Small cell lung cancer (SCLC) has continued to evolve in recent years, in part from immunotherapy (IO)/chemotherapy combinations in the frontline setting with atezolizumab and durvalumab, respectively.

 For the secondline setting, the addition of lurbinectedin (Zepzelca) has shown intriguing data while also raising questions about the agent’s optimal role in this population. These newer strategies and therapeutics in were discussed in detail during an OncLive Peer Exchange

, which was moderated by Taofeek Owonikoko, MD, PhD, professor of medicine in the Division of Hematology-Oncology of the University of Pittsburgh and chief of hematology and oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

Nearly 240,000 new patients will be diagnosed with lung cancer in 2023 in the United States; SCLC accounts for 14% of lung cancers and is a usually more aggressive subtype.

 When diagnosed with SCLC, which commonly peaks between aged 75 and 79 years in men and women, 94% of patients have disease that has spread beyond the lungs. The incidence of all lung cancers, including SCLC, peaks about 5 years earlier in African American men compared with White men. Regarding outcomes, the 2-year survival rate in SCLC has increased to 19% and 16% in 2017 to 2018 among women and men from 10% and 8% in 1975 to 1976, respectively.

While progress in outcomes has been greater in non–small cell lung cancer, recent advances, including molecularly targeted therapies against 

, checkpoint inhibitors that boost immune response, improved staging, and video-assisted surgery have all contributed to progress in treatment of all types of lung cancer, including in SCLC.

 Owonikoko added, however, that outcomes for SCLC remain dismal, as most patients are diagnosed with incurable, extensive-stage disease.

Challenges Surround Early Diagnosis in SCLC

Konstantinos Leventakos, MD, an assistant professor of medicine and oncology at Mayo Clinic in Rochester, Minnesota, added that the biggest challenge in SCLC is that it is fast growing in nature and that more efficient screening methodologies would be useful in identifying the disease earlier. “Have we seen patients being diagnosed with SCLC through screening? Yes, but whether we have seen a meaningful reduction in the mortality because we were able to recognize many patients in early stages are data that we don’t yet have. So while oncologists are pro-screening because it saves lives, more personalized and more SCLC specific strategies are needed.”

Patients should also be treated sooner for pneumonia for an extended time, particularly smokers, and an earlier biopsy could aid in earlier diagnoses. “Once there is a histologic confirmation of SCLC, immediate referral to oncology is required, and the health care system should be ready to accommodate fast referrals for patients with SCLC,” Leventakos said.

Jacob Sands, MD, a thoracic medical oncologist at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, agreed that lung screening is the best way to improve SCLC outcomes as it allows earlier-stage intervention.

Defining the Role of Biomarkers in SCLC Diagnosis and Treatment

Anne Chiang, MD, PhD, an associate professor and associate cancer center director of clinical initiatives at Yale School of Medicine, explained that PD-L1 expression must be assessed prior to determining treatment for an individual patient with SCLC.

The panel reflected on a patient case of a 68-year-old male with SCLC who was also identified to have pleural hepatic and brain metastases. Despite the heavy disease burden, the patient had an ECOG performance status of 0 and started treatment with nivolumab (Opdivo), carboplatin, etoposide. After 2 cycles, as well as following completion of 4 cycles, there was progressive improvement in the pleural pericardial effusions, reduction in the overall metastatic burden, and significant shrinkage in the hepatic metastases. Overall, the patient experienced minimal toxicity with the regimen and a clear improvement in terms of the associated symptoms.

Having a response to treatment after 2 cycles, followed by a deeper response after cycle 4 was uncommon, making Sands optimistic about this particular patient case. However, Chiang said this scenario was typical in her practice.

While Chiang said most patients with SCLC are metastatic, similar to this individual patient, they can have responses to treatment. “We have a responsibility to these patients to prepare them for what may come next. In most cases, there is recurrence. There’s a window to talk to our patients and make sure that they understand and can prepare without giving up hope, for what may come next.”

Frontline standard-of-care (SOC) options for SCLC treatment include the combination of atezolizumab, carboplatin, and etoposide; the second option is platinum plus etoposide and durvalumab (Imfinzi). Both options are FDA approved and widely used, the panel noted. “These are both PD-L1 inhibitors and patients like hearing that these are not toxins,” Sands said.

The indication for atezolizumab was based off findings from the phase 3 IMpower133 trial (NCT02763579), in which the PD-L1 inhibitor plus chemotherapy improved median overall survival to 12.3 months compared with 10.3 months in the chemotherapy plus placebo arm (HR, 0.70; 95% CI, 0.54-0.91; P = .007).

