Jared Weiss, MD


While patients with small cell lung cancer can be responsive to initial treatment with chemotherapy, relapse is an important consideration for clinicians. Many patients will also present with advanced disease at diagnosis, so it is essential that clinicians continue to optimize the management of extensive-stage small cell lung cancer (ES-SCLC).

The treatment of ES-SCLC has included the use of platinum chemotherapy (cisplatin, carboplatin) in combination with etoposide. However, in 2019, the IMpower133 clinical trial led to the approval of atezolizumab in combination with etoposide and carboplatin in the first-line setting. Combination therapy with durvalumab, etoposide, and platinum chemotherapy was also approved in the first-line setting with the CASPIAN clinical trial in 2020. Although these new treatment approaches have advanced the standard of care in ES-SCLC, there continue to be challenges affecting optimal patient management and important areas of unmet need that must be addressed.

Precision Medicine Perspectives in Small Cell Lung Cancer 

series, experts in the management of ES-SCLC reflect on the current therapeutic landscape and highlight some challenges affecting optimal treatment. In the first interview of the series, Jared Weiss, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina provides an overview of recent advancements in the standard of care and underscores the importance of utilizing effective therapeutic approaches while also mitigating and managing the toxicity associated with treatment.

: What do you consider the biggest challenges in treating ES-SCLC?

In my opinion, the unambiguously greatest challenge in treating extensive-stage small cell lung cancer is the lack of therapeutic efficacy. I've been frustrated with extensive-stage small cell lung cancer treatment for some time, as I think many have. It's very frequent that we get these rapid, dramatic, and even complete responses. You have a high log cell kill, you're close to cure, and then you don't get there. This was true even in the era before modern therapeutics. Even back in the era of CAV (cyclophosphamide, doxorubicin, vincristine), we would get complete responses that were not curative. For a long time, we've recognized that, in terms of cell count number, we're getting close to a cure, yet we just about never get there. We're so close, yet for decades have never crossed that finish line.

Even if you step back and say that we don't cure most stage 4 cancers and that we should be a little more realistic, even still, the duration of control that we get is grossly inadequate, and our survival is grossly inadequate. Along the way, our patients suffer not just from the adverse effects of what we do to them—although I would list that as another really important unmet need—they also suffer from the effects of our therapy, so we need therapies that are more effective. Ideally, curing some or really all patients, we need treatments that are less toxic.

: How do these challenges affect a patient's treatment plan?

When thinking about how to treat a patient, we have to recognize that small cell lung cancer tends to present very symptomatically. It likes to grow in the central area of the chest with a lot of lymphadenopathy, so you get central chest syndromes. You get pain, and you get trouble breathing from clipping off the central airways and the central vessels, so there's often an urgency to treat small cell lung cancer. Of the solid tumors, it is the one that I treat the most inpatient. This is probably true for most consultative physicians.

The good part of this, though, is that the chemotherapy works. If you have a patient in the hospital, even in an extreme situation like on a ventilator, when you give them a cycle of chemotherapy, days later, they're doing much better. The major treatment consideration is efficacy. Fortunately, in the short run, efficacy is quite good.

Then of course, another consideration is toxicity minimization. If you look at the historic evolution of cytotoxic chemotherapy in the preimmunotherapy era and look at the front-line evolution from CAV to platinum and etoposide and the second-line evolution from CAV to topotecan, we really don't have an improvement in survival. What we have is an improvement in toxicity profile and patient convenience profile; this matters, even if we wanted more out of it. Then of course, as we entered the immunotherapy era, there is finally an advantage in survival. Not as much as we'd like, but real.

These historic considerations are the same that we face in clinic every day. What do we need to address our patients’ immediate needs? What's the best regimen to give them long-term control? And of course, how can we minimize the adverse effects of therapy? Small cell treatment is toxic; the most common toxicities are myelosuppression and their downstream sequalae, like fatigue. There is need for supportive care interventions because our patients are very much suffering from the treatment in addition to suffering from the disease.

