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Patients with advanced gastric cancer that has progressed to gastric carcinomatosis have traditionally lacked effective treatment options with a poor survival outlook.

 However, a novel approach to chemotherapy administration in the disease space is poised to alter the treatment landscape and improve outcomes for this patient population.

The phase 2 STOPGAP trial (NCT04762953) will assess the safety and efficacy of sequential chemotherapy administered intravenously followed by intraperitoneal chemotherapy with paclitaxel. This approach has not been evaluated for patients with stage IV gastric cancer that has progressed to gastric carcinomatosis in the United States.

“In gastric cancer, the likelihood of peritoneal carcinomatosis is very high compared with other gastrointestinal malignancies; it is approximately 30% to 50%,” Maheswari Senthil, MD, FACS, said in an interview with 

. “The unique aspect of peritoneal carcinomatosis is that the peritoneum is a [highly] protected cavity. The penetration of [the peritoneal cavity with] chemotherapy agents is limited because of the blood-peritoneal barrier.... Although systemic chemotherapy administered intravenously is extremely important, it may not have adequate penetration to treat the carcinomatosis part of the disease.”

Senthil is the principal investigator on the STOPGAP trial. She is also the director of the Peritoneal Malignancy Program at the Chao Family Comprehensive Cancer Center, chief of the Division of Surgical Oncology, and a clinical professor of surgery at the school of medicine at the University of California, Irvine.

Palliative intravenous chemotherapy and/or best supportive care is the current standard for patients with gastric peritoneal carcinomatosis. The median overall survival (OS) for this patient population is approximately 7 months. In a retrospective analysis by Rau et al, 19 patients with peritoneal metastases of gastric cancer treated between August 2008 and December 2017 received systemic chemotherapy alone. These patients experienced a median OS of 4.9 months, and the 1-year survival rate was 0%.

International Findings With Intraperitoneal Chemotherapy Are Promising

Intraperitoneal chemotherapy for gastric cancer with peritoneal carcinomatosis has been evaluated in multiple clinical trials in Asia. A phase 2 clinical trial from Singapore and Japan has evaluated the safety and efficacy of intraperitoneal paclitaxel as well as intraperitoneal docetaxel.

In this study, 40 patients received intraperitoneal paclitaxel at a dose of 20 mg/m

 of intravenous paclitaxel administered on days 1 and 8. The oral fluoropyrimidine derivative S-1 was also given at a dose of 80 mg/m

 daily for 14 consecutive days, followed by 7 days of rest. Patients experienced a median OS of 22.6 months, with a 1-year OS rate of 78%.

Findings from Yamaguchi et al showed that the same treatment regimen administered to 35 patients elicited a median OS of 17.6 months, with a 1-year OS rate of 77% and a 2-year OS rate of 45%.

Imano et al reported findings from an intensive paclitaxel regimen—intraperitoneal paclitaxel at 80 mg/m

 daily for 14 consecutive days. Intravenous paclitaxel 50 mg/m

 was given on days 1 and 8. The median OS was 21.3 months and the 1-year and 2-year OS rates were 69% 46%, respectively.

 Finally, in results from Fushida et al and Fujiwara et al, intraperitoneal docetaxel administered in doses ranging from 35 mg/m

 in combination with S-1, the median OS was 24.6 months and 16.2 months, respectively.

In terms of tolerability, Senthil noted that no unique trends in adverse effects were reported with intraperitoneal administration. “Extrapolating the data from the Asian studies that have extensively used paclitaxel for intraperitoneal administration, this is a very well-tolerated treatment,” she said. “[Additionally], some patients in the Asian studies received [intraperitoneal chemotherapy] for multiple cycles—[some up to 20 cycles], just repeated intraperitoneal administration. The tolerability and extension of use of intraperitoneal chemotherapy could be even more than what we are projecting in STOPGAP.”

Following these encouraging phase 2 data, Japanese investigators initiated the phase 3 PHOENIX-GC trial (UMIN000005930) in patients with gastric cancer with peritoneal metastasis. In the study, the efficacy of intraperitoneal paclitaxel plus systemic S-1 and paclitaxel (n = 114) was compared with standard systemic chemotherapy (n = 50). Patients enrolled in the trial had received no prior therapy or short-term chemotherapy defined as less than 2 months. The primary end point was OS and secondary end points included overall response rate and safety.

Findings from the trial showed that the median OS in the investigational arm was 17.7 months (95% CI, 14.7-21.5) compared with 15.2 months (95% CI, 12.8-21.8) in the control arm (HR, 0.72; 95% CI, 0.49-1.04; 

 = .08). The 3-year OS rates were 21.9% (95% CI, 14.9%-29.9%) and 6.0% (95% CI, 1.6%-14.9%). Both regimens were well tolerated. the findings were maintained across subgroups with the largest benefit observed in those with moderate amount of ascites (HR, 0.38;95% CI, 0.16-0.90; 

 = .03) and women (HR, 0.55; 95% CI, 0.32-0.95; 

Study authors concluded that although the superiority in terms of OS of intraperitoneal paclitaxel plus systemic chemotherapy was statistically insignificant compared with the standard of care, exploratory analyses suggested potential clinical benefits of intraperitoneal paclitaxel in gastric cancer.

STOPGAP Aims to Improve Options in Gastric Cancer

The STOPGAP trial is currently recruiting, and investigators seeking to enroll approximately 35 adult patients with primary gastric or gastroesophageal adenocarcinoma with cytology-positive peritoneal lavage and/or peritoneal carcinomatosis. Eligible patients must have an ECOG performance status of 2 or less, adequate organ and marrow function as defined by investigators, and a life expectancy greater than 6 months (

Patients will be excluded from the trial if they have received systemic treatment for more than 3 months preceding enrollment. Those who have undergone prior surgery that would preclude safe diagnostic laparoscopy and port placement, have evidence of a distant solid organ metastases, or have an active infection that mandates systemic therapy are also not eligible.

“STOPGAP will help us truly understand the subgroup of patients [with gastric cancer] for whom we are able to [generate] the maximum effect in their OS,” Senthil said. “That would help us create even more knowledge about which set of patients benefit from this approach. Then [we would] be able to design the next clinical trial that highly selects for these patients with certain predictive markers, and clinical features that are necessary to derive the most benefit.”

Initially, patients in the single-arm, nonrandomized, open-label trial will receive systemic therapy for 3 months at the clinician’s discretion based on molecular biomarkers. Patients will then undergo diagnostic laparoscopy followed by intraperitoneal port placement.

Investigators will treat patients with an intravenous chemotherapy regimen of paclitaxel, f luorouracil, and leucovorin. Paclitaxel will also be instilled into the peritoneal cavity through the intraperitoneal port at a dose of 40 mg/m

. Treatment will be administered on days 1 and 8 of each 21-day cycle for 3 months.

Four to 6 weeks following the completion of intraperitoneal chemotherapy, restaging imaging will be performed using CT scan and/or diffusion-weighted MRI with contrast. Diagnostic laparoscopy will also be used to assess peritoneal disease burden and treatment response. Patients will then be assigned to a treatment plan based on their response to treatment and extent of disease. If a patient experiences stable disease or a response and a peritoneal cancer index (PCI) score greater than 10, they will continue treatment with the intraperitoneal chemotherapy regimen; patients with disease progression will transition to a second-line regimen; and patients with a response and a PCI score of 10 or less for whom complete cytoreduction is feasible will be considered for cytoreduction with intraperitoneal chemotherapy.