Having cisplatin available, as well as patients who have hemocytopenia because of bone marrow involvement, would put the durvalumab plus platinum/etoposide regimen as his preference in the frontline setting.

In the limited-stage disease setting, Leventakos said data are limited for incorporating immunotherapy. Moreover, in the absence of a clinical trial, standard treatment for those with limited-stage disease is concurrent chemoradiation, which usually comprises cisplatin with etoposide. Leventakos cited frequent situations of starting with 1 cycle of chemotherapy and catch up with radiation in the following cycle or as soon as possible. Also, in the case of a resected SCLC nodule, adjuvant cisplatin, preferably with etoposide, would be his approach.

The phase 3 CASPIAN trial (NCT03043872) explored the efficacy and safety of durvalumab alone or combined with tremelimumab (Imjudo) and platinum-based chemotherapy followed by durvalumab maintenance therapy vs chemotherapy alone as a first-line treatment for patients with ES-SCLC.

 Preliminary findings did demonstrate an overall survival (OS) improvement with the immunotherapy regimen, but it was not found to be statistically significant. However, updated data showed that the durvalumab combination continued to show an improved overall survival (OS) vs chemotherapy alone.

 Specifically, in longer study follow-up, which was a median follow-up of 39.4 months, the median OS at 3 years was 12.9 months vs 10.5 months, respectively (HR, 0.71; 95% CI, 0.60-0.86; 

 = .0003), and the 3-year OS rate was 17.6% vs 5.8%, respectively.

In the other arm of the CASPIAN trial, durvalumab/tremelimumab plus etoposide/cisplatin chemotherapy (EP) also continued to improve OS vs chemotherapy alone. Median OS was 10.4 months (HR, 0.81; 95% CI, 0.67-0.97; 

 = .0200), and the 36-month OS rate was 15.3%. At 3 years, three times more patients with SCLC were estimated to be alive when given durvalumab plus chemotherapy versus chemotherapy alone, with most patients still receiving durvalumab at the data cutoff. These data established durvalumab plus chemotherapy as the first-line SOC for patients with extensive-stage (ES)–SCLC.

“I love showing my patients the tail of the curve for the CASPIAN trial. I show it to them because it’s important that they know that they could be living in 3 years, even if they have disease that has spread to the brain,” Chiang said. “The CASPIAN trial showed us that you can triple the survival from 6% to 18%. We’re working on clinical trials to try to improve that even more.”

First-line durvalumab plus chemotherapy benefited the OS and progression-free survival (PFS) irrespective of the presence of brain metastases in patients with SCLC, supporting its SOC use.

In the durvalumab plus chemotherapy arm of the trial, adverse events (AEs) were reported by few patients before starting treatment in both arms. Baseline AE rates were maintained in both arms up to 24 weeks after starting treatment, except for itchy skin, which increased from 13% at baseline to 34% at cycle 6 in the durvalumab/chemotherapy arm and 12% at baseline to 42% at cycle 8 in the chemotherapy-alone arm. Dizziness increased from 16% to 40% at cycle 5 in the durvalumab/chemotherapy arm.

In a second case scenario, the panel highlighted a 78-year-old female patient who was initially admitted for weight loss and dysphasia. A PET scan showed a significant fluorodeoxyglucose avidity in the mass and a 4R node, and the biopsy led to a SCLC diagnosis. The patient was initially treated for limited-stage disease with concurrent carboplatin and etoposide with radiation, but a recurrence occurred after 7 months. The patient then completed 4 cycles of chemotherapy and atezolizumab before starting maintenance treatment with the PD-L1 inhibitor. Her disease progressed again about 5 months after starting treatment. Lurbinectedin was then started, but following further disease progression, lurbinectedin therapy was discontinued.

Lurbinectedin received FDA approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The decision was based off findings in the multicenter, open-label, multicohort PM1183-B-005-14 trial (Study B-005; NCT02454972), which comprised 105 patients with metastatic SCLC.

Results showed that lurbinectedin led to an overall response rate of 35.2% and a disease control rate of 68.6%.

Second-line options, beyond lurbinectedin, can include a standard chemotherapy doublet, Leventakos said, but treatment in the second-line setting is not being offered as much as it should. “The old classic second-line treatment in the [United States] is an inhibitor with topotecan, while other countries might use irinotecan. In the US, topotecan was the main second-line treatment. Lurbinectedin has changed the second-line setting.”

“Lurbinectedin is a great tool for us. Patients tolerate it well and we’ve had good responses. It’s the second-line tool for most patients. It would be great if we could combine lurbinectedin with immunotherapy,” Chiang said.

