OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Clinical advances in the treatment of small cell lung cancer (SCLC) have lagged behind those of other tumor types, but the delay is not for lack of effort. In recent years, however, improved understanding of disease biology has identified some novel targets that may make these tumors more vulnerable to treatment. One such approach in the frontline setting has been the integration of various immune checkpoint inhibitors into chemotherapy regimens, whereas in the second-line setting, a new chemotherapy agent has recently been added to the treatment armamentarium.

, a panel of thoracic cancer experts discussed the latest developments in treating patients with SCLC in both the first- and second-line settings. They examined the clinical trial data for some newer agents, including some reassuring real-world data, and discussed how they use these agents in clinical practice.

Immune Checkpoint Inhibitors in the First Line

Two immune checkpoint inhibitors are FDA approved for use in combination with chemotherapy in treatment-naïve patients with extensive-stage SCLC: atezolizumab (Tecentriq) and durvalumab (Imfinzi).

 A third agent, pembrolizumab (Keytruda), was explored in the KEYNOTE-604 trial (NCT03066778) but did not meet the prespecified significance threshold for overall survival (OS).

The FDA approved atezolizumab in March 2019 based on data from the phase 3 IMpower133 trial (NCT02763579).

 “IMpower133 was the first major change to frontline treatment for extensive-stage SCLC in 30 or 40 years.…[It] showed that adding the PD-L1 inhibitor atezolizumab concurrently with chemotherapy and as maintenance treatment to carboplatin-etoposide chemotherapy improved both progression-free survival [PFS] and OS with-out adding notable toxicity,” 

, said. He explained that although chemotherapy alone with platinum-etoposide provided reliably high response rates, it was also associated with high relapse rates and a short PFS and OS, spurring the search for better standards of care.

IMpower133 randomly assigned 403 treatment-naïve patients with extensive-stage SCLC to receive carboplatin and etoposide with either atezolizumab (n = 201) or placebo (n = 202).

 The combination showed benefit in OS and PFS after a median follow-up of 13.9 months, which was maintained with data from a median follow-up of 22.9 months (

“When we look at the curves, we see that they separate,” Liu said. “It’s not the degree of benefit we are all waiting for, but it’s clearly an improvement over chemotherapy alone. We are trying to identify the patients who derive benefit.” He noted that biomarker studies have thus far failed to show which patients are most likely to benefit from the addition of atezolizumab, with factors such as tumor mutational burden (TMB) and PD-L1 expression not found to be useful. Although Liu noted that patients with more inflammatory disease have shown enriched benefit with atezolizumab, this finding does not guide who should and should not receive this treatment.

Whereas biomarker studies have been somewhat disappointing, recent real-world data have been exciting. Liu discussed some real-world data for atezolizumab presented at the 2021 American Society of Clinical Oncology Annual Meeting.

 The data come from a retrospective review of The US Oncology Network electronic health records for adults with extensive-stage SCLC who received a diagnosis between October 2018 and December 2019, with follow-up through the end of March 2020. Of the 347 patients included in the study, 77% received atezolizumab. Liu said this shows a very broad uptake of the atezolizumab regimen in clinical practice. More importantly, despite the patients being much older and more diverse having more brain metastases compared with the IMpower133 population, outcomes were similar, with treatment duration, continued therapy, and marked survival being almost identical between the clinical trial and realworld cohorts, Liu explained.

“I love those real-world data because it’s a completely different patient population from what we get in clinical trials. We all realize that in the real world, that’s what we have, [so] it’s very comforting and good to see that the results seem to match what we got in the clinical trial in terms of the clinical efficacy,” 

The FDA approved durvalumab in March 2020 based on data from the phase 3 CASPIAN trial (NCT03043872).

 The CASPIAN trial included 805 treatment-naïve patients with extensive-stage SCLC who were randomly assigned 1:1:1 to durvalumab plus platinum-etoposide (n = 268), durvalumab plus tremelimumab plus platinum-etoposide (n = 268), or platinum-etoposide alone (n = 269).7 Interim analysis comparing results for durvalumab plus platinum-etoposide with platinum-etoposide alone showed significant benefit with the addition of durvalumab, with a median OS of 13.0 months (95% CI, 11.5-14.8) vs 10.3 months (95% CI, 9.3-11.2) in these treatment arms, respectively, (HR, 0.73; 95% CI, 0.590.91; 

 = .0047). At 18 months, 34% (95% CI, 26.9%-41.0%) of patients in the durvalumab arm were alive compared with 25% (95% CI, 18.4%31.6%) in the chemotherapy-alone arm. “It’s very similar to the atezolizumab data, which made everybody feel a little better,” 

Chiang explained that although CASPIAN was similar in design to IMpower133, it had some distinguishing features. She noted that patients could be treated with cisplatin or carboplatin per investigator’s choice and that the trial included patients with asymptomatic brain metastases, including those previously treated with prophylactic cranial irradiation. The trial also included a third arm, which added the anti–CTLA-4 monoclonal antibody tremelimumab to durvalumab plus platinum-etoposide. She noted that the data for this arm were not positive, with a median follow-up of 25.1 months showing a median OS of a little over 10 months in both the tremelimumab and chemotherapy-alone arms.

“Although there wasn’t a difference in OS [with the addition of tremelimumab], if you look at 12 months out at the landmark analysis, or even 24 months out, there are a significant number of patients surviving,” Chiang said, noting it is approximately 20% of all durvalumab-treated patients vs 5% of those treated with only chemotherapy. Furthermore, characterization of long-term clinical benefit in treatment responders suggests those who achieve a PFS of at least 12 months have exceptional 2-year OS rates greater than 75%, with patients receiving durvalumab more than 3 times as likely to derive long-term benefit.

