City of Hope’s Tingting Tan, MD, PhD, on the Changing SCLC Landscape: “There’s Always Reason to Be Hopeful”

Tingting Tan, MD, PhD, a medical oncologist and lung cancer specialist in the Department of Medical Oncology and Therapeutics Research, City of Hope, Newport Beach, California, combines an international reputation for basic research with a compassion for patients. Tan studies molecular signaling pathways in tumor development and the mechanisms of chemotherapy resistance; she has authored highly cited papers exploring the intersection of inflammation, immune cells, and cancer. Earlier this year, she was a co-author on a paper reviewing City of Hope’s integration of academic and community cancer research through multidisciplinary oncology pathways.¹ In an interview with The American Journal of Managed Care®, Tan opened the discussion of small cell lung cancer (SCLC) with a review of a blog post made earlier this year on the importance of lung cancer screening for certain populations.

AJMC®: You recently discussed the importance of early detection in small cell lung cancer. Can you share why lung cancer screening is so important with this population, and who should be screened under revised USPSTF guidelines?

Tan: Small cell lung cancer accounts for about 15% of all lung cancers. It is a very aggressive form of lung cancer, characterized by rapid progression and early metastasis. So, roughly 80% to 85% of small cell lung cancer patients are diagnosed at a later stage, where it is no longer curable—we call this extensive stage small cell lung cancer (ES-SCLC). That’s why screening people for small cell lung cancer enables physicians to diagnose the condition earlier, when treatment still has the potential for cure.

The United States Preventive Services Task Force (USPSTF) rolled out new guidelines [for screening] in March 2021. Previously, the guidelines included patients with 30 pack-years of smoking history who were ages 55 to 80 years old. The current recommendations have expanded this; now we're recommending lung cancer screening for patients aged 50 to 80 years who have a 25-year smoking history, who currently smoke or have quit within the past 15 years.

Screening for lung cancer is basically is a low-dose CT scan that's done on an annual basis. Screening can be stopped if the patient has not smoked for 15 years, or has a health problem that limits life expectancy or the ability to have a long surgery. So, therefore, it's very important to educate and encourage high-risk patients to engage in lung cancer screening.

AJMC®:Treating patients with SCLC with immune checkpoint inhibitors has been hugely successful in some settings, but there were also a few instances where indications have been withdrawn after trial end points were not reached. What are your thoughts on the current place of immune checkpoint inhibitors in SCLC?

Tan: That's a very good question. The use of immune checkpoint inhibitors has been the big breakthrough in small cell lung cancer treatment of the last several decades. The positive findings from the recent large clinical trials—including IMpower133 and CASPIAN trials suggest that initiation of checkpoint inhibitors in combination with platinum and etoposide chemotherapy in the first-line setting provides the most benefits. In terms of single agents, immune checkpoint inhibitors in the second-line setting, such as nivolumab and pembrolizumab, the FDA approvals were withdrawn in the relapsed disease setting based on the fact that phase 3 randomized trials of CheckMate-451 and KEYNOTE-604 were essentially negative statistically for overall survival. So, therefore, using pembrolizumab and nivolumab as a single agent in the relapsed setting is no longer an FDA-approved indication.

However, single-agent immune checkpoint inhibitors remain in [National Comprehensive Cancer Network] guidelines as a Category 3 recommendation, mostly for patients who cannot tolerate chemotherapy. So, despite the advances in immune checkpoint inhibitors, the prognosis of small cell lung cancer remains very poor. More research is needed in searching more effective immunotherapy, either in single agent or combination for to actually improve for, you know, the success of treating small cell lung cancer.

AJMC®:One of your most frequently cited papers (2007) concerns the relationship between inflammation and cancer and how this can offer us insight into pathways that could offer therapeutic targets.² More recently, inflammation has been seen as an element in finding targets that have been lacking in SCLC. Can you discuss your findings and how they relate to the work going on in SCLC today?

Tan: It actually have been well known that there is a strong association between chronic inflammation and cancer development. So, immune cells not only possess the ability to suppress cancer cells, but also under certain circumstances, immune cells can also promote tumor development. Immune cells can interact with each other in the tumor microenvironment to promote tumor growth by producing growth factors—proteolytic enzymes and cytokines, etc.

So, small cell lung cancer is one of the examples where immune cells may play an important role in cancer development. We know that small cell lung cancer is associated with immune-mediated paraneoplastic syndromes, such as Lambert-Eaton syndrome [in which the immune system attacks connections between nerves and muscles]. Also, a majority of small cell lung cancers lack two important tumor suppressor proteins, p53, and RB1, leading to genomic instability and high tumor mutation burden. We know that high tumor mutation burden naturally has been associated with response to immune checkpoint inhibitors, at least in several tumor types. There’s still a lot of research going on trying to target different signaling pathways that regulate these immune cells, to try to find more effective immunotherapies. In small cell lung cancer, there has been research exploring the possibility of combinations of checkpoint inhibitors with vaccine therapy or cellular therapy or small molecule therapy, to target different sites of the external pathway in immune cell response to tumor development.