Cell viability testing in SCLC models confirm high 

–expressing cell lines are 4 times more sensitive to lurbinectedin compared with low 

–expressing cell lines, suggesting a potential biomarker for lurbinectedin.

However, in the relapsed setting, the combination of lurbinectedin plus doxorubicin did not improve OS vs control in patients with relapsed SCLC, though it did demonstrate a favorable hematologic safety profile.

Overall, activity with lurbinectedin has led to the ongoing, randomized phase 3 LAGOON study (NCT05153239) which is evaluating lurbinectedin alone or lurbinectedin/irinotecan vs investigators choice or irinotecan in patients with relapsed SCLC.

“This is an exciting time for SCLC. We’re developing this idea that we can have precision medicine, that there’s not just 1 uniform SCLC, that there are subtypes that we can leverage and hope to be able to understand why some of the trials in the past were negative. Perhaps we didn’t capture the right population,” Chiang concluded. Overall, we are starting to develop some real inroads into helping our patients with SCLC.”

Mathieu L, Shah S, Pai-Scherf L, et al. FDA approval summary: atezolizumab and durvalumab in combination with platinum-based chemotherapy in extensive stage small cell lung cancer. 

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Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. 

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Durvalumab ± tremelimumab in combination with platinum-based chemotherapy in untreated extensive-stage small cell lung cancer (CASPIAN) (CASPIAN). ClinicalTrials.gov. Updated July 19, 2023. Accessed September 19, 2023. 

https://clinicaltrials.gov/study/NCT03043872

Paz-Ares LG, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. 

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Chen Y, Paz-Ares LG, Dvorkin M, et al. First-line durvalumab plus platinum-etoposide in extensive-stage (ES)-SCLC (CASPIAN): Impact of brain metastases on treatment patterns and outcomes. 

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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. 

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Kundu K, Cardnell RJ, Zhang B, et al. SLFN11 biomarker status predicts response to lurbinectedin as a single agent and in combination with ATR inhibition in small cell lung cancer. 

2021;10(11):4095-4105. doi:10.21037/tlcr-21-437

Aix SP, Ciuleanu TE, Navarro A, et al. Combination lurbinectedin and doxorubicin versus physician’s choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial. 

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Besse B, Paz-Ares LG, Peters S, et al. A phase III study of lurbinectedin alone or in combination with irinotecan vs investigator’s choice (topotecan or irinotecan) in patients with relapsed small cell lung cancer (SCLC; LAGOON trial). 

. 2023;41(suppl 16; abstract TPS8613). doi:10.1200/JCO.2023.41.16_suppl.TPS8613

Articles

While progress in outcomes has been greater in non–small cell lung cancer, recent advances, including molecularly targeted therapies against EGFR and ALK, checkpoint inhibitors that boost immune response, improved staging, and video-assisted surgery have all contributed to progress in treatment of all types of lung cancer, including in SCLC.

Novel Frontline Combinations Influence Later-Line Treatment Strategies in SCLC

As longer-term data read out for established regimens in urothelial cancer and up-and-coming therapeutics inch toward approval, optimizing treatment approaches relies on buy-in from multidisciplinary teams and patients.

“It’s great to see how the field is rapidly evolving and how we can provide more options for our patients,” Petros Grivas, MD, PhD, said in a recent 

. “In the past 6 years, we have all these new agents— checkpoint inhibitors, 2 antibody-drug conjugates, targeted therapy— all recently approved and many more to come.”

As more options expand the use of systemic therapies in practice to either avoid or reduce the invasiveness of surgical approaches, discussions across teams as well as with patients are vital. “It’s a balanced discussion about the risks and benefits of trimodal therapy vs surgery,” Mamta Parikh, MD, MS, said. “We often have patients who see radiation oncologists and surgeons….It is important for them to get both perspectives. It comes down to the individual patient—what they’re willing to undergo—and I think clinical trials are so important in this area because I do feel that we may be on the cusp of getting to real bladder preservation for all of our patients with muscle-invasive disease.”

Parikh and Grivas joined a panel of genitourinary cancer experts to unpack how the latest data presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers (ASCO GU) Symposium will influence practice for patients with urothelial carcinomas.

Most patients with high-risk, non–muscle-invasive bladder cancer (NMIBC) with cancer that does not respond or recurs within 12 months have a poor prognosis and will require a radical cystectomy.

