With several agents in development, small cell lung cancer, which constitutes up to 15% of lung cancers, is the focus of increased clinical investigation that may make further treatment inroads.
Gregory Kalemkerian, MD, FACP
Until the approval of immunotherapy agents in small cell lung cancer (SCLC), the treatment landscape for this tumor type had remained virtually unaltered for the past 2 decades. Successive investigations failed to broaden the portfolio of therapies.1 Now, with several agents in development, SCLC, which constitutes up to 15% of lung cancers, is the focus of increased clinical investigation that may make further treatment inroads.
“Nothing had changed much until very recently,” Gregory Kalemkerian, MD, FACP, a specialist in thoracic cancers, explained in an interview with OncologyLive®. “There was always a lot of enthusiasm that if you find the right drugs, you’ll be able to get over the hump and get better outcomes.”
Frontline treatment in SCLC was augmented this year with the approval of the anti—PD-L1 agent atezolizumab (Tecentriq) in combination with carboplatin and etoposide (Figure).2,3 In 2018, the anti—PD-1 antibody nivolumab (Opdivo) was approved as monotherapy in the third-line setting. Other agents are under evaluation in this setting, among them lurbinectedin, which blocks transcription and induces DNA double-strand breaks, leading to apoptosis. Lurbinectedin has shown promise in relapsed SCLC.
But improvements in outcomes in SCLC have unfolded at a slow pace. Approved in 1985, the chemotherapy doublet of etoposide and cisplatin remains the most commonly used frontline therapy for patients with limited-stage SCLC.2,4 Although SCLC is one of the most chemotherapy-sensitive solid tumors, most patients’ disease will recur within 1 year of treatment completion.4
“SCLC was found to be very vulnerable to chemotherapy and radiation therapy. [These treatments elicited] very good responses, but not durable responses in the majority of patients, so the cancer tended to come back very quickly and very vigorously, although initially it responded really well,” said Kalemkerian, a professor in the Division of Hematology and Oncology at the University of Michigan Medical School at Ann Arbor.
Prognosis continues to remain poor for those with relapsed disease: Median survival is approximately 5 to 6 months.5 Moreover, subsequent therapy options for patients with relapsed SCLC are limited, due to the low performance status of many patients with relapsed disease and the limited efficacy of chemotherapy.
“A lot of research over the past 25 to 30 years has gone into looking at different drug combinations and different ways of doing radiation, but nothing [has] really gotten us beyond what we had been achieving in the late ’80s. Patients with limited-stage disease could be treated with chemotherapy and radiation, and about 20% to 25% of them would be cured long-term, but most people relapsed and died from their disease,” Kalemkerian said.
For patients with metastatic disease, the prognosis was worse: “We would treat those patients with chemotherapy, and sometimes radiation as well, and they would do well for several months because the cancer would diminish and they would feel better. But the cancer would come back with a vengeance, and the median time that people survived was about 10 months,” he explained.
Approved in 1999, carboplatin and etoposide became a second chemotherapeutic standard of care for SCLC.2 It represented an alternative to the harsh adverse events associated with cisplatin. Cisplatin/etoposide and carboplatin/etoposide were the first-line standards of care for patients with SCLC until March 2019, which is when the FDA approved atezolizumab in combination with carboplatin and etoposide as a frontline treatment for adult patients with extensive-stage SCLC.
The Front Line
Atezolizumab notably became the first immunotherapy authorized for frontline treatment of extensive-stage SCLC. In SCLC, as with other tumor types, the advent of immunotherapy has offered promise to patients, particularly those with relapsed SCLC.
“In SCLC, immunotherapies were initially explored in patients with relapsed disease who didn’t have many options for treatment, and the benefits were there in a small number of people: 10% to 20% had shrinkage of the cancer, and this shrinkage was more durable,” Kalemkerian said. “Some of these patients have done very, very well, for well beyond a year at this point with [immunotherapeutic] disease control.”
Atezolizumab’s approval in conjunction with carboplatin and etoposide was based on results from the phase III IMpower133 trial (NCT02763579), which enrolled 403 patients with extensive-stage disease who had not received prior chemotherapy.6 Patients were randomized to receive atezolizumab at 1200 mg (n = 201) and carboplatin plus etoposide or placebo and carboplatin plus etoposide (n = 202).
The median overall survival (OS) with atezolizumab was 12.3 months (95% CI, 10.8-15.9) versus 10.3 months in the placebo arm (95% CI, 9.3-11.3).