 “That’s saying if you’re going to do well, you’re going to do really well,” Chiang said.

As with atezolizumab, TMB has not been found to be predictive of response to durvalumab treatment.

 “Whether or not you used a cut point of 10 or 16 mutations per megabase, that wasn’t predictive of response. TMB is not the marker here,” Chiang said.

Practical Perspectives on Chemotherapy-Immunotherapy

“For the most part, [I use] chemotherapy-immunotherapy for all patients,” 

, said. He explained that a growing body of evidence suggests chemotherapy-immunotherapy can be safely used in most patients, including those previously thought to be ineligible, such as those with underlying autoimmune diseases, provided they are closely monitored for immune-related adverse effects (AEs). The only time he would not pursue this approach, Iams said, is in the setting of a severe underlying autoimmune disease with visceral organ damage requiring more than 10 mg of systemic glucocorticoids daily for maintenance. As for selecting between available checkpoint inhibitors, Iams said he “approach[es] atezolizumab and durvalumab as equivalent.”

When asked about the chemotherapy component of first-line SCLC treatment, Chiang said 

she usually uses carboplatin. “We’re talking about patients where we’re running a marathon. This is a disease that’s not curable. We want to provide our patients with the best quality of life they can achieve,” she said. Although she prefers carboplatin, she said she might consider cisplatin for young patients and those with good performance status.

Based on current data, the panelists agreed that adding an anti–CTLA-4 antibody does not have a role in treating SCLC. “When I look at the tail of the curve [in CASPIAN], the tail looks better in the durvalumab-tremelimumab arm and almost catches up to the durvalumab tail. I feel like that’s because of the durvalumab and that the only thing tremelimumab is adding there is cost and a heck of a lot of toxicity,” Liu explained.

Chiang agreed that although there does not appear to be a role for anti–CTLA-4 antibodies in treating the general population of patients with extensive-stage SCLC, she is working on an investigator-initiated trial that may help tease out whether an opportunity exists for these agents to provide benefit somewhere in the treatment course for certain subpopulations with SCLC. In the trial (NCT03670056), patients with relapsed SCLC, including those previously on atezolizumab maintenance, will receive ipilimumab (Yervoy)/nivolumab (Opdivo).

 “We’re doing pretreatment and on-treatment biopsies. There’s something to be said for looking at the tumor microenvironment and specifically the infiltration of T cells, so stay tuned for that. There may be a way anti–CTLA-4 may help juice up the microenvironment so that we get T cells in there so we can have a response,” she said.

Once first-line treatment fails, patients with SCLC are left with few options. The National Comprehensive Cancer Network (NCCN) prefers that treatments for patients who relapse within 6 months include topotecan (Hycamtin) and lurbinectedin (Zepzelca), whereas rechallenge with first-line treatment is preferred for those who relapse after 6 months.11 The role of immune checkpoint inhibitors in the second-line setting remains unclear. Although single-agent nivolumab and pembrolizumab had been granted accelerated approval as treatment for patients with 

relapsed extensive-stage SCLC, this indication was voluntarily withdrawn by their manufacturers after these agents failed to show an OS benefit in confirmatory studies

Table 2. Efficacy Data for Withdrawn Immunotherapy Indications in SCLC

Lurbinectedin prevents transcription factors from binding to their recognition sequences, thereby inhibiting oncogenic transcription and leading to tumor cell apoptosis.

 The agent has also been shown to affect the tumor microenvironment by inhibiting activated transcription in tumor-associated macrophages.

 In June 2020, lurbinectedin received accelerated approval from the FDA for patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy, making it the first drug approved by the FDA for this indication 

in more than 20 years.15 Approval was based on findings from a single-arm, open-label, phase 2 basket trial (NCT02454972) that included 105 patients with recurrent SCLC.

“An overall response by investigator assessment was seen in 37 patients, for an [overall] response rate of 35.2% [95% CI, 26.2%-45.2%],” Vivek Subbiah, MD, said. The disease control rate was 68.6% (95% CI, 58.8%-77.3%), 

the median duration of response was 5.3 months (range, 4.1-6.4), the median PFS was 3.5 months (95% CI, 2.6-4.3), and the median OS was 9.3 months (95% CI, 6.3-11.8).

Lurbinectedin had a manageable safety profile, with the most common grade 3 to 4 AEs, irrespective of causality, being hematological abnormalities, particularly neutropenia (46%), leucopenia (29%), anemia (9%), and thrombocytopenia (7%).14 Serious treatment-related AEs occurred in 10% of patients, of which neutropenia and febrile neutropenia were the most common, with each affecting 5% of patients. No treatment-related deaths occurred.

Subbiah proceeded to discuss a study he presented at the European Society for Medical Oncology Virtual Congress 2020, in which investigators evaluated the activity of lurbinectedin in second-line patients with SCLC who were candidates for platinum rechallenge (ie, relapse after 6 months).

 “Interestingly, the investigator-assessed objective response rate in this cohort was 60%, with a median duration of 5.5 months and disease control rate of 95%. Of note, 60.9% and 27.1% of patients were alive at 1 and 2 years, respectively,” Subbiah said. Based on 

these findings, he noted that “lurbinectedin is an effective treatment for platinum-sensitive relapsed SCLC, especially in patients with a chemotherapy-free interval of greater than 180 days,” potentially making this option as viable as the NCCN’s preferred approach of rechallenge in these patients.

Putting Treatment Options Into Perspective 

In patients who are candidates for rechallenge, Liu said he considers the length of benefit of the original treatment. “If there’s a long period of benefit, I revisit the platinum-etoposide and see whether I can kick lurbinectedin or topotecan as another option down the line. This is off trial, of course. We’re really pushing for trials in this subset,” he said, adding that when rechallenging with chemotherapy-immunotherapy, he maintains the checkpoint inhibitor in select patients, despite a lack of data to support this decision.

