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Combination Immunotherapy and Inhibitors of DNA Damage Repair in the Treatment of Small Cell Lung Cancer

A Conversation With Lauren Averett Byers, MD


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Because SCLC is not typically treated with surgical resection, we haven’t had large tissue banks of SCLC tumors with which to do genomic and molecular profiling.
— Lauren Averett Byers, MD

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Unlike non–small cell lung cancer (NSCLC), which has seen a paradigm shift in treatment modalities with the discovery of genetic signatures (including EGFR mutations) that are responsive to targeted drugs, systemic treatment of small cell lung cancer (SCLC) has remained largely unchanged for over 3 decades.1 The result is that 5-year survival rates for this aggressive cancer are stubbornly stuck at an abysmal 7%, with most of the nearly 31,000 patients diagnosed each year with SCLC surviving only up to 1 year.1

Even the recent introduction of immunotherapy for SCLC—earlier this year, the U.S. Food and Drug Administration (FDA) approved atezolizumab in combination with carboplatin and etoposide for the front-line treatment of patients with extensive-stage SCLC2—has only marginally improved overall survival for patients with this disease. According to the results from the IMpower133 randomized clinical trial, patients treated with a combination of atezolizumab and carboplatin and etoposide had a median overall survival of 12.3 months vs 10.3 months for patients treated with chemotherapy and a placebo.3

Now, data from preclinical research in SCLC are showing a potential breakthrough in this difficult-to-treat cancer. Lauren Averett Byers, MD, Associate Professor of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, and her colleagues have found that using a combination of the poly ADP-ribose polymerase (PARP) inhibitor olaparib or the checkpoint kinase 1 (CHK1) inhibitor prexasertib together with an immune checkpoint inhibitor against programmed cell death ligand 1 (PD-L1) significantly increased the effect of PD-L1 blockade and augmented cytotoxic T-cell infiltration inducing tumor regression in SCLC in vivo mouse models. In addition, the researchers found that DNA damage response inhibition activated the STING/TBK1/IRF3 innate immune pathway, leading to increased levels of chemokines, including CXCL10 and CCL5, which activated cytotoxic T lymphocytes. The findings suggest that olaparib and other DNA damage repair inhibitors prompt a rapid immune response in SCLC cells, making them more susceptible to immunotherapy.4

SMALL CELL LUNG CANCER

For more on a novel treatment being investigated in resistant and sensitive small cell lung cancers, see an interview with Luis G. Paz-Ares, MD, PhD, on The ASCO Post Newsreels at www.ascopost.com/videos.

“Immunotherapy has become incredibly important for many cancers, especially lung cancer. But with SCLC, even though it has a high mutation burden, it is largely immunologically ‘cold,’ making it invisible to the immune system, so responses to immunotherapy are lower than you might predict,” explained Dr. Byers. “We know that cancers with more DNA damage or defects in repairing DNA damage seem to respond better to immunotherapy; so we thought that using PARP inhibitors or cell-cycle checkpoint inhibitors or other drugs that prevent DNA repair and cause DNA damage might help enhance response to immunotherapy, and that’s what our preclinical study showed.”

According to Dr. Byers, plans are underway to launch clinical trials investigating this combination approach of adding a targeted therapy to immune therapy in patients with SCLC by the end of 2019.

The ASCO Post talked with Dr. Byers about how her research may advance the development of more effective therapies for patients with SCLC and how oncology care may become more personalized over the next decade, improving survival rates for these patients.

Why Is SCLC So Deadly?

Why is SCLC more aggressive and deadlier than -NSCLC? What are the molecular differences contributing to the distinct clinical behavior of these two cancers?

This question was the focus of our earlier research. We wanted to understand why SCLC behaved so differently from NSCLC and whether there were distinct drug targets and new therapeutic opportunities for our patients. We approached this question in the lab by looking at the differences between which proteins and cancer pathways were active in SCLC compared with NSCLC. We found that PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLC and that growth of the cancer cells was inhibited by PARP1 and EZH2 knockdown.5

We thought it was because all SCLCs have lost some of the key genes that are the gatekeepers of DNA and the cell cycle, for example, TP53 and RB1; that means these cancers have a high number of mutations, are replicating quickly, and need to tolerate

Screening is still not an effective method for detecting SCLC at an early, more curable stage, mainly because the cancer metastasizes early in disease development….
— Lauren Averett Byers, MD

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or survive the amount of DNA damage they inherently have. The fact that the cells had high levels of proteins that helped repair some of that damage was important for the cells, and we started testing many PARP and CHK1
inhibitors in our laboratory models. We saw immediate activity with these drugs against the cancer and that led to the start of clinical trials to test those drugs in various combinations in patients.

In 2018, in a randomized phase II trial that combined the PARP inhibitor veliparib with temozolomide in patients with recurrent SCLC, we found significant improvement in the overall response rate in patients treated with the combination therapy compared with those treated with temozolomide alone, 39% vs 14%, respectively.6 While we were conducting the trial, our group and other SCLC investigators discovered that there was a candidate biomarker, SLFN11, that might help us predict which patients would benefit most from the addition of a PARP inhibitor.

It was an exciting discovery, because we found that adding veliparib to temozolomide in those patients whose tumors expressed SLFN11 resulted in significantly longer progression-free survival, 5.7 months vs 3.6 months, and overall survival, 12.2 months vs 7.5 months.

Overcoming Treatment Challenges

Why has progress been so slow in the treatment of SCLC?

There are a couple of reasons why treating SCLC has been so challenging. One is that it is an extremely aggressive disease. And, two, although most patients do experience a benefit from their initial therapy, which has historically been chemotherapy but is now a combination of chemotherapy and immunotherapy, they typically become resistant to their treatment within a few months. At that point, subsequent therapies have little effect on the cancer.

