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

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.

In this new 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.

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

WEISS: 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.

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

WEISS: 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.

TARGETED ONCOLOGY™: 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?

WEISS: 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.

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

WEISS: 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.

TARGETED ONCOLOGY™: 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?

WEISS: 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.