In contrast, Iams and Chiang said they do not continue the checkpoint inhibitor. Chiang said she goes back to the platinum-etoposide for 6 months. Although she acknowledged the lurbinectedin data are impressive, she is concerned that they are from a small study that did not include patients with brain metastases. “For patients whom we’ve been trying to keep out of the hospital, especially during this pandemic, I’ve been using some oral topotecan or potentially temozolomide if they have brain metastases,” she said. Taxanes are another good option for patients with brain metastases, Chiang said, adding that, anecdotally, she has seen some patients have a very good response to taxanes following checkpoint inhibitor therapy. “I don’t know whether there’s something that is boosted by adding chemotherapy post progression, as in the INSIGNA trial [NCT03793179]. Hopefully, we’ll learn something about that,” she said.

Although the FDA approvals of nivolumab and pembrolizumab were withdrawn, these agents remain options in the NCCN SCLC guidelines.

 “The NCCN small cell guidelines group ultimately voted to keep both of these drugs—although as a category 3—which indicates some discordance in the consensus,” Chiang said. She noted this discordance is not surprising because some patients have been found to do extremely well with a single-agent immune checkpoint inhibitor, even if the confirmatory trials did not show an OS 

benefit with these agents. Therefore, although nivolumab and pembrolizumab would now be used off label, she said they remain good options, especially for patients “who can’t tolerate chemotherapy or who have good performance status and can still be treated.”

Despite significant advances being made in SCLC, Subbiah noted that progress is approximately 15 years behind that of the non–small cell lung cancer field. “I’m sure there’s going to be a future renaissance of biomarkers and personalized therapy. Defining the subsets in SCLC represents the first step in our understanding of what drugs work best for which patient, at least preclinically. It at least gives us a guide for a path forward for personalized approaches,” he said. To help propel treatment forward, he encouraged physicians to enroll their patients with SCLC into clinical trials.

FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. March 18, 2019. Updated March 19, 2019. Accessed September 9, 2021. bit.ly/2VE30ZU 

FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. March 27, 2020. Updated March 30, 2020. Accessed September 9, 2021. bit.ly/38YFEkL 

Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: randomized, double-blind, phase III KEYNOTE-604 study. 

. 2020;38(21):23692379. doi:10.1200/JCO.20.00793 

Horn L, Mansfield AS, Szczęsna 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 

Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). 

 2021;39(6):619-630. doi:10.1200/JCO.20.01055 

Nadler ES, Vasudevan A, Davies K, Wang Y, Johnson A, Ogale S. Real-world evidence of cancer immunotherapy (CIT) combination treatment in first-line (1L) extensive-stage small cell lung cancer (ES-SCLC). 

. 2021;39(suppl 15):8561. doi:10.1200/ JCO.2021.39.15_suppl.8561 

Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. 

. 2019;394(10212):1929-1939. doi:10.1016/S01406736(19)32222-6 

Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus plati

num-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. 

. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8

Goldman JW, Garassino MC, Chen Y, et al. Durvalumab (D) ± tremelimumab (T) + platinum-etoposide (EP) in 1L ES-SCLC: characterization of long-term clinical benefit and tumour mutational burden (TMB) in CASPIAN. 

. 2020;31(suppl 4):S1212-S1213. doi:10.1016/j.annonc.2020.08.2328 

Ipilimumab and nivolumab in recurrent extensive stage small cell lung cancer after receiving platinum-based chemotherapy. ClinicalTrials.gov. Updated July 20, 2020. Accessed September 11, 2021. https://clinicaltrials.gov/ct2/show/NCT03670056 

NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 1.2022. Accessed September 11, 2021. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf Bristol Myers Squibb statement on Opdivo (nivolumab) small cell lung cancer U.S. indication. News release. 

Bristol Myers Squibb; December 29, 2020. Accessed September 11, 2021. bit. ly/3nnfctr 

Merck provides update on Keytruda (pembrolizumab) indication in metastatic small cell lung cancer in the US. News release. Merck; March 1, 2021. Accessed September 11, 2021. bit.ly/391eU2Z 

FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. FDA. Updated 20, 2018. Accessed September 13, 2021. bit.ly/3nIEvGH 

Owonikoko TK, Park T, Govindan R, et al. Nivolumab and ipilimumab as maintenance therapy in extensive-disease small-cell lung cancer: CheckMate 451. 

. 2021;39(12):13491359. doi:10.1200/JCO.20.02212 

Spigel DR, Vicente D, Ciuleanu TE, et al. Second-line nivolumab in relapsed small-cell lung cancer: CheckMate 331. 

. 2021;32(5):631-641. doi:10.1016/j.annonc.2021.01.071 

FDA approves pembrolizumab for metastatic small cell lung cancer. FDA. Updated June 18, 2019. Accessed September 13, 2021. bit.ly/2YUVk6L 

Rudin CM, Awad MM, Navarrow A, et al. KEYNOTE-604: pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC). 

 2020;38(suppl 15):9001. doi:10.1200/JCO.2020.38.15_suppl.9001 

Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. 

. 2020;21(5):645654. doi:10.1016/S1470-2045(20)30068-1 

Singh S, Jaigirdar AA, Mulkey F, et al. FDA approval summary: lurbinectedin for the treatment of metastatic small cell lung cancer. 

. 2021;27(9):2378-2382. doi:10.1158/10780432.CCR-20-3901 

Subbiah V, Pas-Ares L, Besse B, et al. Activity of lurbinectedin in second-line SCLC patients candidates for platinum re-challenge. 