The single-arm, multicohort phase 2 KEYNOTE-057 trial (NCT02625961) evaluated the safety and efficacy of the PD-1 inhibitor pembrolizumab (Keytruda) monotherapy in patients with BCG-unresponsive high-risk NMIBC who were ineligible or declined to undergo radical cystectomy. Results from cohort A supported the FDA approval of pembrolizumab monotherapy for this patient population in January 2020.

Cohort B of KEYNOTE-057 included patients with papillary tumors without carcinoma in situ (CIS) and the primary end points were 12-month disease-free survival (DFS) rate of high-risk NMIBC and complete response (CR) rate. After approximately 45 months of follow-up, pembrolizumab showed notable antitumor activity in patients with non-CIS papillary high-risk NMIBC unresponsive to BCG. There were no new safety concerns, and the toxicity was manageable and consistent with cohort A. Results indicate that pembrolizumab monotherapy may be beneficial for patients with non-CIS papillary high-risk NMIBC that is refractory to BCG and who also declined or were ineligible for radical cystectomy.

Among patients in this cohort (n = 132), the 12-month DFS rate for high-risk NMIBC rate was 43.5% (95% CI, 34.9%-51.9%). The 24- and 36-month DFS rates were both estimated to be 34.9% (95% CI, 26.4%-43.4%). The median DFS was 7.7 months (95% CI, 5.5-13.6). Regarding DFS for any disease, the 12-month DFS rate was 41.7% (95% CI, 33.1%-50.0%), and the 24-, and 36-month DFS rates were both 33.0% (95% CI, 24.7%-41.5%). Of note, trial investigators called attention to patients with progressive disease at baseline (n = 18), for whom the 12-month DFS rate was 23.5% (95% CI, 7.3%-44.9%).

Progression-free survival (PFS) outcomes were also favorable for pembrolizumab in cohort B, with a 12-month PFS rate of 88.2% (95% CI, 80.0%-93.2%) for worsening of grade, stage, or death and 88.2% (95% CI, 79.4%-93.3%) for progression to metastatic disease or death. The median PFS for grade/stage was 44.5 months (95% CI, 34.6-not estimable [NE]) and 46.2 months (95% CI, 36.8-NE) for invasive or metastatic disease.

“There was very good disease control, a very high cystectomy-free rate,” Grivas noted adding that “the toxicity signal was what we would expect and there were no new safety signals. Something to look at in the non–muscle-invasive disease space.”

To build on these signals, novel combinations are being explored to boost efficacy with pembrolizumab. For example, the immune checkpoints TIGIT and LAG-3 are known to contribute to treatment resistance in many cancers, so investigators are seeking to leverage these with dual-inhibition approaches. Thus, cohort C of the KEYNOTE-057 trial will evaluate the efficacy and safety of pembrolizumab and the TIGIT inhibitor vibostolimab or the LAG-3 inhibitor favezelimab in patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. Tumor evaluations will take place every 12 weeks until year 2 and then every 24 weeks for up to 5 years. The primary efficacy end point is the 12-month complete response rate of high-risk NMIBC.

“There’s a lot of efforts right now in terms of intravesical therapy and trying to develop larger trials for BCG-unresponsive disease and studies that also include randomization,” Andrea B. Apolo, MD, said. “There’s a lot of activity right now for patients with NMIBC that are BCG unresponsive.”

Leveraging Findings From Adjuvant Therapy Trials

Patients with muscle-invasive urothelial carcinoma (MIUC) have a high recurrence rate despite treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical cystectomy in eligible patients.

 Immunotherapy for patients with high-risk muscle-invasive disease has been established in the adjuvant setting with agents such as nivolumab (Opdivo) demonstrating durable improvements.

 Other treatment options, such as atezolizumab (Tecentriq), have missed the mark in this population, and the role of pembrolizumab in this setting remains to be seen.

The approval of nivolumab followed the DFS primary end point in the phase 3 CheckMate 274 trial (NCT02632409) being met in the intention-to-treat (ITT) group and in patients with PD-L1 expression of at least 1%.

 Specifically, CheckMate 274 enrolled patients with highrisk MIUC after radical resection. Patients were randomly assigned 1:1 to nivolumab (n = 353) or placebo (n = 356) for a maximum of 1 year of treatment. Patients had pathologic evidence of UC at high risk of recurrence and an ECOG performance status 1 or less. Primary end points were DFS in ITT patients and in patients with PD-L1 expression of at least 1%. DFS was also analyzed in prespecified subgroups.

