Jane Langille

Although chemotherapy remains the standard treatment for small cell lung cancer (SCLC) in first- and second-line settings, notable progress in immunotherapies have recently taken place, begging the question of how these agents will be optimized in this tumor type.

Platinum-based chemotherapy, the standard first-line treatment for SCLC, achieves response rates of 60% to 80% in patients with extensive-stage disease. However, nearly all patients relapse; median survival time is 1 to 2 years post diagnosis,

and only 5% of patients are alive at 2 years.

Until recently, the only approved second-line therapy was topotecan (Hycamtin), which is associated with a median duration of response of just 3.3 months.

The rationale for the use of immunotherapies in SCLC stem partly from a high average tumor mutational burden (TMB), which has been a predictor of response in other tumor types such as bladder cancer and nonsmall cell lung cancer (NSCLC). Further, a strong association between the disease and the immune system is seen in the correlation with paraneoplastic syndrome that occurs as a consequence of cancer and may be associated with better prognoses.

Combining platinum-based chemotherapy with immunotherapy may take advantage of potential synergies between the 2 treatment types.

&ldquo;The rationale is that chemotherapy results in maximum cell death and antigen release, increasing the activation of T cells and their trafficking into the tumor microenvironment, potentially resulting in response to the checkpoint inhibitor,&rdquo; Leora Horn, MD, MSc, a medical oncologist at Vanderbilt University Medical Center, said in an interview with

. &ldquo;But we still do not know for whom these drugs work best, or why.&rdquo;

Two single-arm basket trials, KEYNOTE-028 and KEYNOTE-158, showed promising clinical response rates. These nonrandomized trials tested the PD-1 inhibitor pembrolizumab (Keytruda) in patients with SCLC who progressed on or after platinum-based chemotherapy and at least 1 other prior therapy. In an analysis of both trials, the objective response rate (ORR) for 83 eligible patients was 19.3%.4 For the 16 responding patients, rates lasted 6 months or longer in 94%, 12 months or longer in 63%, and 18 months or longer in 56%. Based on these compelling results, the FDA approved pembrolizumab for treating metastatic SCLC in the second-and-third-line settings in June 2019.

The CheckMate 032 trial, which examined the efficacy of the antiPD-1 agent nivolumab (Opdivo) in patients with metastatic solid tumors, saw notable responses and clinical outcomes in a subgroup of 109 patients with SCLC who had progressed after platinum-based chemotherapy and at least 1 other therapy. The ORR was 12%, and in the 13 responding patients, responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39%. Furthermore, responses did not seem to be contingent on PD-L1 status. A total of 17.2% of patients were progression-free at 6 months, and overall survival (OS) at 12 and 18 months was 28.3% and 20.0%, respectively.1 The FDA granted accelerated approval for nivolumab for the treatment of metastatic SCLC in the third-line setting in August 2018.

The landmark phase III IMpower133 trial was the first study showing improved outcomes for combination chemotherapy and immunotherapy compared with chemotherapy and placebo in the first-line setting in patients with extensive-stage SCLC (ES-SCLC). A total of 403 patients were randomized and received carboplatin and etoposide with either atezolizumab (Tecentriq), a PD-L1 inhibitor, or placebo during an induction phase, followed by maintenance with atezolizumab or placebo. The atezolizumab group had a significantly longer median OS (12.3 vs 10.3 months; HR, 0.70; 95% CI, 0.54-0.91;

= .007) and progression-free survival (PFS; 5.2 vs 4.3 months; HR, 0.77; 95% CI, 0.62-0.96;

= .02), compared with the chemotherapy and placebo group, respectively.

Based on these results, the FDA approved the combination regimen for first-line treatment of ES-SCLC in March 2019.

&ldquo;The IMpower133 regimen has been our standard of care since the results were released,&rdquo; Stephen V. Liu, MD, associate professor of medicine at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC, and senior investigator on IMpower133, said in an interview with

. &ldquo;It is a &lsquo;category 1, preferred&rsquo; option in the National Comprehensive Cancer Network guidelines

and is considered the global standard of care.&rdquo;

Although about 60% of NSCLC cases are PD-L1 positive, only about 18% to 32% pf patients with SCLC, in contrast, have positive expression of the marker.

In studies so far, responses to nivolumab alone or in combination with ipilimumab (Yervoy) did not correlate with PD-L1 status in SCLC, arguing against its use as a biomarker.

Investigators have also explored TMB as a potential biomarker because of the association between tumors with high TMB and improved response to checkpoint blockade. An in-depth analysis of results from the randomized and nonrandomized cohorts of CheckMate 032 used whole-exome sequencing to assess the association between TMB status and outcomes in SCLC. The combination provided a better clinical benefit than nivolumab alone; moreover, the efficacy of nivolumab and ipilimumab in combination was greater in patients with high TMB. In both groups of patientsthose treated with nivolumab monotherapy or nivolumab plus ipilimumab&mdash;ORRs were higher in patients with high-TMB status (21.3% and 46.2%, respectively) than in patients with low-TMB status (4.8% and 22.2%, respectively). A higher TMB also conferred higher estimated 1-year PFS rates (21.2% and 30.0%, respectively) compared with low-TMB (not calculable and 6.2%, respectively) or medium-TMB (3.1% and 8.0%, respectively).