 2020;31(suppl 4):S1034-S1035. doi:10.1016/j. annonc.2020.08.1545

Articles

Clinical advances in treatment of small cell lung cancer have lagged behind those of other tumor types, but the delay is not for lack of effort. 

Will Slow and Steady Progress in Treating SCLC Win the Race?

Sacituzumab govitecan-hziy (Trodelvy) demonstrated a significant survival improvement over single-agent chemotherapy treatment of physician’s choice (TPC) for patients with metastatic triple-negative breast cancer (mTNBC), according to data presented by Hope S. Rugo, MD, FASCO. 

video series, which features experts delving into key trial results presented at conferences, Rugo provided her insights on the final analysis data from the international phase 3 ASCENT trial (NCT02574455). The findings were initially presented at the 2021 American Society of Clinical Oncology Annual Meeting.

In previously published findings, the novel antibody-drug conjugate (ADC) sacituzumab govitecan resulted in a median progression-free survival (PFS) of 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6 with single-agent TPC (HR, 0.41; 95% CI, 0.320.52; 

 < .001) among patients without brain metastases treated in the study. The median overall survival (OS) with sacituzumab govitecan was 12.1 months (95% CI, 10.7-14.0) vs 6.7 months (95% CI, 5.8-7.7) with single-agent TPC in the overall population (HR, 0.48; 95% CI, 0.38-0.59; 

In a subanalysis of the ASCENT study, efficacy outcomes were assessed in the brain metastases–negative population for each individual chemotherapeutic agent. The investigators determined the singleagent chemotherapy before patients were randomized from one of the following choices: eribulin (n = 126), vinorelbine (n = 47), capecitabine (n = 31), or gemcitabine (n = 29).

According to the subgroup analysis, gemcitabine had the longest median PFS at 2.7 months (95% CI, 1.6-4.8) vs the other single-agent TPCs. Specifically, the median PFS with eribulin was 2.1 months (95% CI, 1.5-2.8), 1.6 months (95% CI, 1.4-2.7) with vinorelbine, and 1.6 months (95% CI, 1.4-2.4) with capecitabine.

Further, gemcitabine elicited the longest median OS at 8.4 months (95% CI, 5.0-9.6), vs 6.9 months (95% CI, 5.8-7.8) with eribulin, 5.9 months (95% CI, 4.5-6.7) with vinorelbine, and 5.2 months (95% CI, 3.5-8.6) with capecitabine (

). These data were reported in comparison with a median PFS of 5.6 months (HR, 0.41; 95% CI, 0.32-0.52; 

 < .001) and a median OS of 12.1 months with sacituzumab govitecan (HR, 0.48; 95% CI, 0.38-0.59; 

“mTNBC is a disease that has had limited treatment options, and a number of chemotherapy agents are used in sequence,” said Rugo, a professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and the 2020 Giants of Cancer Care® award winner in the Education category.

“Eribulin has been a commonly used monotherapy for previously treated mTNBC based on data from the EMBRACE trial [NCT00388726], but median PFS in heavily pretreated patients has been poor at less than 3 months.”

“[Sacituzumab govitecan] has become an early standard of care with rapid adoption throughout the United States, where we are treating patients with TNBC and have access to [the agent]. There is tremendous interest around the world for having as quick access to sacituzumab govitecan as possible.”

In April 2021, the FDA approved sacituzumab govitecan for patients with unresectable locally advanced or metastatic TNBC who have received at least 2 prior systemic therapies, with at least one of them for metastatic disease, based on findings from ASCENT. The agency previously granted an accelerated approval in April 2020 for patients with mTNBC who have received at least 2 prior therapies for metastatic disease; ASCENT was the confirmatory trial for the accelerated approval.

Due to this heterogenous disease’s lack of therapeutic targets, mTNBC has been historically limited to single-agent chemo-therapy treatment options. Although this remains the standard of care for previously treated mTNBC, ADCs have made head-way as viable treatment options for this patient population.

Sacituzumab govitecan is an ADC that binds to Trop-2–expressing cancer cells. It is internalized with the subsequent release of SN-38 via hydrolysis of the linker, resulting in DNA damage that leads to apoptosis and cell death.

In ASCENT, a multicenter, open-label, randomized trial, investigators enrolled 529 patients with unresectable locally advanced or mTNBC who had relapsed after at least 2 prior chemotherapies. One of those therapies could be in the neoadjuvant setting if progression occurred within 12 months. Of the total patient population, 235 and 233 patients were negative for brain metastasis in the sacituzumab govitecan and TPC arms, respectively.

The median age was 54 years (range, 27-82). Forty-two percent of patients had hepatic metastases, 9% had 

 mutations, and 70% had TNBC at diagnosis. Twelve percent had baseline previously treated and stable brain metastases (n = 61; 32 in the sacituzumab govitecan arm, 29 in the TPC arm). Overall, 29% of patients had received prior PD-1/PD-L1 therapy (

Patients were randomized (1:1) to receive sacituzumab govitecan 10 mg as an intravenous infusion on days 1 and 8 of a 21-day cycle or a single-agent TPC. At the data cutoff of March 11, 2020, 15 patients (6%) remained on treatment in the sacituzumab govitecan arm and 0 patients remained on treatment in any TPC agent arm. The most common reason for treatment discontinuation was disease progression.

Additional efficacy end points stratified in the subanalysis were objective response rates (ORRs) and clinical benefit rates (CBRs) for the ADC vs individual chemotherapy regimens. The ORR with sacituzumab govitecan was 35%, vs 5%, 4%, 6%, and 3% with eribulin, vinorelbine, capecitabine, or gemcitabine, respectively. Ten patients in the sacituzumab govitecan arm had a complete response vs 2 patients in the eribulin arm; no patients achieved a complete response in the other chemotherapy groups. The median duration of response for the sacituzumab govitecan group was 6.3 months and ranged from 2.8 to 3.6 months for the TPC groups.