The primary end points of the study are 1-year PFS. Secondary end points include OS and patient-reported quality-of-life outcomes. Other outcome measures include expression of plasma and ascites exosomal gene signature (EXOSIG) and EXOSIG to treatment response. Study authors estimate that the trial will be completed in June 2025.

“There are implications from this study that could be extrapolated to other cancers,” Senthil said. “The general concept of normothermic intraperitoneal chemotherapy is something that we will take away from the study. Right now, normal thermic intraperitoneal chemotherapy is not routinely administered in patients with carcinomatosis. then we should be expanding this approach to other diseases for which it can be applied. I am looking forward to a future where we can customize treatment approaches for individual patients.”

Senthil M. Ph II trial of sequential systemic therapy + intraperitoneal paclitaxel in gastric/GEJ cancer. UCI Center for Clinical Research. Accessed August 30, 2022. bit.ly/3CGZjWe

Rau B, Brandl A, Thuss-Patience P et al. The efficacy of treatment options for patients with gastric cancer and peritoneal metastasis. 

 2019;22(6):1226-1237. doi:10.1007/s10120019-00969-1

Kono K, Yong WP, Okayama H, et al. Intraperitoneal chemotherapy for gastric cancer with peritoneal disease: experience from Singapore and Japan. 

. 2017;20(suppl 1):122-127. doi:10.1007/ s10120-016-0660-y

Ishigami H, Fujiwara Y, Fukushima R, et al. Phase III trial comparing intraperitoneal and intravenous paclitaxel plus S-1 versus cisplatin plus S-1 in patients with gastric cancer with peritoneal metastasis: PHOENIX-GC trial. 

. 2018;36(19):1922-1929. doi:10.1200/JCO.2018.77.8613

Study of sequential systemic therapy + intraperitoneal paclitaxel in gastric/GEJ peritoneal carcinomatosis (STOPGAP). ClinicalTrials.gov. Updated March 9, 2021. Accessed August 30, 2022. https://www. clinicaltrials.gov/ct2/show/NCT04762953

Articles

A novel approach to chemotherapy administration in advanced gastric cancer that has progressed to gastric carcinomatosis is poised to alter the treatment landscape and improve outcomes for this patient population.

Intraperitoneal Chemotherapy Technique Aims to Dramatically Improve Outcomes in Gastric Carcinomatosis

Treatment with soluble EphB4-human serum albumin (sEphB4-HSA) plus pembrolizumab (Keytruda) elicited synergistic activity and an improved overall survival (OS) and objective response rate (ORR) compared with historical data for PD-1/PD-L1 monotherapy in patients with platinum-refractory metastatic urothelial carcinoma, according to findings from a phase 2 trial (NCT02717156) published in the 

At a median follow up of 22.9 months (range, 1.3-54.7) in the intention-totreat (ITT) analysis, the median OS was 14.6 months (95% CI, 9.2-21.5); the P value was .014 for rejecting the null hypothesis that the median survival would be 6.9 months or less. The median progression-free survival (PFS) was 4.1 months (95% CI, 1.5-5.7), and 26 patients (37%) had an objective response (95% CI, 26%-48%). The disease control rate (DCR) was 66% (95% CI, 55%-77%).

The regimen also had acceptable toxicity, and the tolerability monitoring boundary was not crossed, with a total of 11 events in 11 patients. 

“The combination of sEphB4-HSA and pembrolizumab can be administered with acceptable toxicity and improves key efficacy end points especially in [the] sEphB4-HSA drug target (EphrinB2)–positive subgroup and forms the basis for further investigation in high-grade urothelial carcinoma,” lead study author Sarmad Sadeghi, MD, PhD, and coauthors wrote in the publication. Sadeghi is an associate professor of clinical medicine at Keck School of Medicine at the University of Southern California in Los Angeles.

Additional results indicated that at a median follow-up of 22.5 months (range, 3.5-54.7) among the patients with EphrinB2 expression (n = 46), the median OS was 21.5 months (95% CI, 12.4–not reached), and the median PFS was 5.7 months (95% CI, 2.7-27.9). The ORR was 52% (95% CI, 37%-67%), which included a complete response rate of 24% (95% CI, 12%-36%) and a partial response rate of 28% (95% CI, 15%-41%). The DCR was 80% (95% CI, 69%-92%).

Notably, response was maintained at 6, 12, and 24 months in 88%, 74%, and 69% of the patients, respectively. The median duration of response (DOR) was not reached in either the ITT population or the EphrinB2-positive cohort.

Poor outcomes are associated with metastatic urothelial carcinoma following failure on standard frontline chemotherapy, and approved PD-1 inhibitors have low response rates in the second-line setting. 

EphB4 is highly expressed in urothelial cancer and leads to increased tumor cell invasion, proliferation, and survival. Interaction of high EphrinB2 in tumor vessels and EphB4 on tumor cells promotes angiogenesis and impedes immune cell traffic into the tumor. sEphB4-HSA binds EphrinB2 and inhibits bidirectional signaling and tumor growth and increases immune cell trafficking into the tumor.

In preclinical models, the combination of sEphB4 and PD-1 inhibition was more active than either agent alone, supporting further evaluation. In this phase 2 trial, 70 patients with metastatic urothelial carcinoma that recurred or progressed after platinum-based chemotherapy received sEphB4-HSA in combination with pembrolizumab. 

When stratified by PD-L1 status and EphrinB2 status, those with PD-L1–positive disease (n = 18) had an ORR of 61%. In this population 13 patients had EphrinB2-positive disease and an ORR of 69%. Among the EphrinB2-negative disease, the ORR was 40%. In the PD-L1 or unknown group (n = 52), the ORR was 29%. Those with EphrinB2-positive disease (n = 33) had an ORR of 45%; and those with EphrinB2-negative disease had an ORR of 0%.

To be eligible for enrollment, patients had to be at least 18 years of age and have histologically confirmed urothelial carcinoma with disease progression after platinum-based chemotherapy for advanced disease or recurrence within 12 months of receiving platinum-based adjuvant or neoadjuvant therapy for localized muscle-invasive disease; at least 1 measurable lesion according to RECIST v1.114 criteria, and an ECOG performance status (PS) of 0 or 1. 

Patients received 200 mg of intravenous (IV) pembrolizumab once on day 1 and 10 mg/m

 of IV sEphB4-HSA once daily on days 1, 8, and 15 every 3 weeks. Treatment was continued until RECISTdefined disease progression, development of unacceptable toxicity, patient or investigator decision, or completion of 2 years of therapy. 

The primary end points of the trial were tolerability and OS. The secondary end points were PFS, ORR, DOR, and toxicity. The median age of participants was 67 years. Sixty-four patients received only 1 prior line of therapy; 6 patients received more than one line of therapy. Baseline sites of disease included the lymph nodes (n = 45; 64%), lungs (n = 24; 34%), liver (n = 18; 26%), and bone (n =9; 13%). 

