line option. In my practice, it remains the preferred option in second line, but in reflecting, we still have a very real unmet need.

Expert oncologist Jared Weiss, MD, considers safety and efficacy data from the ATLANTIS study of lurbinectedin in combination with doxorubicin in relapsed small cell lung cancer.

The ATLANTIS Study of Lurbinectedin/Doxorubicin

 This patient was treated with lurbinectedin. Let’s look at trial design, efficacy, and safety results from the phase 2 basket trial that led to this approval. This was 105 patients with extensive-stage small cell [lung cancer] in second line taken from a larger-basket trial. The response rate was 35% overall; 22% in those with a chemotherapy-treatment-free interval of less than 90 days, and 45% in chemotherapy-treatment-free interval of greater than 90 days. Two-thirds of patients had response to prior chemotherapy as you’d expect, since the chemotherapy-treatment-free interval had to be at least 30 days and because it’s small cell. PFS [progression-free survival] was 3.5 months overall, 2.6 months in the chemotherapy-refractory patients, and 4.6 months in those who were sensitive. Overall survival was also different among these groups; overall was 9.3 months, but in those with the short chemotherapy-treatment-free interval, it was 5 months. In those with the long chemotherapy-treatment-free interval, it was 12 months.

As we might expect, the toxicity was largely hematologic, but it was mostly lower grade. Anemia happened in almost every patient, but only 9% at grade 3, no grade 4. Leukopenia happened in half of patients at grade 1 and 2, and 29% of patients in grade 3 and 4. Neutropenia occurred in 26% of patients at grade 1 or 2, 21% at grade 3, and 25% at grade 4. Thrombocytopenia occurred in 37% at grades 1 and 2, and 3% at grade 3. The other major toxicities were also largely laboratory related as opposed to end organ. In terms of things patients feel more directly, as you would expect, there was some nausea and fatigue with the cytotoxic agent, but very few at high grade. The same can be said for decreased appetite, vomiting, and diarrhea. My experience, with the extremely important caveat that it’s a small number of patients, is not quite as favorable as the basket trial. I’ve had a little bad luck with patients not responding and a tolerability profile may be a little worse than the toxicity tables from the trial would suggest, but I highly caution against substituting experience with a small number of patients against the larger number in a controlled trial with careful data gathering.

Thought leader in lung cancer, Jared Weiss, MD, reviews safety and efficacy data from the phase 2 basket trial of lurbinectedin in selected advanced solid tumors.

Safety and Efficacy of Lurbinectedin in Solid Tumors

 All patients relapse, as our case illustrates. Let’s talk about what options are then available in second-line [treatment] for this patient, and in patients like this 1. Of course, we need to come back to patient values. What does the patient want? There’s a spectrum from “Doc, don’t hurt me—let me die in peace” to “Doc, I need to live as long as possible no matter how brutal the adverse effects.” Most patients are somewhere in between. If we want to respect patient values, we need to know them; to know them, we need to start by asking. Our patients have had cancer typically less than a year, so it’s our job to not simply give them cafeteria list options but to educate their values and their decision-making with information.

Let’s talk about that information. Thinking about what’s possible, I start by thinking about whether this is a platinum-sensitive or a platinum-resistant case; there’s something of an intercontinental divide in how this is defined. Historically, in North America, we’ve defined platinum sensitive as at least 6 months of a chemotherapy-treatment-free interval, from the last dose of platinum until progression. In Europe, it’s more commonly defined as 90 days. There’s no clear regression discontinuity between 90 and 180 days; it’s more of a spectrum. With that controversy acknowledged, in a case like this where progression is at 7 months, it’s quite comfortable to call this a platinum-sensitive case.

What can we expect from the reinitiation of platinum if we consider in a case such as this? There was a randomized study for patients with a chemotherapy-treatment-free interval of at least 90 days. That fit this patient, with a randomization between topotecan or carboplatin plus etoposide. Progression-free survival was improved from 2.7 to 4.7 months, but overall survival was not superior to topotecan. So reinitiation of platinum, now or at some subsequent point, would be an option for this patient. Interestingly, other chemotherapeutic second-line options also work better in patients with longer chemotherapy-treatment-free intervals; this may be more of a general marker of cytotoxic sensitivity. Other agents may certainly be considered in this context. Lurbinectedin is approved as a single agent in the second line at a dose of 3.2 mg/m². In noncomparative data, it appears to be a little less toxic and a little more effective than topotecan. Even with this cytotoxic agent, it works better in a patient like this with a longer chemotherapy-treatment-free interval.

With lurbinectedin, overall survival in that basket study was 5 months in those with a chemotherapy-treatment-free interval of less than 90 days. But in a patient like this, with a chemotherapy-treatment-free interval of at least 90 days, it was 12 months. Although lurbinectedin may have appeared less toxic than chemotherapy, it was still toxic consistent with a cytotoxic regimen with myelosuppression being a leading problem. Finally, in considering this patient’s options, is topotecan. Topotecan is not a well-loved drug in thoracic oncology, but it’s been very hard to beat historically. Immunotherapy failed to beat topotecan in the second line, and when the combination of Adriamycin [doxorubicin] and lurbinectedin was compared with dealer’s choice of CAV [cyclophosphamide, doxorubicin, vincristine] or topotecan, there was also a failure to improve survival.

Finally, there’s topotecan. Topotecan is not a well-loved drug in thoracic oncology, but historically it’s been very hard to beat. Immunotherapy failed to beat topotecan in second line. Recently, when Adriamycin and lurbinectedin together were compared with dealer’s choice of CAV [cyclophosphamide, doxorubicin, vincristine] or topotecan in second line, this also failed to beat topotecan. I would note that with preceding trilaciclib, topotecan is less toxic, because its major toxicities are myelosuppression and its downstream sequelae.

Key opinion leader in thoracic oncology, Jared Weiss, MD, discusses the role of second-line treatment for relapsed ES-SCLC after first-line therapy and maintenance immunotherapy.

Jared Weiss, MD | Authors

Articles

Unmet Needs and Future Directions in ES-SCLC

The ATLANTIS Study of Lurbinectedin/Doxorubicin

Safety and Efficacy of Lurbinectedin in Solid Tumors

Second-Line Treatment After Maintenance Immunotherapy