The CBR with sacituzumab govitecan was 45%, vs 8%, 6%, 10%, and 14% with eribulin, vinorelbine, capecitabine, or gemcitabine, respectively. CBR was defined as the percentage of patients with a confirmed best overall response of complete response or partial response, and stable disease greater than 6 months.

Thus, Rugo highlighted the fact that none of the agents individually tested in the TPC arm did not offered any significant outcomes when directly compared against sacituzumab govitecan.

“You can see the big separation and how similar the TPC arms fall in their [KaplanMeier] curves,” Rugo said. “[Also, ORR] was extremely low for the agents and they were all very similar so one did not stand out.”

Regarding safety, the investigators reported a number of grade 3/4 treatment-related adverse effects (AEs) observed in the safety population with sacituzumab govitecan (n = 258) vs eribulin (n = 123), respectively. These included neutropenia (51% vs 31%), leukopenia (10% vs 5%), diarrhea (10% vs 0%), anemia (8% vs 2%), febrile neutropenia (6% vs 2%), fatigue (3% vs 5%), and peripheral neuropathy (0% vs 2%).

Additionally, grade 3/4 AEs with sacituzumab govitecan vs a pooled analysis of patients treated with vinorelbine, capecitabine, and gemcitabine (n = 101) included neutropenia (51% vs 36%), leukopenia (10% vs 6%), diarrhea (10% vs 1%), anemia (8% vs 8%), febrile neutropenia (6% vs 2%), and fatigue (3% vs 6%).

Discontinuation rates because of AEs for sacituzumab govitecan, eribulin, vinorelbine, capecitabine, and gemcitabine were 5%, 2%, 10%, 7%, and 9%, respectively. One treatment-related death was reported in the TPC arm (eribulin; neutropenic sepsis).

“What we learned supports what we understood from the parent ASCENT trial and shows how effective sacituzumab govitecan is compared with TPCs, but it also gave us important additional information about safety management,” Rugo said. “The more we look at safety and think about prospective management of safety, the better we can help our patients stay on effective therapy and also retain quality of life.”

In an analysis of health-related quality-of-life (HRQOL) data presented at the European Society for Medical Oncology Annual Congress 2021, sacituzumab govitecan showed statistically significant and clinically meaningful improvements over TPC.

Specifically, the agent prolonged time to first deterioration of in nearly all HRQOL domains and significantly shortened the time to improvement in physical functioning and pain.

 The median time to first clinically meaningful deterioration for physical functioning was 22.1 weeks with sacituzumab govitecan vs 12.1 weeks with TPC (HR, 0.61; 95% CI, 0.49-0.75). For pain the median time to deterioration was 21.6 weeks vs 9.9 weeks with TPC (HR, 0.48; 95% CI, 0.48-0.74).

The benefit extended to other HRQOL domains including fatigue and role functioning; however, the median time to deterioration in the global health status and quality of life domain for those treated with TPC at 15.1 weeks compared with 14.1 weeks with sacituzumab govitecan (HR, 0.87; 95% CI, 0.70-1.07).

In her discussion of the subgroup analysis Rugo concluded that sacituzumab govitecan should be considered as a new standard of care in patients with pretreated mTNBC. She added that ongoing clinical trials are evaluating moving sacituzumab govitecan into the first-line setting as well as the postneoadjuvant and neoadjuvant settings.

“There are also clinical trials evaluating sacituzumab govitecan in combination with checkpoint inhibitors,” Rugo noted. “There’s great interest in capitalizing on those potential immune effects of ADCs [with] these combinations.”

O’Shaughnessy J, Punie K, Oliveira M, et al. Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC). 

. 2021;39(suppl 15):1077. doi:10.1200/JCO.2021.39.15_suppl.1077 

Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485 

FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 8, 2021. Accessed September 12, 2021. bit.ly/38tqmUM 

Trodelvy. Prescribing information. Immunomedics, Inc; 2021. Accessed September 12, 2021. bit.ly/2TBUCcl 

Loibl S, Loirat D, Tolaney S, et al. Health-related quality of life (HRQoL) in the ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC). Presented at: European Society for Medical Oncology Annual Congress 2021. September 16-21, 2021; virtual. Abstract 257P.

Hope S. Rugo, MD, FASCO, provides her insights on the final analysis data from the international phase 3 ASCENT trial.

Sacituzumab Govitecan May Be New Standard of Care in Metastatic TNBC

Hepatocellular cancer (HCC), the most common primary liver malignancy, is the fourth-leading cause of cancer-related deaths globally. HCC is a heterogenous malignancy resulting from diverse causes of chronic liver injury and cirrhosis, with viral hepatitis, alcoholic cirrhosis, nonalcoholic steatohepatitis, and hemochromatosis being the most common etiologic factors. Despite recent advancements in the treatment of HCC, the 5-year survival rate is less than 20%. Surgery and liver transplantation are the primary curative modalities for patients with early-stage HCC; however, a majority of patients with HCC are not amenable for surgical resection or locoregional therapy including ablation, embolization, or radiation therapy.

Until recently, systemic therapeutic options were limited for patients with advanced HCC—sorafenib (Nexavar) was the only FDA-approved therapy for more than a decade. Immunotherapy, tyrosine kinase inhibitors (TKIs), and monoclonal antibodies targeting VEGF have all received FDA approval, broadening the plethora of treatment options for this patient population. 