Thirty-nine patients (56%) had an ECOG performance status of 0 and 31 (44%) patients had an ECOG performance status of 1. Stratification of Bellmunt risk demonstrated that 27% of patients had no risk factors, 37% had 1 risk factor, and 36% had 2 or more risk factors. Fourteen (20%) patients had upper-tract disease as their primary site of disease. Forty-six (66%) patients were EphrinB2 positive. 

The median duration of therapy was 15 weeks (range, 3-120). Eight patients remain on treatment, and 37 patients (60%) discontinued treatment because of disease progression. Of the 25 patients who stopped treatment for reasons other than progressive disease, 15 remain without subsequent systemic treatment and 21 received subsequent systemic therapy.

Any-grade adverse effects (AEs) occurring in at least 10% of patients included hypertension (74%), fatigue (44%), anemia (17%), anorexia (13%), headache (13%), nausea (13%), proteinuria (11%), rash (11%), hyperuricemia (10%), increase in aspartate aminotransferase (AST; 10%), and pruritus (10%). 

Six patients (8.6%) discontinued treatment because of grade 3 toxicity: arthralgia (n = 1), edema (n = 1), abdominal pain (n = 1), and supraventricular tachycardia (n = 1), increase in AST and alanine aminotransferase (n = 1), and endocrine disorder (n = 1). 

Four (6%) patients died on treatment because of organ failure attributed to pembrolizumab (n = 1), aspiration pneumonia (n = 1), and overall decline in health and clinical progression of disease (n = 2). Five patients withdrew from the trial, and 6 patients discontinued therapy per the recommendation of the treating physician. 

Hypertension was the most common toxicity attributed to sEphB4-HSA; 74% of patients experienced any-grade hypertension, and 46% had grade 3 or 4 hypertension.

Severe immune-related AEs included myositis in 1 patient, which resulted in death. Grade 2 pneumonitis occurred in 1 patient. Other immune-mediated AEs resolved with corticosteroids and without sequelae. 

“A larger controlled phase 3 trial is required to confirm the efficacy signal observed in this study,” the study authors concluded. “A phase 2 study of this combination in metastatic urothelial carcinoma is under way, which includes a frontline cohort and an EphrinB2-positive biomarker-selected previously treated cohort (NCT04486781).”

Sadeghi S, Quinn D, Dorff T, et al. EphrinB2 inhibition and pembrolizumab in metastatic urothelial carcinoma. J Clin Oncol. Published online August 19, 2022. doi:10.1200/JCO.21.02923 

Chrencik JE, Brooun A, Kraus ML, et al. Structural and biophysical characterization of the EphB4·EphrinB2 protein-protein interaction and receptor specificity. J Biol Chem. 2006;281(38):28185-28192. doi:10.1074/jbc.M605766200

Oncology Live®

Treatment with soluble EphB4-human serum albumin plus pembrolizumab elicited synergistic activity and an improved overall survival and objective response rate compared with historical data for PD-1/PD-L1 monotherapy in patients with platinum-refractory metastatic urothelial carcinoma.

EphrinB2 Emerges as Targetable Option  in Urothelial Carcinoma

Evidence-based decisions have leveraged the use of immunotherapy (IO) combination atezolizumab (Tecentriq) plus bevacizumab (Avastin) for patients who receive a diagnosis of hepatocellular carcinoma (HCC). Approved in 2020, the combination has become a category 1 recommendation in the National Comprehensive Cancer Network guidelines and set the standard for first-line treatment.

However, decisions may vary for patients who present with unfavorable clinical profiles. This includes those at an elevated risk of bleeding, Child-Pugh status, or contraindications such as autoimmune disease.2 Other contenders in the armamentarium include alternate immunotherapy combinations and single-agent tyrosine kinase inhibitors (TKIs) may hold a role for select patients with advanced HCC, but clearer stratification factors and real-world data are needed to solidify their role in the treatment landscape. 

“If a patient is a candidate for IO and does not have contraindications to VEGF therapy, they’re going to get atezolizumab/bevacizumab,” Anthony B. El-Khoueiry, MD, said in a recent 

. “If they’re not a candidate for combination—and that’s in the eye of the beholder to some extent, maybe liver function is weighing in—you can use single-agent sorafenib, or single-agent anti–PD-1/PD-L1, and if they have IO contraindications, they’re going to get a TKI. With the new regimens that come on board we’ll see the data and how positive or negative they are.”

El-Khoueiry and a panel of liver cancer experts held a case-based discussion centered on updates in the systemic treatment of patients with advanced HCC and the clinical factors that may influence decisions that diverge from the standard IO/IO approach.

To guide the discussion of first-line systemic treatment options, the case of a woman aged 63 years with chronic active hepatitis C infection was referenced. After starting antiviral therapy, she presented with elevations on liver function tests, which prompted a CT scan of the abdomen. Multifocal infiltrative liver lesions were observed in the right lobe with evidence of vascular invasion by the tumor and the patient received a diagnosis of HCC.

“This is a patient who has ChildPugh A cirrhosis, has prototypical BCLC [Barcelona clinic liver cancer] staging with a tumor invading a large blood vessel,” Pierre Gholam, MD, said. “She does not appear to have any significant contraindications to the combination of atezolizumab and bevacizumab and based on the evidence that would be our go-to first-line model.” 

Mark Yarchoan, MD, concurred adding, “This is the preferred first-line systemic regimen for individuals who are eligible for it.” Yarchoan cited data from the phase 3 IMbrave150 study (NCT03434379) in which the combination was evaluated against single-agent sorafenib (Nexavar).

 “This was a positive study regarding every end point that we care most about: overall survival [OS], progression-free survival [PFS], objective response rate [ORR], and even quality of life. You really need a reason not to use it in first line.”

Updated data from IMbrave 150, published in 2022, highlighted the prolonged clinically meaningful benefit with the combination in the first line.

 Further, real-world data of the regimen showed that the combination may be administered beyond the criteria of the IMbrave 150 study and support its role as an option for patients with liver impairment including ChildPugh B status.

Among 202 evaluable patients, 154 had ChildPugh A classification and 48 had Child-Pugh B classification. The median OS for all-treated patients was 14.9 months (95% CI, 13.6-16.3) with a 6-month OS rate of 77% and a 12-month OS rate of 60%. When stratified by Child-Pugh classification the median OS for those with A classification was 16.8 months (95% CI, 14.1-23.9) vs 6.7 months (95% CI, 4.3-15.6) for those with B classification. The median PFS of the overall population was 6.8 months (95% CI, 5.2-8.5) and the was 7.6 months (95% CI, 6.2-8.9) for patients with Child-Pugh A and 3.4 months (95% CI, 2.6-4.2) for patients with Child-Pugh B classifications.

Responses, evaluated using RECIST 1.1 criteria, were comparable to the rates seen in IMbrave 150. In the overall population evaluable for response (n = 174), the objective response rate was 25% and was 26% and 21% in the Child-Pugh A (n = 140) and Child-Pugh B (n = 34) populations, respectively.

Addressing the increased risk of bleeding, the investigators of the real-world analysis noted, “the proportion of patients who experienced bleeding events in our study was comparable between patients with Child-Pugh A and patients with Child-Pugh B, not diverging from rates observed in IMbrave150.”

Moderator Tanios S. Bekaii-Saab, MD, asked for considerations that may deter from the use of the combination.