Another study examined the potential predictive role of TMB using targeted next-generation sequencing] (NGS) data in 52 patients with relapsed or refractory SCLC treated with immune checkpoint inhibitors. The investigators found no significant difference in ORR between patients with a high TMB (defined as above the 50

percentile) and those with a low TMB. However, both median PFS (3.3 vs 1.2 months; HR, 0.37; 95% CI, 0.20-0.69;

<.01) and median OS (10.4 vs 2.5 months; HR, 0.38; 95% CI, 0.19-0.77;

<.01) were significantly longer in patients with a high TMB versus a low TMB, respectively. When TMB was examined in tertiles, 1-year PFS and OS rates improved with increasing mutational load.

, Ricciuti and colleagues concluded, &ldquo;These findings show that targeted NGS, a readily-available clinical diagnostic test, can be used to identify patients with SCLC who are most likely to benefit from treatment with immune checkpoint inhibitors.

However, analyzing TMB with either sequencing technique remains challenging, because the samples are small and are more difficult to obtain compared with samples of NSCLC tumors. &ldquo;In CheckMate 032, they had to select patients at sites that are good at obtaining tissue, and only half the patients had enough tissue for testing. In practice, there will be far less,&rdquo; said Liu. &ldquo;If a new biomarker in the future requires sequencing tissue, that is going to be hard to do on a large scale. A blood-based biomarker would be more ideal.&rdquo;

Active clinical trials are exploring new combinations of immunotherapies with chemotherapies and radiation in the first-line setting of SCLC.

A press release in June 2019 announced impressive results from the phase III CASPIAN trial, the first to test the practice of combining immunotherapy with durvalumab (Imfinzi) and different platinum-based regimens with the objective of expanding effective first-line treatment options for ES-SCLC. According to AstraZeneca, the manufacturer of durvalumab, adding the monoclonal antibody to standard first-line chemotherapy resulted in a statistically significant and clinically meaningful improvement in OS.

The 3-arm study enrolled 988 patients to receive treatment with etoppside and either cisplatin or carboplatin plus either durvalumab,&nbsp;durvalumab&nbsp;and tremelimumab &nbsp;or chemotherapy alone (FIGURE).

The investigators reported that the durvalumab arms also received a consolidation phase of the PD-L1 inhibitor for 1 year (NCT03043872).

The FDA granted durvalumab orphan drug status for the treatment of ES-SCLC on July 12, 2019, based on CASPIAN data; the trial met its primary endpoint of delivering a significant improvement in OS.

The results have not been reported but will be presented at an upcoming medical conference. &ldquo;These results support the principle that PD-L1 [inhibitors] plus chemotherapy improve survival like it did in IMpower 133,&rdquo; said Liu.

ADRIATIC, another active phase III trial, examines durvalumab alone and in combination with tremelimumab in patients with limited-stage (LS)-SCLC (NCT03703297). The study design builds on chemotherapy and radiation, the standard of care for these patients, and adds immunotherapy as consolidation for patients who have not progressed following concurrent chemoradiation. The multicenter study is still enrolling participants and seeks to recruit 600 in total. ADRIATIC follows the earlier PACIFIC trial, which saw positive improvements in OS for patients with stage III NSCLC who received concurrent chemoradiation followed by durvalumab, compared with those who received chemoradiation plus placebo (NCT02125461).

The phase III KEYNOTE-604 trial is evaluating whether pembrolizumab plus standard-of-care chemotherapy of etoposide and platinum can prolong PFS and OS in the first line, with ES-SCLC (NCT03066778).

Finally, the NRG-LU005 trial, sponsored by the National Cancer Institute in collaboration with NRG Oncology, is a phase II/III trial that is testing the efficacy of carboplatin and radiation with or without atezolizumab in patients with LS-SCLC. The study is seeking to recruit 506 participants who will be randomized to the 2 treatment arms, 1 with and 1 without the immunotherapy (NCT03811002).

No head-to-head clinical trial evidence exists that compares combination checkpoint blockade with nivolumab and ipilimumab versus other therapies for patients with SCLC. To estimate the comparative efficacy of the combination versus other therapies, a group of investigators conducted a systematic review to make an indirect comparison of nivolumab plus ipilimumab with chemotherapies in patients with refractory SCLC or disease progression after at least 1 prior line of chemotherapy or chemoradiation. The median OS among the trials ranged from 5.7 to 9.2 months. Nivolumab plus ipilimumab was associated with a more durable tumor response and more favorable long-term survival versus intravenous topotecan or amrubicin in second-line therapy. The study investigators, led by Shannon Cope, MSc, concluded that &ldquo;compared with chemotherapies for recurrent SCLC, nivolumab &plusmn; ipilimumab improves the duration of response, which may translate to long-term survival benefits.&rdquo;

&ldquo;We have had a lot of quick successes in SCLC over a few years with immunotherapies alone or in combination with chemotherapy, but there is plenty of room for more,&rdquo; Horn said. &ldquo;We still have remaining questions about markers of response, who should or should not receive these drugs, how to prevent toxicities, and how to treat progression that does not respond to checkpoint inhibition.&rdquo;

Promising results observed in recent clinical trials continue to augur the hope for immunotherapies to provide significant and meaningful improvements in clinical outcomes for patients with SCLC. The search for a predictive biomarker has been challenging, but Liu anticipates that its discovery will be associated with the next big advancement in the field.