For patients with advanced HCC not amenable for surgical resection, treatment options include locoregional or systemic therapy; there is no role for adjuvant therapy following surgical resection or locoregional therapy for HCC. Investigators are evaluating the role of immune checkpoint inhibitors as adjuvant therapy post surgery, ablation, and embolization in multiple trials. In addition to the stage of disease, performance status and comorbidities, treatment of HCC is guided by Child-Pugh score and Barcelona Clinic Liver Cancer (BCLC) staging system. Historically, locoregional treatment is recommended for patients with BCLC stage B and systemic therapy for BCLC stage C. Benefit of systemic therapy is primarily limited to patients with Child-Pugh score A5 or A6.

Sorafenib was approved by the FDA based on data from the phase 3 SHARP trial (NCT00105443), which demonstrated an improved median overall survival (OS) of 10.7 months vs 7.9 months with placebo (HR, 0.69; 95% CI, 0.55-0.87; P < .001); the median time to radiologic progression was 5.5 months vs 2.8 months, respectively (HR, 0.58; 95% CI, 0.45-0.74; P < .001).

 These results were validated in another randomized trial (NCT00492752) conducted in the Asia-Pacific region.

 For nearly a decade after the SHARP trial, no targeted therapy demonstrated survival benefit compared with sorafenib as first-line therapy.

Lenvatinib (Lenvima), a small molecular tyrosine kinase inhibitor targeting VEGF, FGFR, PDGFR, RET and c-kit, was compared with sorafenib in a phase 3 randomized inferiority trial (NCT01761266) that included 1492 eligible patients.3 Lenvatinib was associated with improved median progression-free survival (PFS) of 7.4 months (95% CI, 6.9-8.8) vs 3.7 months (95% CI, 3.6-4.6) with sorafenib. The objective response rate (ORR) for patients treated with lenvatinib (n = 478) was 24.1% vs 9.2% with sorafenib (n = 476); however, a similar median OS was reported at 13.6 (95% CI, 12.1-14.9) vs 12.3 months (95% CI, 10.4-13.9), respectively (HR, 0.92; 95% CI, 0.79-1.06). Treatment-related adverse events were similar in both arms.

 This trial led to FDA approval of lenvatinib for patients with advanced HCC in first-line setting.

Promising activity of immune checkpoint inhibitors in a phase 2 trial led to multiple phase 3 trials in first and later lines of treatment (Table

). Investigators of IMbrave150 (NCT03434379), a phase 3 trial, randomized patients with advanced HCC in 2:1 fashion to atezolizumab (Tecentriq) plus bevacizumab (Avastin) and sorafenib arms, respectively.5 The combination of atezolizumab plus bevacizumab was associated with improved OS (HR, 0.58; 95% CI, 0.42-0.79; P < .001) with 12-month OS rate of 67.2% with the combination (n = 336) compared with 54.6% with sorafenib (n = 165). The median PFS was 6.8 months (95% CI, 5.7-8.3) in the combination arm compared with 4.3 months (95% CI, 4.0-5.6) in the control arm. Notably, patients were excluded if they had untreated or incompletely treated esophageal or gastric varices, autoimmune disease, or coinfection with hepatitis B or C.

In contrast to above trial, the phase 3 CheckMate 459 trial (NCT02576509) failed to demonstrate a significant survival benefit for nivolumab compared with sorafenib as first-line therapy in unselected patients with HCC.

 Subgroup analysis did suggest potential benefit in patients who had PD-L1–positive tumors.

Combination therapy with lenvatinib plus pembrolizumab (Keytruda) has demonstrated promising activity. Among 100 treated patients the doublet elicited an ORR of 46% (95% CI, 36.0%-56.3%), a median PFS of 9.3 months (95% CI, 5.6-9.7), and a median OS of 22 months (95% CI, 20.4-not estimable) in a single-arm trial (NCT03006926).7 Based on these exciting results, a phase 3 trial evaluating this combination is under way (LEAP-002; NCT03713593). 

Multiple therapeutic agents are approved for patients with advanced HCC progressing or intolerant to first-line therapy with sorafenib. Regorafenib (Stivarga), cabozantinib (Cabometyx), and ramucirumab (Cyramza), all targeting VEGFR, were approved based on results of randomized phase 3 trials that demonstrated a survival benefit when compared with placebo. The median OS in the experimental arms in these trials was in the range of 8.5 to 10.6 months.

There were some differences in eligibility criteria in these trials. For example, in the RESORCE study (NCT01774344), which compared regorafenib with placebo, patients were excluded if they discontinued sorafenib because of adverse events. To be eligible for the REACH-2 trial (NCT02435433) evaluating ramucirumab, patients should have α-fetoprotein (AFP) levels greater than 400 ng/mL (or > 1.5 times the upper limit). In contrast, the CELESTIAL trial (NCT01908426), which randomized patients to cabozantinib or placebo, is the only randomized trial that allowed patients who had received prior immunotherapy to be eligible.

Immune checkpoint inhibitors have demonstrated limited activity in second-line setting and the FDA has granted acceler-ated approval to pembrolizumab, nivolumab (Opdivo), and ipilimumab (Yervoy) plus nivolumab. The phase 3, randomized KEYNOTE-240 trial (NCT02702401) eval-uating pembrolizumab failed to meet the prespecified composite end point of PFS and OS, despite a longer median OS being reported for the pembrolizumab arm vs placebo (13.9 vs 10.6 months, respectively; HR, 0.781; 95% CI, 0.611-0.998; P = .0238).

Results of the CheckMate040 trial (NCT01658878) showed that treatment with nivolumab was associated with a median OS of 15.1 months (95% CI, 13.2-18.8) and an ORR of 14% among 154 patients who had previously received sorafenib.9 However, with the negative results of the CheckMate 459 trial in first-line setting, FDA indication of single-agent nivolumab in HCC was withdrawn.