“When combining these agents [there is concern] for risk of bleeding, primarily related to portal hypertension,” Gholam said. “I think one would be well-advised to assess portal hypertension risk in this patient with Child-Pugh A status. We can now do this to some extent noninvasively, although certainly the broader hepatology and medical oncology community has relied on endoscopy to assess for the presence of esophageal or gastric varices. The fact that cross-sectional imaging does not show splenomegaly, abdominal varices, or esophageal varices is reassuring [for this patient]. Depending on where the tumor is located, [liver elastography] may or may not be a good test because, remember, if you have a tumor, this could alter the stiffness of the liver and may give you erroneous information. But that is a possibility. There are other tests for assessment of fibrosis, but, in general, nothing points to limitations in our ability to initiate atezolizumab/bevacizumab. There’s no uncontrolled hypertension and there doesn’t appear to be any underlying autoimmune disease that would be adversely affected by that combination.”

In terms of considering other factors that may point clinicians to an alternative, those with nonviral HCC may benefit from treatment with the TKI lenvatinib (Lenvima).

 Data from a prospective study of patients with advanced HCC or intermediate HCC who were not eligible for locoregional therapies showed that those who received atezolizumab plus bevacizumab (n = 190) had inferior outcomes compared with lenvatinib (n = 569). Among all-treated patients, the median OS was 17.8 months (95% CI, 15.8-43.8) with the TKI vs 12.1 months (95% CI, 11.1-16.8) for patients treated with the combination (HR, 0.71; 95% CI, 0.50-1.06; P = .1028). An analysis of patients with nonalcoholic fatty liver disease (ANFLD)/ nonalcoholic steatohepatitis (NASH) showed an OS advantage favoring single-agent TKI treatment. The median OS was 21.2 months (95% CI, 18.4-30.6) with lenvatinib (n = 254) vs 12.1 months (95% CI, 10.0-16.8) with the combination (n = 82; HR, 0.46; 95% CI, 0.25-0.88; P = .0181).

“When sorafenib came out there was an impression that there was an enhanced response in patients who had viral hepatitis,” Gholam said. “In fact, there were studies, some of which I participated in, which showed that perhaps sorafenib has a weak antiviral activity, reduces hepatitis C viral load by perhaps a half log. This has continued as TKIs came to the forefront.”

Gholam pointed to a study from Heikenwälder et al in a paper published in Nature which analyzed outcomes with immunotherapy in patients with NASH.

Investigators noted that unconventional activation of CD8-positive/PD1-positive T cells drive carcinogenesis in the setting of fatty liver disease and, in turn, diminish response to IO therapy. “I think this issue is at the same time important and also poorly understood,” Gholam said. “Does that mean that I would make different treatment decisions if I had a patient in front of me who had NAFLD in terms of deciding what treatment option to give them? Within the parameters that outlined in the discussion, I would still choose the [atezolizumab/bevacizumab] option. But this is an important question to ask because fatty liver disease has now become the leading cause of liver disease worldwide. Hepatitis C is on the decline because it is universally curable.”

Alternative First-Line Combinations are Under Evaluation

Alternative combination strategies have been evaluated in the first-line setting vs single-agent TKIs; however there has been no movement to dethrone the approved IMbrave 150 regimen. Specifically, data from the phase 3 HIMALAYA trial (NCT03298451) have set the IO combination of durvalumab (Imfinzi) and tremelimumab on course as a viable option for this patient population.

 However, without an approval, it holds a place as a benchwarmer for the time being.

Investigators assessed a regimen known as STRIDE, which includes a single dose of tremelimumab (300 mg) plus durvalumab (1500 mg every 4 weeks). “HIMALAYA was intended to examine the concept of IO/IO combinations looking at the combination of anti–PD-L1 durvalumab with anti-CTL4 tremelimumab,” El-Khoueiry said. “The way tremelimumab was given in this study is with 1 loading dose based on preclinical evidence that the dose could alter the immune microenvironment, and then [treatment could [continue with] durvalumab as a single agent. This loading dose of tremelimumab was a higher dose than normally used at 300 mg compared with the traditional dose of 75 mg.”

Patients were randomly assigned to STRIDE (n = 393), single-agent durvalumab (n = 389), or sorafenib (n = 389). Median OS was 16.43 months (95% CI, 14.16-19.58) with STRIDE vs 13.77 months (95% CI, 12.25-16.13) with sorafenib (HR, 0.78; 96.02% CI, 0.65-0.93; P = .0035). The HR for OS for durvalumab vs sorafenib alone was noninferior (HR, 0.86; 95.67% CI, 0.73-1.03). The OS rates at 36 months were 30.7%, 24.7%, and 20.2%, respectively.

“Some of the strengths of this trial are that it’s really the largest randomized phase 3 study in first-line HCC,” El-Khoueiry said. “It is very mature with long follow-up. For the first time we’re seeing 36-month OS rates. Certainly, at 36 months, the combination still was superior to sorafenib, so those curves diverge and stayed separate for a long time.” 

Yarchoan noted that cross-study comparisons between the 2 positive data sets presents challenges. “These are different trials, but when we need to pick a regimen, we do what we have to do, which is try to parse apart signals from the data,” he said. “The strength of IO/IO, as we all know, is the tail of the curve and sure enough, the tail of the curve for durvalumab/tremelimumab is very nice. We don’t have that length of follow-up yet for atezolizumab/bevacizumab, but the response rate is clearly higher.”

In terms of selecting patients for the HIMALAYA regimen vs the IMbrave 150 regimen, Yarchoan said, “If you need a response for someone with a lot of disease where you really need to get some disease control, I think from the available data [it’s atezolizumab plus bevacizumab.” However, he adds that for patients who are “VEGF ineligible—patients with very recent surgery, recent stroke, recent heart attacks, recent bleeds—those are the patients for whom there’s no question that durvalumab/tremelimumab is a compelling regimen.”

El-Khoueiry concurred, “I would follow the same approach where atezolizumab/bevacizumab is the go-to regimen with durvalumab/ tremelimumab being the backup option. We’ll see how that regimen performs in real-world as well. That remains to be seen.” 

The HIMALAYA combination was granted a priority review in April 2022 and the FDA is expected to decide on the application in the fourth quarter of 2022.

Unlike HIMALAYA, data from the phase 3 COSMIC-312 (NCT03755791) failed to make meaningful gains with the novel combination of cabozantinib (Cabometyx) plus atezolizumab in the first-line setting. Approved as a single agent for patients with HCC who have been previously treated with sorafenib, when added to the immune checkpoint inhibitor, cabozantinib elicited mixed results.

At a median follow-up of 15.8 months, data showed the combination produced a clinical benefit in PFS; however, that benefit did not extend to OS. Investigators enrolled 837 patients and randomly assigned them to the cabozantinib/atezolizumab arm (n = 432), sorafenib arm (n = 217), or cabozantinib alone (n = 188). The median PFS was 6.8 months (99% CI, 5.6-8.3) with the investigative combination vs 4.2 months (99% CI, 2.8-7.0) with sorafenib (HR, 0.63; 99% CI, 0.44-0.91; P = .0012). At the interim analysis for OS, the median OS was 15.4 months (96% CI, 13.7-17.7) compared with 15.5 months (96% CI, 12.1–not estimable) in the combination and sorafenib groups, respectively (HR, 0.90; 96% CI, 0.69-1.18; P = .44).