“IMpower133 demonstrated the significant clinical benefit of adding immunotherapy to chemotherapy. If we look at how many people live longer than a year, with the immunotherapy it’s 52%, and without immunotherapy, it was 38%. So that’s a [14 percentage gain in terms of] people living longer,” said Kalemkerian.
“It’s a pretty good benefit, but it’s still unfortunately a relatively small group of people who are benefiting. It’s an advance, but it’s not the ultimate answer for the majority of people with this disease,” he added.
The Second Line
As first-line treatment progress stalled for many years, so did progress in the secondline. Topotecan hydrochloride (Hycamtin) is currently the sole FDA-approved secondline treatment option for patients with SCLC in the United States and Europe.2 The topoisomerase inhibitor is currently indicated for intravenous (IV) use in those with platinum-sensitive SCLC whose disease progressed after initial or subsequent chemotherapy and for those with relapsed SCLC, respectively.7
The use of topotecan in this patient population is supported by results from 2 key randomized studies.8 The first compared topotecan with cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) in 211 patients with SCLC for whom firstline chemotherapy had failed.9 Patients were randomized to receive either a topotecan infusion (n = 107) or a CAV infusion (n = 104).
Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was also greater in the topotecan arm for dyspnea, anorexia, hoarseness, fatigue, and interference with daily activity (P ≤.043). Investigators concluded that topotecan was as effective as CAV in the treatment of patients with recurrent SCLC and led to better management of several symptoms.
The second study that supported the use of topotecan was a phase III trial that compared best supportive care (BSC; IV topotecan) with oral topotecan and BSC in 141 patients with relapsed SCLC who were not considered candidates for standard IV therapy.10 Findings showed that BSC with oral topotecan was superior to BSC alone in prolonging survival. The median survival with BSC was 13.9 weeks (95% CI, 11.118.6) versus 25.9 weeks with oral topotecan (95% CI, 18.3-31.6). The 6-month survival rate was also higher in the topotecan group at 49% compared with 26% for those who received BSC alone.
The Third Line
In August 2018, nivolumab notably became the first FDA-approved agent in the thirdline setting.2 It was also the first checkpoint inhibitor indicated for the treatment of patients with SCLC, specifically those with disease progression following platinum-based chemotherapy and 1 other line of therapy.11 The decision was based on data from the phase I/II CheckMate 032 trial (NCT01928394), in which the objective response rate (ORR) was 12% (95% CI, 6.5%-19.5%) for nivolumab after platinum-based chemotherapy and 1 other prior line of therapy.
In June 2019, single-agent pembrolizumab (Keytruda) received an accelerated approval for the treatment of patients with metastatic SCLC who have disease progression on or after platinum-based chemotherapy and ≥1 other prior line of therapy.12 Pooled data from cohort G of the phase II KEYNOTE-158 study (NCT02628067) and cohort C1 of the phase Ib KEYNOTE-028 trial (NCT02054806) showed that pembrolizumab elicited a 19% overall response rate (95% CI, 11%-29%) in this patient population, in addition to a complete response rate of 2% and a partial response rate of 17%.
Durvalumab (Imfinzi) monotherapy and lurbinectedin (PM01183) monotherapy have shown potential in the first- and second-line settings, respectively. In July 2019, the FDA granted an orphan drug designation to durvalumab for the treatment of patients with SCLC.13 The designation is awarded to current and emerging therapies intended for the treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States.
Durvalumab’s orphan drug designation followed the announcement of data from the 3-arm, phase III CASPIAN trial (NCT03043872), which compared durvalumab with chemotherapy in patients with extensive stage SCLC and demonstrated a statistically significant improvement in OS. The trial enrolled 988 treatment-naïve patients with extensive-stage SCLC.14 Patients were randomized 1:1:1 to frontline durvalumab plus etoposide and either cisplatin or carboplatin, durvalumab plus the CTLA-4 inhibitor tremelimumab and chemo-therapy, or chemotherapy alone. In both experimental arms, patients received ≤4 cycles of chemotherapy; in the control arm, patients were allowed ≤6 cycles of chemotherapy and prophylactic cranial irradiation. The data from the CASPIAN trial were presented at the 2019 International Association for the Study of Lung Cancer (IASLC) World Conference on Lung Cancer in Barcelona. The median OS increased from 10.3 months (95% CI, 9.3-11.2) with etoposide-platinum chemotherapy alone to 13.0 months (95% CI, 11.5-14.8) with the addition of durvalumab, translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.591-0.909; P =.0047).15 The 12-month and 18-month survival also improved with the PD-L1 inhibitor: the 12-month OS rate was 53.7% in the durvalumab arm and 39.8% with chemo-therapy alone. The 18-month OS rate was 33.9% with durvalumab and 24.7% without.