One of the major challenges to finding more effective therapies for SCLC is that because the disease is not typically treated with surgical resection, we haven’t had large tissue banks of SCLC tumors with which to do genomic and molecular profiling. This is in contrast to NSCLC and other cancers, where profiling large numbers of tumors has accelerated progress toward more personalized therapies and treatments are selected based on a tumor’s mutations, PD-L1 status, or other biomarkers. SCLC has one of the highest mutation burdens of any solid tumor, but so far there have not been any druggable mutations that are the drivers of the cancer in the way, for example, that the EGFR mutation is a driver in NSCLC.

Recently, from our research and the research of others, we are learning that we can use different types of biomarkers, especially gene or protein expression, to identify distinct subgroups of patients with SCLC that might respond to different treatment approaches, such as targeted or immune therapies.7

Evaluating the Benefit of Screening

SCLC is linked to smoking. What is the current thinking on the value of lung cancer screening for high-risk patients?

Right now, screening is still not an effective method for detecting SCLC at an early, more curable stage, and improving outcomes, mainly because the cancer metastasizes early in disease development, so even small tumors are likely to be widely metastatic at diagnosis. Unfortunately, most patients, between 60% and 70%, will have extensive-stage disease at diagnosis.8

Results from the National Lung Screening Trial showed that although screening high-risk people with a significant smoking history with low-dose computed tomography imaging for the early detection of lung cancers was effective in improving survival for patients with NSCLC, early detection did not have the same impact on survival for patients with SCLC,9 so there is a lot of room for improvement. New, early-detection approaches for SCLC are being investigated, but right now, we don’t have an established method for effective screening. As a result, our primary focus at this time is on more effective treatments.

Developing New Treatment Strategies

Is the front-line standard of care for SCLC still platinum-based chemotherapy and radiation therapy?

Yes, chemotherapy, together with radiation for limited-stage disease, remains a key component of front-line treatment of SCLC. Recently, however, the FDA approval of atezolizumab in combination with carboplatin and etoposide for the first-line treatment of patients with extensive-stage SCLC2 was the first change in this setting in decades. Despite this landmark advance, there is clearly still room for improvement. Based on our preclinical research showing that response to immunotherapy is enhanced by treatment with PARP inhibitors and other targeted therapies, we are excited to move these new combinations forward into clinical trials.

It would be great to bring them into the earlier treatment setting. We are already considering using some of these novel combinations in the maintenance setting, rather than waiting for patients to relapse. That is one strategy we are excited about exploring further.

Improving Survival Rates

What potential advances do you see being made over the next 5 years to improve survival rates in patients with SCLC?

There have been some recent key discoveries in therapeutic approaches to SCLC. The development of immunotherapies has opened up new avenues and treatment opportunities for our patients in clinical trials, and we are now seeing immunotherapy becoming standard practice in this cancer.

We are seeing a clear signal that there are different types of SCLC, and early preclinical and clinical trial research suggests that patients respond differently to targeted therapy based on their tumor subtype.
— Lauren Averett Byers, MD

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The National Cancer Institute has made a major initiative to promote and support research in SCLC; research in this area over the past few years has increased, and we are starting to see those research advances being translated into the clinic. Going forward in the next several years, I expect we will see the identification of additional biomarkers in SCLC, which will allow us to match patients to specific treatments based on their biomarker profile.

Five years from now, my hope is that we will routinely be taking an approach that is similar to what we do in NSCLC, in which we test a patient’s tumor upfront for specific biomarkers and then determine the most effective treatment for the patient’s particular type of SCLC. Based on recent data, we are seeing a clear signal that there are different types of SCLC, and early preclinical and clinical trial research suggests that patients respond differently to targeted therapy based on their tumor subtype. We will probably find additional biomarkers that allow us to further refine treatment and will be able to translate this new information into how we design clinical trials in the future and how we select patients for those trials and treatment.

I am hopeful that we are at an inflection point in our understanding that SCLC is not just one disease and that we have a path forward in terms of personalizing treatment for patients based on their individual tumor biomarker profiles. 

DISCLOSURE: Dr. Byers is a consultant/advisor for AbbVie, AstraZeneca, LUNGevity, PharmaMar, Genmab, Bristol-Myers Squibb, Sierra Oncology, and Alethia Biotherapeutics; and has received institutional research funding from AbbVie, Tolero Pharmaceuticals, Genmab, AstraZeneca, and Sierra Oncology.

REFERENCES

1. Byers LA, Rudin CM: Small cell lung cancer: Where do we go from here? Cancer 121:664-672, 2015.

2. U.S. Food & Drug Administration: FDA approves atezolizumab for extensive-stage small cell lung cancer. Available at www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-atezolizumab-extensive-stage-small-cell-lung-cancer. Accessed June 20, 2019.

3. Horn L, Mansfield AS, Szczesna A, et al: First-line atezolizumab plus chemotherapy in extensive-stage small cell lung cancer. N Engl J Med 379:2220-2229, 2018.

4. Sen T, Rodriguez BL, Chen L, et al: Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer. Cancer Discov 9:646-661, 2019.

5. Byers LA, Wang J, Nilsson MB, et al: Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov 2:798-811, 2012.

6. Pietanza MC, Waqar SN, Krug LM, et al: Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer. J Clin Oncol 36:2386-2394, 2018.

7. Gazdar AF, Bunn PA, Minna JD: Small-cell lung cancer: What we know, what we need to know and the path forward. Nat Rev Cancer 17:765, 2017.

8. Farago AF, Keane FK: Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res 7:69-79, 2018.

9. Aberle DR, DeMello S, Berg CD, et al: Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 369:920-931, 2013.


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