“COSMIC-312 was a bit of a disappointment to many of us,” Yarchoan said. “The study was positive regarding PFS, which was one of the coprimary end points, but missed the OS endpoint. The OS curves were at least, thus far, overlapping with the sorafenib curves. I’m not quite sure what happened. Cabozantinib is a very active agent in HCC. It’s an agent that I think many of us use in the second line where it performs very well.”

In terms of response, cabozantinib/atezolizumab elicited an objective response of 11% (95% CI, 8.1%-14.2%) compared with 4% (95% CI, 1.6%7.1%) with sorafenib. The median time duration of response was 10.6 months vs 8.8 months, respectively, and median time to progression was 7.0 months vs 4.6 months.

“The response rate of 11% is numerically lower than we’ve seen with PD-L1 monotherapy,” Yarchoan added. “Although the challenge here is that the sorafenib arm also had a very low response rate of approximately 4%, which is lower than we’ve seen in other recent studies, which were in the range of 15%. I don’t know if the radiology [was different], if there was stage migration, for example treating patients who had TACE [transarterial chemoembolization] lesions that may be less likely to show true response.” 

Yarchoan noted that with other agents showing an OS benefit in the front line, the combination will not move forward. Other studies, including the phase 3 LEAP-002 trial (NCT03713593), evaluating pembrolizumab (Keytruda) in combination with lenvatinib also failed to demonstrate a significant improvement in OS vs lenvatinib alone.

“It seems unlikely that any of those are going to displace the current standard,” BekaiiSaab said. “As exciting as it is to see another phase 3 trial, I don’t know if it’s going to break that ceiling.”

Despite the combination therapies outperforming single-agent sorafenib in phase 3 trials, there is still a place for TKIs for select patient populations. “We talk about IO/IO combinations, but we still have other elements in our armamentarium—the TKIs, such as lenvatinib or sorafenib. Who are the patients for whom you would pick one of these TKIs as your first-line option?” Bekaii-Saab asked the panel. 

Overall, El-Khoueiry said it would depend on the characteristics and patient preference. “The easy answer is patients who have clear contraindications to immunotherapy, those with active autoimmune disease,” he said. “There’s data indicating that patients with a distant history of autoimmune disease may be able to tolerate IO. It’s those with active autoimmune disease or disease that has required recent immunosuppression, who would be the bulk of patients who would get a TKI. Otherwise, I think it would be just a decision that an individual doesn’t want to have intravenous therapy or doesn’t want to travel for treatment. A TKI would be more convenient.”

In choosing the proper TKI for patients, Vogel said he would choose lenvatinib based on the “compelling” real-world data. “For 10 years we have used sorafenib [and] there is a time to change and try something new,” he said adding that sorafenib may still have a role for patients with Child-Pugh B status. “For those with good liver function, it’s lenvatinib.” 

The evidence to support Vogel’s choice of lenvatinib comes from the REFLECT study (NCT01761266) in which the agent was evaluated against sorafenib. Overall, the agent was noninferior in terms of OS (HR, 0.92; 95% CI, 0.79-1.06); however, in an analysis characterizing outcomes based on characteristics, lenvatinib demonstrated early and durable response. The objective response among 478 patients was 18.5%, which investigators noted were comparable to the data reported with single-agent IO therapies.

Evidence-based decisions have leveraged the use of immunotherapy combination atezolizumab plus bevacizumab for patients who receive a diagnosis of hepatocellular carcinoma. 

Immunotherapy Drives First-line Systemic Treatment for Advanced HCC

Investigators are making progress in delineating the optimal use of radiation therapy for the treatment of patients with small cell lung cancer (SCLC), which remains a cornerstone of therapy for the malignancy, particularly in limited-stage disease, according to Billy W. Loo Jr, MD, PhD, FASRO, FACR.

“There are a number of ways that our treatments have been evolving,” Loo said in a recent interview with 

. “Continued optimization of radiation therapy in terms of dose intensity and acceleration, better management of the potential for brain metastases, and combinations with immunotherapy are all under development.”

Loo is a professor of radiation oncology (radiation therapy), director of thoracic radiation oncology, and director of new technologies in the Department of Radiation Oncology at Stanford Cancer Institute, Stanford University School of Medicine in California. He discussed key issues in SCLC during the 

 hosted by Physicians’ Education Resource

In contrast to non–small cell lung cancer (NSCLC), few therapies have been introduced in recent years for treating patients with SCLC. Why is there a disparity?

There are some key differences between the clinical behavior of SCLC and NSCLC, one of which is that the pace of growth of SCLC is more rapid. That has been an issue because fewer patients are diagnosed in an earlier stage of SCLC. However, stage for stage, the survival outcomes historically for NSCLC and SCLC treated with definitive therapy are somewhat similar. So, it is very important to be able to treat [patients with] SCLC in a time-efficient way.

For biological differences, we have not been as successful at finding specific molecular subtypes or genetic oncogene drivers in SCLC as we have in NSCLC and that’s part of why there have been fewer new therapies for SCLC. A very active area of investigation, of course, is combinations with immunotherapy, which have shown a dramatic impact in NSCLC. The data are being acquired and emerging in SCLC and we hope that we will see some similar improvements.

What recent developments have the potential to improve outcomes?

Specifically with regard to radiation therapy, which has been one of the key pillars of treatment of limited-stage SCLC with the goal of cure, what has been shown historically is that the pace of the radiation—compressing the treatment interval into a shorter period of time—has been important.

In the past, one of the challenges with accelerated radiation is that it causes more toxicity. However, with modern improvements in the delivery of radiation therapy, we are able to sculpt the dose more carefully [so that it is] concentrated where the tumors are and less where the normal tissues are, and we can ameliorate some of the dose-limiting toxicities. Recent data that have emerged in some pilot randomized trials in Europe and in China

 suggest that we can get to higher doses than we have in the past with accelerated radiation therapy. Those studies seem to be associated with better survival outcomes. That is potentially a very promising approach in terms of optimizing radiation therapy.

What pending studies may make a difference in this space?

One of the important questions is how to manage the risk of brain metastases in SCLC, particularly in the early stage or limited stage. Older historical data have shown a survival benefit to doing prophylactic cranial irradiation as a way of heading off the development of symptomatic metastases. In the past, that has shown a survival benefit, but that is based on older data where we didn’t have as good staging as we do now, for example, with MRI scans. A question now is in a truly earlier stage with proper staging, is there a benefit to prophylactic cranial irradiation? Can it be optimized? That is being studied in an ongoing clinical trial, MAVERICK [SWOG 1827; NCT04155034].

Another emerging area that is still being defined with respect to the treatment of brain metastases—this is more for extensive-stage SCLC that has involved the brain—is the role of stereotactic radiation as opposed to whole brain radiotherapy. Some very interesting data have emerged, somewhat counterintuitive to notions in the past, [showing] that stereotactic radiation may indeed be an effective treatment for brain metastases in SCLC. There is at least 1 ongoing randomized clinical trial including [patients with] both limited- and extensive-stage SCLC and treatment of brain metastases [NRGCC009; NCT04804644].

What is important for your oncology colleagues to know about treating patients with SCLC?