&ldquo;Right now, the only strategy we have that has improved survival is the IMpower133 regimen and the data that will be presented from CASPIAN,&rdquo; Liu said. &ldquo;The long and meaningful benefit of immunotherapy in SCLC is probably limited to a subset of patients who will do well with the treatment [and] we continue to look at optimal ways to combine radiation therapy with chemotherapy and immunotherapy.&rdquo;

Ready N, Farago AF, de Braud F, et al. Third-line nivolumab monotherapy in recurrent sclc: CheckMate 032. J Thorac Oncol. 2019;14(2):237-244. doi: 10.1016/j.jtho.2018.10.003.

Ricciuti B, Kravets S, Dahlberg SE, et al. Use of targeted next generation sequencing to characterize tumor mutational burden and efficacy of immune checkpoint inhibition in small cell lung cancer. J Immunother Cancer. 2019;7(1):87. doi: 10.1186/s40425-019-0572-6.

Armstrong SA, Liu SV. Immune checkpoint inhibitors in small cell lung can- cer: a partially realized potential [published online June 17, 2019]. Adv Ther. doi: 10.1007/s12325-019-01008-2.

Chung HC, Piha-Paul SA, Lopez-Martin J, et al. Pembrolizumab after two or more lines of prior therapy in patients with advanced small-cell lung cancer (SCLC): results from the KEYNOTE-028 and KEYNOTE-158 studies. Cancer Res. 2019;7(13 suppl; abstr CT073). doi: 10.1158/1538-7445.SABCS18-CT073.

FDA approves pembrolizumab for metastatic small cell lung cancer. FDA website. bit.ly/2FkBXaH. Updated June 18, 2019. Accessed July 26, 2019.

FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. FDA website. bit.ly/2OiAZ5y. Updated August 20, 2018. Accessed July 25, 2019.

Horn L, Mansfield AS, Sczcęsna A, et al; IMpower133 Study Group. First- line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer.

2018;379(23):2220-2229. doi: 10.1056/NEJMoa1809064.

FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA website. bit.ly/2Jkowds. Updated March 19, 2019. Accessed July 25, 2019.

NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 1.2019, April 9, 2019. National Comprehensive Cancer Network website. bit.ly/2JTv4zC. Accessed July 26, 2019.

Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.

. 2016;17(7):883-895. doi: 10.1016/S1470-2045(16)30098-5.

Hellmann M, Antonia S, Ponce S, et al. MA09.05 Nivolumab alone or with ipilimumab in recurrent small cell lung cancer (SCLC): 2-year survival and updated analyses from the Checkmate 032 trial. J Thorac Oncol. 2017;12(1 suppl):S393-S394. doi: 10.1016/j.jtho.2016.11.446.

Hellmann MD, Callahan MK, Awad MM, et al. Tumor mutational burden and efficacy of nivolumab monotherapy and in combination with ipilimumab in small-cell lung cancer. Cancer Cell. 2018;33(5):853-861.e4. doi: 10.1016/j. ccell.2018.04.001.

Imfinzi improves overall survival at interim analysis in the phase III CASPIAN trial in 1st-line extensive-stage small cell lung cancer [news release]. Gaithers- burg, MD: AstraZeneca; June 27, 2019. bit.ly/2SGobo4. Accessed July 26, 2019.

Paz-Ares LG, Jiang H, Huang Y, Dennis PA. A phase 3, randomized study of first-line durvalumab (D) &plusmn; tremelimumab (T) + platinum-based chemother- apy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.

. 2017;35(suppl 15;abstr TPS8586). doi: 10.1200/ JCO.2017.35.15_suppl.TPS8586.

Imfinzi granted US orphan drug designation for small cell lung cancer [news release]. Gaithersburg, MD: AstraZeneca; July 12, 2019. bit.ly/32lVIIE. Accessed July 25, 2019.

Cope S, Keeping ST, Goldgrub R, et al. Indirect comparison of nivolumab &plusmn; ipilim- umab (CheckMate 032) versus other treatments for recurrent small-cell lung cancer [published online June 25, 2019].

Articles

Although chemotherapy remains the standard treatment for small cell lung cancer in first- and second-line settings, notable progress in immunotherapies have recently taken place, begging the question of how these agents will be optimized in this tumor type.

Jane Langille | Authors

Articles

Immunotherapies Show Promising Advancements in Small Cell Lung Cancer