Durvalumab is also being evaluated in the phase III ADRIATIC trial (NCT03703297). Investigators are exploring the efficacy and tolerability of the agent in patients with limited-stage SCLC whose disease has not progressed following concurrent chemoradiation therapy. Beyond the SCLC setting, durvalumab is indicated for the treatment of patients with unresectable, stage III non—small cell lung cancer (NSCLC).
Lurbinectedin monotherapy could be a treatment landscape—expanding agent in SCLC in the second line. The single-agent is the focus of an ongoing phase II basket trial (NCT02454972) that is examining the antitumor activity of lurbinectedin in terms of ORR in advanced solid tumors in SCLC, among other cancers. The ORR was 35.2% in the second line for the SCLC cohort, leading the study to meet its primary endpoint.16 PharmaMar, the developer of lurbinectedin, announced its intent to submit a new drug application for the agent.17
The ORR consisted of all partial responses, which occurred in 37 of 105 patients. An additional 35 patients had stable disease, for a disease control rate of 68.6% (95% CI, 58.8%-77.3%). Overall, 65% of patients had a decrease in tumor size and responses occurred in 5 of 8 patients who had failed prior immunotherapy. Twenty-eight patients (26.7%) had progressive disease, and 5 patients were not evaluable.
The median duration of response was 5.3 months (95% CI, 4.1-6.4). The response rate was higher in patients with sensitive disease, defined as those with a chemotherapy-free interval (CTFI) ≥90 days. Among these patients, the ORR was 45% compared with 22.2% in patients with resistant disease (CTFI <90 days).
Investigators presented new data from the SCLC cohort of the phase II basket trial at the IASLC World Conference. Lurbinectedin demonstrated an acceptable safety profile and led to an ORR of 40.5% (95% CI, 29.9-51.7) in patients (n = 84) with a CTFI ≥30 days.18 For patients with resistant disease and a CTFI of 30 to 89 days (n = 24), the ORR was 29.2% (95% CI, 12.6-51.5). There is currently no approved treatment for this patient population. The ORR was 45% (95% CI, 32.1-58.4) in 60 patients with sensitive disease and a CTFI ≥90 days.
Results from 2 phase IB trials that evaluated lurbinectedin in combination with paclitaxel or irinotecan in patients with relapsed SCLC were also shared. Investigators said both doublet regimens showed promising activity after first-line therapy in SCLC that was consistent with that observed in other trials in which lurbinectedin was given alone or in combination.19 The ORR for those with a CTFI >90 days was 67% among 7 patients treated with lurbinectedin and paclitaxel (Taxol) and 38% among 12 patients treated with lurbinectedin and irinotecan. Median PFS was 4.8 months (95% CI, 1.8-12.5) and 5.6 months (95% CI, 1.4-8.3) in the lurbinectedin-paclitaxel and lurbinectedin-irinotecan arms, respectively.
Clinical Efforts for Improvement
The recent SCLC-focused clinical trials reflect renewed interest in developing novel treatments for this disease. “Thirty years ago, there were quite a few studies going on in SCLC, as many as in NSCLC, but once NSCLC started to hit stride with targeted therapies, the interest in SCLC waned because there was no progress, so people thought it was fruitless,” Kalemkerian said.
“The number of trials that the industry would support really tapered off for a couple of decades. In the past 5 years or so there’s been another uptick in the number of trials being done in SCLC—that’s definitely a plus.”
Kalemkerian notes that clinical trials in the SCLC setting, to date, have led only to modest advances. “If there’s been an improvement, it’s been a fairly incremental improvement, and not a blockbuster improvement,” he said.
However, he remains confident that continuing study of SCLC will yield impactful developments. “There’s a lot of work being done by some very talented researchers who are trying to dissect molecular pathways and identify different subsets of SCLC and then try to find the vulnerabilities of each of those subsets for a targeted type of treatment,” he said. “I think we’re on the cusp of doing something good.”