One important [facet] is that the optimal use of radiation therapy, which is my specialty, is still actively evolving. In the care of patients with SCLC, just as with NSCLC, it is critical to have that input and feedback from radiation oncology and to have that multidisciplinary coordination. That is particularly important in the care of patients with SCLC, who tend to have a more aggressive course of disease and who may have more baseline comorbidities.

Grønberg BH, Killingberg KT, Fløtten Ø, et al. High-dose versus standard-dose twice-daily thoracic radiotherapy for patients with limited stage small-cell lung cancer: an open-label, randomised, phase 2 trial. 

. 2021;22(3):321-331. doi:10.1016/S1470-2045(20)30742-7

Qiu B, Li QW, Liu JL, et al. Moderately hypofractionated once-daily compared with twice-daily thoracic radiation therapy concurrently with etoposide and cisplatin in limited-stage smallcell lung cancer: a multi-center, phase II, randomized trial. 

. 2021;111(2):424-435. doi:10.1016/j.ijrobp.2021.05.003

Investigators are making progress in delineating the optimal use of radiation therapy for the treatment of patients with small cell lung cancer, which remains a cornerstone of therapy for the malignancy, particularly in limited-stage disease.

Changes Improve Radiation Therapy in SCLC

During the past 15 years, breakthrough discoveries have revolutionized the treatment landscape for most patients with lung cancer, progress that has helped fuel an overall drop in cancer mortality.

 However, options remain limited for the subgroup of patients with small cell lung cancer (SCLC). 

Against this backdrop, the treatment paradigm for patients with SCLC is evolving slowly beyond standard chemotherapy. Immune checkpoint inhibitor (ICI) combinations with chemotherapy have been incorporated into first-line treatment protocols for patients with extensive-stage SCLC (ES-SCLC) and the approval of lurbinectedin (Zepzelca), a novel form of chemotherapy, has expanded options for progressive disease.

Meanwhile, data for novel ICI combinations presented at recent medical conferences strengthen the case for such strategies in ES-SCLC, experts say. Additionally, efforts to study disease variation have uncovered molecular drivers of SCLC subtypes that may be useful in developing targeted therapies. 

“Small cell lung cancer, despite being an uncommon disease, is one of the more aggressive cancers we know. It has a poor overall survival, and, despite making many survival-extending advances, both in targeted therapeutics as well as immunotherapy in non–small cell [lung cancer], we haven’t really done that well in the small cell [lung cancer] population,” Joshua K. Sabari, MD, said during an 

 educational webinar in July 2022.3 Sabari is an assistant professor in the Department of Medicine at NYU Grossman School of Medicine in New York, New York.

“Clearly, more needs to be done. We need to understand the biology of this disease better, but as that research takes place, we need to follow best treatment practices as we now understand them,” Sabari said. 

That includes diagnosing patients and initiating therapy as early as possible during the course of disease, and closely monitoring responses for signs of recurrence and brain metastases, Sabari said. Lung cancer experts who participated in a recent 

 expressed excitement about an increasing number of clinical trials for patients with SCLC and the potential for research to yield novel, more effective therapies. However, they also noted that many patients are not benefiting from currently available options.

“When you look at the US population of patients diagnosed with small cell lung cancer, 40% of them may not get any treatment at all,” Taofeek Owonikoko, MD, PhD, said. He is chief of the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine in Pennsylvania and associate director for translational research at UPMC Hillman Cancer Center. 

“That reflects the belief by most of our non-oncology colleagues in other specialties such as pulmonary and internal medicine that once you have a diagnosis of small cell there’s no effective treatment, [the patient] shouldn’t even bother going through any treatment,” Owonikoko said. “...Maybe over time, with education with our peers and colleagues, we are going to be able to change that paradigm.”

An estimated 236,740 patients are expected to receive a diagnosis of lung cancer in the United States in 2022, with approximately 85% of those cases classified as non–small cell lung cancer (NSCLC) and 15% as SCLC.

Improvements in detection and treatment have helped drive down the mortality rates from lung cancer, significantly contributing to an overall decline in cancer mortality of 2% per year from 2015 through 2019, according to the American Cancer Society.6 However, most of the lung cancer gains are attributed to treatment advances for patients with NSCLC, because ICIs and molecularly targeted therapies have transformed the paradigm.

The discrepancy in outcomes for the 2 major subtypes is reflected in the 5-year relative survival rate, which is 26% for patients with NSCLC and 7% for those with SCLC.7 With treatment, median overall survival (OS) for patients with SCLC ranges from 6 months to 24 months, depending on the extent of disease and stage at diagnosis.

Among patients with new SCLC diagnoses, approximately 12,000 are expected to present with limited-stage disease whereas about 23,000 will have extensive-stage disease. In limited- stage disease, the tumor is confined to 1 hemithorax, the mediastinum, or the supraclavicular nodes, such that the tumor fits within a single radiation field. Any disease that cannot be safely confined to a single radiation field is defined as extensive.

For patients with limited-stage SCLC, the goal of treatment is often curative through chemotherapy plus thoracic radiation therapy and, for some patients, surgical resection. For the majority of patients who are diagnosed with ES-SCLC, preferred systemic primary treatment involves combining a PD-L1 inhibitor, either atezolizumab (Tecentriq) or durvalumab (Imfinzi), with a chemotherapy doublet, according to National Comprehensive Cancer Network guidelines.9 Although the risk of relapse is high, more than 60% of patients consistently respond to cytotoxic therapies, including many patients with metastatic disease.

Several studies have now demonstrated an improvement in overall survival with the addition of ICI therapy to chemotherapy in the front line, although most of the gains are relatively modest. 

The FDA approved atezolizumab in combination with carboplatin and etoposide for the f irst-line treatment of adults with ES-SCLC in March 2019. A year later, the agency gave the go-ahead for durvalumab in combination with etoposide and either carboplatin or cisplatin as a first-line treatment for patients with ES-SCLC.

“If we look back on the past decade, the biggest advance is the addition of PD-L1 inhibitory therapy being added to the standard platinum etoposide regimen,” Jared Weiss, MD, said during the 

 program. “If you look at the evolution of frontline therapy before that, it was based on toxicity advantages and convenience advantages. These matter, but PD-L1 is our first survival advantage in a long time.” Weiss is an associate professor of medicine-oncology at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina.

The FDA approved the atezolizumab regimen based on findings from the phase 3 IMpower133 trial (NCT02763579) for 403 patients who had received no prior chemotherapy for extensive-stage disease and had ECOG performance status 0 or 1.

Median OS was 12.3 months (95% CI, 10.8-15.9) for patients receiving atezolizumab with chemotherapy and 10.3 months (95% CI, 9.3-11.3) for participants receiving placebo plus chemotherapy (HR, 0.70; 95% CI, 0.54-0.91; P = .0069). Median progression-free survival (PFS) was 5.2 months (95% CI, 4.4-5.6) with atezolizumab compared with 4.3 months (95% CI, 4.2-4.5) with placebo (HR, 0.77; 95% CI, 0.62-0.96; P = .0170). The objective response rate (ORR) was 60% with the atezolizumab regimen vs 64% with chemotherapy alone.

The combination of durvalumab plus chemotherapy gained approval based on OS results from 537 patients treated in the phase 3 CASPIAN trial (NCT03043872). The median OS was 13.0 months (95% CI, 11.5-14.8) in the durvalumab plus chemotherapy arm compared with 10.3 months (95% CI, 9.3-11.2) in the chemotherapy-alone arm (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).