AJMC®: That leads to my next question. In other solid tumors it has been easier to find biomarkers that allow for treatment based on therapeutic targets. This has been less so in SCLC—the disease is aggressive, and patients then relapse and their disease progresses quickly. How is your work in understanding molecular signaling pathways helping us understand these processes, which lead to treatment resistance?

Tan: A lot of research is ongoing—a lot [of work] is promising, but still in the preliminary stage. My previous research was focused on the regulation of the p53 independent pathway—leading or regulating apoptosis. As you know, p53 is the most frequently mutated tumor suppressor gene in malignancies, so understanding the molecular mechanisms of cell death in p53 mutant cells is crucial in drug development to overcome drug resistance in these cancers with p53 mutations. So, currently, a lot of the research is preclinical—it includes immunotherapy, gene editing, and small interfering, like siRNA silencing, and small molecules to target a mutant p53 and try to restore the wild type p53 activities of mutant p53. It has been a very challenging but exciting field.

AJMC®: One of the characteristics of the immune checkpoint inhibitors and some other newer therapies is that they can offer reduced the side effects. In working with patients, what do they tell you about side effects and why that matters in trying to make progress in this disease?

Tan: Often, when a small cell lung cancer patient presents with ES-SCLC, [they] are quite symptomatic and frail, so it's very challenging to have them go through intense chemotherapy treatment. Most patients will report fatigue and [gastrointestinal] toxicities. These are most common are nausea, vomiting, constipation or diarrhea. When adding immunotherapy in combination with chemotherapy, it does not seem to add significant toxicities, but sometimes we need to keep in mind that due to the potential overactivation of the immune system, immunotherapy can cause rash, abnormal thyroid function or colitis—there is a different toxicity profile due to immunotherapy. We always look for therapies with minimal side effects. The goal is to find very effective treatments in in an individualized fashion.

The research has been focused on the development of predictive biomarkers to help select the best treatment for each individual patient. Recent events in lung cancer research through molecular profiling of small cell lung cancers through subtyping [puts] our patients into different categories. Hopefully, in the near future, we can match the patients based on their biomarkers with a more effective and less toxic therapy.

AJMC®: When you meet with a patient and their family after a diagnosis of SCLC today, compared with five years ago, how is that meeting different? Can you walk us through what that discussion is like today?

Tan: Immunotherapy can be incorporated into many cancers, and most patients come in asking you about the role of immunotherapy, even at their initial visit. I think the incorporation of checkpoint inhibitors in the treatment of small cell lung cancer definitely has given patients more hope. As I said before, this is the biggest breakthrough in small cell lung cancer treatment in the last several decades.

Five years ago, small cell lung cancer patients were still only given a chemotherapy option, with platinum-based chemotherapy. Roughly 50% to 60% patient would have a good response to treatment. But this is a disease that relapses—it almost always will relapse—and your overall survival is less than 5%. So, it has been a very difficult disease, but at least now, when I talk to patients, with ES-SCLC, I can explain to them about the new advances in small cell lung cancer treatment to give them hope.

For example, we talked about how we can combine chemotherapy with immunotherapy in the first-line setting, which has shown modest benefit in overall survival. And we have made improvements in radiation therapy as well. Five years ago, whole brain radiation hadn't been a broad recommendation for small cell lung cancer with brain metastases, and prophylactic whole brain radiation was often recommended, too. But now, more patients are being considered for stereotactic radiation, which causes way less toxicity. Many patients are offered close monitoring with MRI surveillance, then prophylactic whole brain radiation to try to improve the patient's quality of life. We also have a new agent that's been approved for relapse disease as well. Lurbinectedin is a new effective treatment for relapsed small cell lung cancer patients that was FDA approved in June last year.

So, in reviewing how much progress we have made in the last just last few years, you [can give] patients hope. When patients hear about this, they are motivated to continue treatment and you know, I’m very happy that I have more things to offer to my patients these days. One other point I want to make is that we always try to offer hope. There’s always reason to be hopeful about the future of treatment…We continue to pioneer treatment in lung cancer, with a lot of exciting clinical trials involving biomarker testing, immunotherapy, and different combinations. In our institution, this is definitely a very rapidly evolving landscape. A lot of novel therapeutic regimens for small cell lung cancer are being developed, so I stay hopeful for my patients.

References

1. Bosserman LD, Cianfrocca M, Yuh B et al. Integrating academic and community cancer care and research through multidisciplinary oncology pathways for value-based care: a review and the City of Hope experience. J Clin Med. 2021;10(2):188. doi:10.3390/jcm10020188.
2. Tan TT, Coussens LM. Humoral immunity, inflammation and cancer. Curr Opin Immunol. 2007;19(2):209-216. doi: 10.1016/j.coi.2007.01.001