: Regarding recent approvals, first line use of atezolizumab, carboplatin, and etoposide gained approval in 2019, and then durvalumab, carboplatin or cisplatin, and etoposide gained approval in 2020. How have these approvals changed decision-making for first-line therapy for ES-SCLC?

First-line treatment of extensive-stage small cell lung cancer changed dramatically in 2019 with the approval of atezolizumab. For a very long time until then, the evolution of frontline regimens never improved survival. Enter IMpower-133: This was a randomized study of carboplatin and etoposide, plus either placebo or the PD-L1 inhibitor atezolizumab. We have an improvement in progression-free survival, we have an improvement in overall survival, and there was not much extra toxicity. There were some immune-related adverse events that you see with the addition of atezolizumab, of course, but looking at the safety profile globally, there was not a terribly big increase.

The same was pretty much replicated in 2020 in the CASPIAN study with the addition of the PD-L1 inhibitor durvalumab to platinum and etoposide. This was a 3-arm randomized study; the third arm had the CTLA-inhibitor tremelimumab. That really didn't improve outcomes any further, so I'll focus on what was approved, deservedly: the addition of durvalumab.

If you look at the forbidden but omnipresent cross-trial comparisons, the curves were nearly superimposable from IMpower-133, which to me reflects that the agents are more similar than different and that both companies conducted their trials fairly and appropriately. There were minor differences in inclusion criteria and enrolled patients, but the main meaning of having 2 trials with similar safety, PFS (progression-free survival), and OS (overall survival) is that it is true. In science, we like to have everything confirmed with another case study. The addition of the PD-L1 inhibitor, the approved ones being atezolizumab or durvalumab, to standard platinum and etoposide improved survival in extensive-stage small lung cancer. This, of course, has changed the standard of care. In the US and other countries that can afford it, the absolute unambiguous standard of care for patients eligible for a checkpoint inhibitor is platinum, etoposide, and a checkpoint inhibitor.

: What do you consider the most significant unmet needs in the management of ES-SCLC?

We've spoken already about the unmet need of actually curing people, and even if we can't do that, of having more durable control with the drugs. We have spoken about the unacceptable toxicity profile of our current standards of care. The 1 additional theme that I might mention for unmet needs is dealing with the patient and their systems as a whole.

While I love my smokers and non-smokers the same and have no desire to stigmatize anybody, we do need to recognize that smoking brings with it smoking-associated comorbidities. In addition to decreased socioeconomic resources, the patients’ bodies come to their cancer more beaten up with things like COPD (chronic obstructive pulmonary disease) and more limited blood counts. They're less able to tolerate and benefit from the standard of care in addition to the greater difficulty in traveling to academic centers and getting trials. Optimal care of the patient with extensive-stage small cell lung cancer involves not only less toxic therapy, better supportive care, and therapies that work better, but it also requires an extensive network to support the patient to be able to get those more advanced standards of care applied to them.

Additionally, lung cancer is a heavily stigmatized cancer that disproportionately affects patients with fewer financial resources and social capital to bring to their treatment. If you contrast this, for example, with a patient with estrogen receptor positive breast cancer, or a patient with HPV (human papillomavirus)-positive head and neck cancer, these are patients who can afford to travel for trials, who can get many opinions. In contrast, many of my patients with small cell lung cancer have trouble paying for the tank of gas to get to the doctor's visit.

: Chemotherapy-induced myelosuppression (CIM) can result from some treatment regimens. How significant of an issue is CIM and to what extent does it affect a patient’s treatment course?

The problem is actually quite common if you look at the toxicity tables of the regimens that have defined our standard of care. If you look at IMpower-133, if you look at CASPIAN, if you look at the phase I basket results of lurbinectedin, and if you look at any of the dozen or so topotecan trials, what you can see is that the majority of patients are experiencing adverse events. The most common of these are myelosuppressive events, which until very recently we couldn't do a whole lot about.