Investigator-assessed median PFS was 5.1 months (95% CI, 4.7-6.2) in the durvalumab arm and 5.4 months (95% CI, 4.8-6.2) in the chemotherapy-alone arm (HR, 0.78; 95% CI, 0.65-0.94). The ORR was 68% in the durvalumab group vs 58% with chemotherapy alone.

Both ICI regimens maintained an OS benefit in updated findings reported in 2021. The median OS was 12.3 months (95% CI, 10.8-15.8) vs 10.3 months (95% CI, 9.3-11.3), respectively, for the atezolizumab-based and chemotherapy-alone regimens in IMpower133 (HR, 0.76; 95% CI, 0.600.95; P = .0154). At 18 months, the OS rate among patients who received atezolizumab was 34.0% compared with 21.0% for participants treated with chemotherapy alone.

Similarly, the median OS rate was 12.9 months (95% CI, 11.3-14.7) with durvalumab plus chemotherapy compared with 10.5 months (95% CI, 9.3-11.2) for chemotherapy alone in updated findings from CASPIAN (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The addition of durvalumab to chemotherapy resulted in a 32.0% OS rate at 18 months vs 24.8% with chemotherapy alone. (CASPIAN also included a third arm in which patients received durvalumab, the CTLA-4 inhibitor tremelimumab, and platinum-etoposide therapy, but that regimen did not significantly improve OS).

Although the addition of PD-L1 inhibitors to standard chemotherapy represents a step forward for the SCLC paradigm, many patients do not respond to these therapies, Charles M. Rudin, MD, PhD, noted during the program.

“When they do work, they can be transformative,” Rudin said. “There are patients who have durable responses even in extensive-stage disease so these [therapies] can really change a person’s fate. That’s something that was a long time coming and has clearly redefined our standard of care.” 

Rudin is chief of the thoracic oncology service, codirector of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research at Memorial Sloan Kettering Cancer Center in New York, New York. He is a leading investigator into the use of ICIs in patients with SCLC.

In August 2022, Rudin and colleagues presented long-term follow-up results from the phase 3 KEYNOTE-604 study (NCT03066778) at the 2022 World Conference on Lung Cancer sponsored by the International Association for the Study of Lung Cancer.

 The study tested the first-line use of pembrolizumab (Keytruda), a PD-1 inhibitor, combined with a chemotherapy doublet vs chemotherapy alone for patients with stage IV SCLC with no prior systemic therapy or unstable brain metastases and an ECOG performance score of 0 or 1. The dual primary end points were PFS and OS. 

In all, 453 patients were randomly assigned to receive pembrolizumab (n = 228) or placebo (n = 225) plus etoposide with carboplatin or cisplatin every 3 weeks for 4 cycles. These regimens were followed in the experimental arm by pembrolizumab monotherapy and by placebo in the control arm for up to 31 cycles with optional prophylactic cranial irradiation. However, approximately 15% of patients in the chemotherapy-alone group subsequently received ICI therapy. 

In previously reported findings, there was a trend toward an OS improvement with the pembrolizumab-containing regimen, but the outcome did not meet a prespecified threshold for statistical significance (HR, 0.80; 95% CI, 0,640.98; P = .0164).

In the updated data, the median OS in the intention-to-treat (ITT) population after approximately 3.5 years’ follow-up was 10.8 months (95% CI, 9.2-12.9) among patients who received pembrolizumab compared with 9.7 months (95% CI, 8.6-10.7) for chemotherapy alone (HR, 0.76; 95% CI, 0.63-0.93). The median PFS in the ITT population was 4.8 months (95% CI, 4.3-5.4) with pembrolizumab and 4.3 months (95% CI, 4.2-4.5) for chemotherapy alone (HR, 0.70; 95% CI, 0.57-0.85).

Of note, 18 patients who completed 35 cycles of pembrolizumab therapy had better outcomes. The median OS was not reached (NR; 95% CI, 16.6NR) and the 2-year OS rate was 72.2% (95%CI, 39.5%-89.2%), which corresponded to approximately 4 years after randomization. 

In presenting the data, Rudin emphasized that 15.5% of patients treated with the pembrolizumab regimen were still alive at 36 months vs 5.9% of participants who received chemotherapy alone. “We’re seeing about a tripling of 3-year survival,” Rudin said. “Although both of these curves are lower than we would like them to be, to me it’s a substantial benefit and similar to what we’ve seen with other checkpoint inhibitors for this disease.” 

Moreover, he noted, 6.9% of patients in the pembrolizumab arm maintained a PFS benefit at 3 years, including 10.1% with a duration of response (DOR) of at least 42 months. “These patients are remaining progression-free at the tail of the curve for multiple years now,” Rudin said, adding that such an approach could be a “transformative thought” for patients. 

Next steps for pembrolizumab-based combinations for patients with ES-SCLC include the phase 3 KEYVIBE-008 study (NCT05224141) as first-line therapy. The study is evaluating MK-7684A, a coformulation of vibostolimab and pembrolizumab, plus etoposide with platinum chemotherapy vs atezolizumab plus chemotherapy followed by MK-7684A or atezolizumab, respectively. Vibostolimab is a monoclonal antibody directed at the TIGIT immune checkpoint.

In another study, Rudin and colleagues sought to determine whether the addition of tiragolumab, a TIGIT inhibitor, to atezolizumab plus chemotherapy would improve outcomes for patients with treatment-naïve ES-SCLC. Investigators randomly assigned 490 patients to tiragolumab (n = 243) or placebo (n = 247) combined with atezolizumab, carboplatin, and etoposide in the phase 3 SKYSCRAPER-02 trial (NCT04256421).

The use of tiragolumab failed to improve OS and PFS in all patients who received treatment (HR, 1.02 and 1.08, respectively) and in the primary analysis set of participants without a presence or history of brain metastases at baseline (HR, 1.04 and 1.11), according to findings presented at the 2022 American Society of Clinical Oncology Annual Meeting in June (2022 ASCO).

However, investigators noted that the median OS outcomes in the control arm of atezolizumab plus chemotherapy confirmed its place as a first-line standard of care. The median OS was 12.9 months (95% CI, 12.1-14.5) in the full analysis set and 13.6 months (95% CI, 12.3-15.2) in the primary analysis set.

As development of FDA-approved ICIs continues for SCLC indications, the novel PD-1 inhibitor serplulimab (HLX10) has demonstrated an OS benefit in combination with chemotherapy as a frontline treatment for patients with ES-SCLC in research conducted in China and several other countries. Interim findings from the phase 3 ASTRUM-005 study (NCT04063163) were presented at the 2022 ASCO.

In the study, 585 patients were randomly assigned 2:1 to receive either serplulimab (n = 389) or placebo (n = 196) with carboplatin plus etoposide, followed by serplulimab monotherapy or placebo, respectively. Key eligibility criteria included no prior systemic therapy for ES-SCLC and an ECOG performance score of 0 or 1. 