Further data from a combination arm of CheckMate040 showed that ipilimumab plus nivolumab administered at a dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for 4 doses followed by nivolumab 240 mg every 2 weeks was associated with longest median OS (22.8 months) and remarkable ORR of 32% (95% CI, 20%-40%) among 50 patients.11 This combination is now being tested in first-line setting in the CheckMate 9DW trial (NCT04039607) and results are eagerly awaited.

Systemic therapeutic strategy for advanced HCC continues to evolve. For patients with no contraindication to immunotherapy and without untreated gastroesophageal vari-ces, combination of atezolizumab plus bevacizumab is the recommended first-line treatment.12 For patients who are ineligible to receive this combination, either lenvatinib or sorafenib is a reasonable choice. There is a lack of published data to suggest a preferred treatment option after progression on atezolizumab plus bevacizumab. Thus, optimal treatment sequencing strategy remains undefined.

Our recommendation is to consider atezolizumab plus bevacizumab as first-line therapy; followed by TKI including lenvatinib, sorafenib, cabozantinib or regorafenib as second-line therapy; followed by another TKI which was not used in second regorafenib, cabozantinib, or ramucirumab as third line (Figure). Patients enrolled in the CELESTIAL trial, which examined the efficacy of cabozantinib, could receive more than 1 line of prior therapy, including immunotherapy. If sorafenib was well-tolerated and patients had prolonged disease control, they may preferentially benefit from regorafenib as next line of therapy. The combination of ipilimumab plus nivolumab has demonstrated promising activity but remains untested in patients treated with prior checkpoint inhibitors. Similarly, efficacy of ramucirumab remains unclear in patients who failed bevacizumab in the first line.

There are several areas of unmet need for patients with advanced HCC. For example, benefit with systemic therapy is limited to patients with good performance status with Child-Pugh score 7 or lower, excluding a vast proportion of patients. The development of promising systemic therapies with manageable adverse event profiles suggests that investigators should compare these systemic options with locoregional therapy for patients with high-risk disease. Finally, there is an urgent need to develop biomarkers that can help in selecting patients for different treatment options.

Global Liver Institute (GLI) is the only liver focused nonprofit organization operating in both the United States and Europe. GLI’s mission is to improve the lives of individuals and families impacted by liver disease through promoting innovation, encouraging collaboration, and scaling optimal approaches to help eradicate liver diseases. By working across disease states and convening all stakeholders, GLI aims to amplify the voices of those impacted by liver diseases and cancers. One of these initiatives is GLI’s Liver Cancers Council, in which Dr. Richard Kim is an active and engaged member helping to lead the charge for patient advocacy. For more information and resources please visit https://www.globalliver.org/.

Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. 

. 2008;359(4):378-390. doi:10.1056/NEJ-Moa0708857

Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. 

. 2009;10(1):25-34. doi:10.1016/S1470-2045(08)70285-7

Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocel-lular carcinoma: a randomised phase 3 non-inferiority trial. 

. 2018;391(10126):1163-1173. doi:10.1016/S0140-6736(18)30207-1

Nair A, Reece K, Donoghue MB, et al. FDA supplemental ap-proval summary: lenvatinib for the treatment of unresectable hepatocellular carcinoma. 

. 2021;26(3):e484-e491. doi:10.1002/onco.13566

Finn RS, Qin S, Ikeda M, et al; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocel-lular carcinoma. 

. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745

Yau T, Park JW, Finn RS, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). 

 2019;30(suppl 5):V874-V875. doi:10.1093/annonc/mdz394.029

Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepato-cellular carcinoma. 

. 2020;38(26):2960-2970. doi:10.1200/JCO.20.00808

Finn RS, Ryoo BY, Merle P, et al: KEYNOTE-240 Investigators. Pembrolizumab as second-line therapy in patients with ad-vanced hepatocellular carcinoma in KEYNOTE-240: a random-ized, double-blind, phase III trial. 

 2020;38(3):193-202. doi:10.1200/JCO.19.01307

El-Khoueiry AB, Melero I, Yau TC, et al. Impact of antitumor activity on survival outcomes, and nonconventional benefit, with nivolumab (NIVO) in patients with advanced hepatocellular carcinoma (aHCC): subanalyses of CheckMate-040. 

. 2018;36(suppl 4):475. doi:10.1200/JCO.2018.36.4_suppl.475

Bristol Myers Squibb statement on Opdivo (nivolumab) monotherapy post-sorafenib hepatocellular carcinoma U.S. indication. News release. Bristol Myers Squibb. July 23, 2021. Accessed September 3, 2021. bit.ly/2XnbB3A

Yau T, Kang YK, Kim TY, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular car-cinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. 

. 2020;6(11):e204564. Published correction in 

. 2021;7(1):140. doi:10.1001/jamaoncol.2020.4564

NCCN. Clinical Practice Guidelines in Oncology. Hepatobiliary cancers, version 4.2021. Accessed September 3, 2021. bit.ly/3tP1OiQ

Hepatocellular cancer, the most common primary liver malignancy, is the fourth-leading cause of cancer-related deaths globally. 

Pivotal Trial Results Look to Shake Up HCC Treatment

On February 22, 2021, the FDA approved the PD-1 inhibitor cemiplimab-rwlc (Libtayo) for the first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (tumor proportion score > 50%) as determined by an FDA-approved test, with no 

 Advanced disease was defined as patients who are not candidates for surgical resection, definitive chemoradiation, or who have metastatic disease.