Chemotherapy-induced myelosuppression is a major harm to treatment. While dose density doesn't have a great impact on survival in small cell lung cancer the way it does in breast cancer or some lymphomas, there are meaningful harms to needing to delay and reduce doses. It is inconvenient for patients. It's inconvenient for providers. It causes substantial anxiety.

Further, neutropenia very much hurts people. Febrile neutropenia can be a fatal event, it can delay chemotherapy, and it results in the need for drugs like pegfilgrastim that have adverse effects like bone pain. When you get to anemia, which causes fatigue, fatigue is the quality-of-life issue that perhaps we have the most trouble controlling in clinic, and for many patients, this affects them the most.

I think myelosuppression deserves a renewed focus. For years, we haven't thought that much about myelosuppression other than maybe neutropenia because we had a bit of a learned helplessness. This was the cost of business for giving cytotoxic drugs, and we started to say, "Well, of course, you get tired. Of course you get anemic." The introduction of effective drugs to protect neutrophils has changed this. Trilaciclib, which can help with the myelosuppression, now means that we can actually do something about it.

Articles

In this companion article, Dr. Jared Weiss provides key insights into recent advancements in the standard of care for extensive-stage small cell lung cancer and examines challenges affecting treatment.

EP. 2B: Challenges Affecting the Management of Extensive-Stage Small Cell Lung Cancer

In my opinion, the unambiguously greatest challenge in treating extensive-stage small cell lung cancer is [the] lack of therapeutic efficacy. The duration of control that we get is grossly inadequate, [and] our survival is grossly inadequate. Along the way, our patients suffer not just from the [adverse] effects of what we do to them—although I would list that as another really important unmet need—they also suffer from the effects of our therapy, so we need therapies that are more effective. Ideally, curing some or really all patients, we need treatments that are less toxic.

First-line treatment of extensive-stage small cell lung cancer changed dramatically in 2019 with the approval of atezolizumab. For a very long time until then, the evolution of frontline regimens never improved survival. Enter IMpower-133: This was a randomized study of carboplatin and etoposide, plus either placebo or the PD-L1 inhibitor atezolizumab. We have an improvement in progression-free survival, we have an improvement in overall survival, and [there was] not much extra toxicity. There were some immune-related adverse events that you see with the addition of atezolizumab, of course, but looking at the safety profile globally, [there was] not a terribly big increase.

The same was pretty much replicated in 2020 in the CASPIAN study with the addition of the PD-L1 inhibitor durvalumab to platinum and etoposide. The addition of the PD-L1 inhibitor, the approved ones being atezolizumab or durvalumab, to standard platinum and etoposide improved survival in extensive-stage small lung cancer. This, of course, has changed the standard of care. In the US and other countries that can afford it, the absolute unambiguous standard of care for patients eligible for a checkpoint inhibitor is platinum, etoposide, and a checkpoint inhibitor.

If you look at the toxicity tables of the regimens that have defined our standard of care. If you look at IMpower-133, if you look at CASPIAN, if you look at the phase I basket results of lurbinectedin, [and] if you look at any of the dozen or so topotecan trials, what you can see is that the majority of patients are experiencing adverse events. The most common of these are myelosuppressive events, which until very recently we couldn't do a whole lot about.

For years, we haven't thought that much about myelosuppression other than maybe neutropenia because we had a bit of a learned helplessness. This was the cost of business to giving cytotoxic drugs, and we started to say, "Well of course, you get tired. Of course you get anemic." It was a learned helplessness, but that changed some with the introduction of effective drugs to protect neutrophils. The [drugs] had their own imperfections, but to me, trilaciclib is important not only for the drug itself, which I am using in every eligible [patient with] small cell [lung cancer], but [also] for the way we think about supportive care for blood counts in general. We should be thinking about myelosuppression again now that we can actually do something about it.

Videos

Dr. Jared Weiss of the University of North Carolina Lineberger Comprehensive Cancer Center considers treatment challenges and unmet needs in the current standard-of-care management of extensive-stage small cell lung cancer. 

EP. 2A: Treatment Challenges and Unmet Needs in Extensive-Stage Small Cell Lung Cancer

 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

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.