After a median follow-up of 12.3 months, the median OS in the serplulimab group was 15.4 months (95% CI, 13.3-not evaluable) compared with 10.9 months (95% CI, 10.0-14.3) in the placebo arm (HR, 0.63; 95% CI, 0.49-0.82); P < .001). The median PFS was 5.7 months (95% CI, 5.5-6.9) with the serplulimab regimen vs 4.3 months (95% CI, 4.2-4.5) with placebo plus chemotherapy (HR, 0.48; 95% CI, 0.38-0.59). The ORR was 80.2% with serplulimab and 70.4% with chemotherapy alone.

In April 2022, the FDA granted orphan drug status for serplulimab as a treatment for SCLC, which qualifies the drug for certain financial incentives, according to Shanghai Henlius Biotech, Inc, the company developing the drug.19 In China, the National Medical Products Administration approved serplulimab for microsatellite instability–high solid tumors in March 2022 and is considering a new drug application for the agent in first-line ES-SCLC.

Although ICI therapy is solidifying a place in the frontline treatment of ES-SCLC, its efficacy as monotherapy for progressive disease has faded. In 2018, the FDA granted an accelerated approval for nivolumab (Opdivo), a PD-1 inhibitor, as a second-line therapy for patients with metastatic SCLC whose disease progressed after treatment with platinum-based chemotherapy and at least 1 other line of therapy, based on response rates and DOR data from the phase 1/2 CheckMate-032 trial (NCT01928394). However, Bristol Myers Squibb withdrew the indication in December 2020 after data from confirmatory studies failed to support a benefit.

A similar scenario unfolded with pembrolizumab, which also received an accelerated approval as a second-line therapy in patients with metastatic SCLC that progressed after prior chemotherapy in June 2019, based on tumor response rate and from cohort G of the phase 2 KEYNOTE-158 trial (NCT02628067) and cohort C1 of the phase 1 KEYNOTE-028 (NCT02054806) study. Merck withdrew the indication in March 2021 after findings from subsequent clinical trials did not confirm an OS improvement.

Meanwhile, lurbinectedin was introduced into the treatment landscape for second-line therapy in June 2020. Until then, the only FDA-approved option for second-line therapy for SCLC was topotecan (Hycamtin), a topoisomerase I inhibitor that gained its initial indication in the malignancy in 1998.

Lurbinectedin is an alkylating drug that binds to DNA, setting off a cascade of events that may disrupt DNA binding proteins and repair pathways, resulting in cell death. The agent also may affect the tumor microenvironment through several mechanisms that cause apoptosis of peripheral blood monocytes and tumor-associated macrophages, decrease expression of the inflammatory chemokines, and reduce tumor angiogenesis.

The FDA granted an accelerated approval for lurbinectedin in adults with metastatic SCLC with disease progression on or after platinum-based chemotherapy based on findings from the phase 2 PM1183-B-005-14 trial (Study B-005; NCT02454972).

Among 105 patients treated during the study, the investigator-assessed ORR was 35% (95% CI, 26%-45%) and the median DOR was 5.3 months (95% CI, 4.1-6.4). Outcomes were better for the cohort of 60 patients who had platinum-sensitive SCLC, defined as recurrence or progression 90 days or longer after the last dose of platinum-containing therapy. For these patients, the investigator-assessed ORR was 45% (95% CI, 32%-58%) and the median DOR was 6.2 months (95% CI, 3.5-7.3).

In December 2021, investigators launched the confirmatory phase 3 LAGOON trial (NCT05153239), which was designed to establish the efficacy of lurbinectedin for full FDA approval. The trial, which has a target enrollment of approximately 700 patients, is randomly assigning participants to 1 of 3 arms: lurbinectedin monotherapy at 3.2 mg/m2 intravenously (IV); lurbinectedin at 2.0 mg/m2 IV plus irinotecan 75 mg/m2 IV; investigator’s choice of topotecan at 2.3 mg/m2 orally or 1.5 mg/m2 IV, or irinotecan at 350 mg/m2 IV. The primary end points are OS and PFS.

In NSCLC, the development of tyrosine kinase inhibitors has made treatment for the tumor type a prime example of molecularly targeted therapy.

 However, similar progress has proved elusive in SCLC. Nearly all cases of SCLC are associated with smoking and its mutational profile reflects the impact of tobacco carcinogens in driving disease. Whereas NSCLC is driven by activating oncogenic alterations, the development of SCLC involves the dual inactivation of the tumor suppressor genes TP53 and RB1.

“Genetically, what we see across the board in patients with small cell lung cancer is inactivation or loss of TP53, a gene responsible for fixing other abnormalities. We also see loss of RB1 or retinoblastoma, and these 2 alterations are very difficult to target in patients with small cell lung cancer,” Sabari said. “Unlike EGFR mutations, for example, which we can act upon with tyrosine kinase inhibitors, there are no FDA-approved therapies for these alterations in small cell.” 

Although genomic analysis is not yet used to develop prognoses or drive treatment, investigators have identified 4 distinct subtypes of SCLC based on differential levels of transcription factor expression: ASCL1 (SCLC-A subtype), POU2F3 (SCLC-P), NEUROD1 (SCLC-N), and YAP1 (SCLC-Y). The subtypes account for approximately 70%, 16%, 11%, and 2% of cases, respectively.

In 2021, investigators identified an inflamed subtype (SCLC-I) characterized by low expression of ASCL1, NEUROD1, and POU2F3, according to Carl M. Gay, MD, PhD, and colleagues at The University of Texas MD Anderson Cancer Center in Houston. An analysis of SCLC circulating tumor cells in xenograft models showed that the SCLC-I subtype is more likely to respond to ICI therapy whereas the other subtypes might respond to inhibitors targeting PARP, aurora kinases, or BCL-2.

“Based on these separate classifications of small cell lung cancer, we’re starting to tease out potential subsets of patients who may benefit from specific therapies,” Sabari said. “More recently, there is a paper from Carl Gay’s group at MD Anderson that takes this to the next level to seek a more inflamed subtype of small cell lung cancer [in which] patients may benefit further from immunotherapy than others. Again, these subclassifications are not currently used in clinical practice, but they may help in the future with prognosis, treatment, and, more importantly, the development of clinical trials for specific subsets of patients.”

Toschi L, Rossi S, Finocchiaro G, Santoro A. Non-small cell lung cancer treatment (r)evolution: ten years of advances and more to come. Ecancermedicalscience. 2017;11:787. doi:10.3332/ecancer.2017.787 

Michelotti A, de Scordilli M, Bertolo E, De Carlo E, Del Conte A, Bearz A. NSCLC as the paradigm of precision medicine at its finest: the rise of new druggable molecular targets for advanced disease. Int J Mol Sci. 2022;23(12):6748. doi:10.3390/ijms23126748 

Sabari JK. Small cell lung cancer: a review of epidemiology, treatment landscape, and long-term management. OncLive® webinar. July 19, 2022. Accessed August 24, 2022. https://bit.ly/3wpOwvC 

Vol. 23/No. 18 | Oncology Live®

Intraperitoneal Chemotherapy Technique Aims to Dramatically Improve Outcomes in Gastric Carcinomatosis

EphrinB2 Emerges as Targetable Option in Urothelial Carcinoma

Immunotherapy Drives First-line Systemic Treatment for Advanced HCC

Changes Improve Radiation Therapy in SCLC

Progress on New Therapies Stirs Hope in SCLC

Benchmarks in Clinical Trial Design Require Closer Examination by Oncologists