The approval was based on data from the phase 3 EMPOWER-Lung 1 trial (NCT03088540), which showed that patients treated with cemiplimab (n = 356) experienced an overall response rate (ORR) of 37% (95% CI, 32%-42%) compared with 21% (95% CI, 17%-25%) in patients treated with chemotherapy (n = 354). Notably, the median duration of response (DOR) was much higher in the cemiplimab cohort, registering at 21.0 months (1.9+ to 23.3+) compared with 6.0 months (1.3+ to 16.5+) for patients treated with chemotherapy. The median overall survival (OS) in the cemiplimab group was 22.1 months (95% CI, 17.7-not estimable) vs 14.3 months (95% CI, 11.7-19.2) in the chemotherapy group (HR, 0.68; 95% CI, 0.53-0.87; P = .0022).2 

, Ahmet Sezer, MD, a professor in the Department of Medical Oncology at Başkent University in Ankara, Turkey, discussed how the approval of cemiplimab could potentially make a huge impact for patients with advanced NSCLC.

: What makes cemiplimab a novelty in the advanced NSCLC setting?

Cemiplimab is a fully humanized monoclonal antibody targeting the immune checkpoint receptor PD-L1 on T cells. Like other PD-1 inhibitors cemiplimab binds to PD-1 and has been shown to block cancer cells from using the pathway to suppress T-cell activation. In advanced NSCLC, PD-1 inhibitors have become a key component of the treatment of patients with advanced NSCLC without 

 mutations. However, there is still a need to optimize chemotherapy treatment options for patients with high PD-L1 expression levels.

In this pivotal phase 3 trial, EMPOWER-Lung 1, cemiplimab demonstrated an impressive level of efficacy and was superior in extending OS compared with chemotherapy. This reinforces the potential of cemiplimab as a valuable treatment option for appropriate patients with advanced NSCLC with PD-L1 expression of at least 50%.

In addition, [investigators of] EMPOWER-Lung 1 enrolled more advanced patient populations, [which] are usually underrepresented in [other] advanced NSCLC trials. Among these patients, 12% [had] pretreated and stable brain metastases and 16% [had] locally advanced NSCLC [and were] not candidates for definitive chemotherapy radiation. As a result [of this protocol], the medical community now has valuable new clinical evidence that could enhance our understanding of how to treat advanced NSCLC.

Please elaborate on the efficacy and toxicity data that were observed in EMPOWER-Lung 1.

EMPOWER-Lung 1 compared first-line cemiplimab monotherapy with platinum-based chemotherapy in patients with advanced NSCLC with PD-L1 expression of at least 50%. The primary end points were OS and provision for survival. Secondary end points included ORR, DOR, and safety.

Cemiplimab demonstrated impressive efficacy early on and EMPOWER-Lung 1 was stopped early because of a highly significant improvement in OS compared with chemotherapy. Specifically, cemiplimab reduced the risk of death by 33% among all patients, and 43% in those with PD-L1 expression of at least 50%. These results were achieved with a greater than 50% crossover rate to cemiplimab following disease progression on chemotherapy. [Additionally, this is] the largest population of patients with pretreated and stable brain metastases among advanced NSCLC [included in a] pivotal trial to date.

To summarize, these results support cemiplimab as a new monotherapy option for patients with first-line advanced NSCLC with a PD-L1 expression of at least 50%. The safety profile of cemiplimab is consistent with the previous 2 reported profiles of the agent and other PD-L1 inhibitors in NSCLC and other tumor types. 

Additional details have been published in 

How will this approval affect the treatment paradigm for patients with NSCLC with high PD-L1 expression? 

Physicians, myself included, who treat [patients with] NSCLC are a data-driven group and appreciate having multiple treatment options. Given the impressive level of efficacy demonstrated in the EMPOWER-Lung 1 trial, I believe cemiplimab has the potential to make a meaningful difference for the many patients battling these difficult-to-treat cancers. 

Additionally, [data from] EMPOWER-Lung 1 helps address current gaps in knowledge surrounding advanced NSCLC treatment, because it allows for certain patient and disease characteristics particularly underrepresented in [other] advanced NSCLC trials.

Are there any unanswered questions with the agent that future research should address?

We see many different patients with advanced NSCLC. Each patient is unique, and they can have a variety of disease characteristics that need to be considered. In short, there is still a lot we don’t know about advanced NSCLC treatment, and more research is always needed. However, I believe EMPOWER-Lung 1 is an important step and offers physicians valuable new data that can help them in treating various patients they come across in daily clinical practice.

FDA approves cemiplimab-rwlc for non-small cell lung cancer with high PD-L1 expression. FDA. February 22, 2021. Accessed September 3, 2021. bit.ly/3tNGiLz 

Libtayo. Prescribing information. Regeneron Pharmaceuticals Inc; 2021. Accessed September 3, 2021. bit.ly/3hIBQZG 

Sezer A, Kilickap S, Gümüş M, et al. Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial. 

. 2021;397(10274):592-604. doi:10.1016/S01406736(21)00228-2

 Ahmet Sezer, MD, discusses how the approval of  cemiplimab  could  potentially make a huge impact for patients with advanced non–small cell lung cancer.

Vol. 22/No. 19 | Oncology Live®

Will Slow and Steady Progress in Treating SCLC Win the Race?

Sacituzumab Govitecan May Be New Standard of Care in Metastatic TNBC

Pivotal Trial Results Look to Shake Up HCC Treatment

Cemiplimab Earns High Marks in First-Line Treatment of Advanced NSCLC

Investigators Aim to Fill Unmet Need of Intermediate- to High-Risk MDS With ENHANCE Trial

IO Combo Anchors a New Front Line Taking Shape in Unresectable HCC

Challenges to Scientific Expertise: Future Implications for Oncology