At a median follow-up of 36.1 months, the median DFS was 22.0 months (95% CI, 18.8-36.9) with nivolumab arm vs 10.9 months (95% CI, 8.3-15.2) with placebo in ITT patients. Additionally, the median DFS was 52.6 months (95% CI, 25.8-NE) with nivolumab (n = 140) vs 8.4 months (95% CI, 5.6-17.9) with placebo (n = 142) in patients with PD-L1 expression of at least 1%. DFS benefit was seen in most subgroups analyzed. Safety data were consistent with the primary analysis. Overall survival (OS) will be evaluated. At follow-up, nivolumab continued to show DFS benefits vs placebo. These results further support adjuvant nivolumab as a standard of care for patients with high-risk MIUC after radical resection.

“Adjuvant chemotherapy has been used for years and has shown an improvement in PFS,” Apolo said. “There are important data showing that chemotherapy immediately after surgery does improve outcomes, although the trial did not fully accrue to give the OS benefit. We do see a benefit when patients are treated earlier with systemic therapy. If the patient already received neoadjuvant therapy, then we can talk about immunotherapy.”

The phase 3 IMvigor010 trial (NCT02450331) compared atezolizumab with observation as adjuvant therapy in patients with high-risk MIUC. IMvigor010 is, to our knowledge, the largest, first-completed phase 3 adjuvant study to evaluate the role of a checkpoint inhibitor in MIUC, Shilpa Gupta, MD, explained. The trial did not meet its primary end point of improved DFS with adjuvant atezolizumab, and the use of adjuvant checkpoint inhibitor therapy in the setting evaluated in IMvigor010 is not supported at this time.

“It’s important to enroll on trials…to address some of these unmet needs,” Gupta said. “We learned a lot from IMvigor010. Although it was a negative trial for the primary end point, it did teach us a lot about minimal residual disease [MRD] in these patients.”

Gupta noted a poster presentation on circulating tumor DNA (ctDNA) analysis in the IMvigor010 study given during the 2023 ASCO GU Symposium.

 Investigators reported that ctDNA detection at a postsurgical time point was prognostic for DFS and OS. In the observation arm of the trial, patients were stratified by positive (n = 66) or negative (n = 118) ctDNA status. The median DFS was 3 months for those with ctDNA positivity vs not reached for those with ctDNA negativity (HR, 4.86; 95% CI, 3.09-7.60; 

 < .0001). The median OS was 13 months vs not reached, respectively (HR, 5.47; 95% CI, 3.19-9.40; 

“We’re working in exciting times right now where we have some biomarkers that may be able to select the patients that respond better or benefit the most,” Apolo said. “The problem with adjuvant therapy is that we overtreat patients. That’s why it’s hard to see the benefit that the therapy does because a lot of the patients may be cured, and that’s true of all forms. It’s hard to select the patients [who] meet the [criteria for] therapy. That’s why I think ctDNA is very exciting.”

“I have not started using the FDA-approved ctDNA test in clinical practice,” Parihk said. “We have some trials that are evaluating this, but as of now I think that it’s a fascinating area and the IMvigor data are interesting, but I’m not ready to allow it to guide my clinical practice quite yet. We need more trials that will help us further determine how to incorporate MRD into our practice.”

Other trials examining adjuvant immunotherapy include the phase 3 AMBASSADOR trial (NCT03244384), which is exploring the use of pembrolizumab in patients with localized MIBC and locally advanced UC. Monoclonal antibodies can enhance the immune response and help fight cancer by recognizing and blocking checkpoint molecules. OS and DFS are the primary outcome measures in this study, which is expected to complete in 2025.

 “I’m awaiting the AMBASSADOR trial results and would be very excited to report that out,” Apolo said. “It’s such an important trial because the CheckMate-274 [trial] is showing an improvement in DFS. We really want to see what other agents show since the IMvigor010 did not show the data. I’m excited about the AMBASSADOR trial.”

In the clinic, Apolo said that she discusses adjuvant therapy options based on established findings and takes the patient’s prior courses of therapy into consideration. “I do discuss adjuvant chemotherapy with patients if they have not received chemotherapy,” she said. “If they’ve already received chemotherapy, then I discuss adjuvant checkpoint inhibitor [therapy] with nivolumab and discuss the PFS data. We still don’t have survival data, but the PFS data are positive, and it does look like it improves outcomes in patients in terms of DFS in the adjuvant setting, so it is something that I will discuss with patients and offer it to them.

“In terms of upper tract [disease] that’s a little harder. We don’t want to base decisions on subgroup analyses, and that’s what we have right now for adjuvant checkpoint [inhibitors]. The subgroup analysis in patients with upper tract disease did not look like it benefitted them as much as the bladder primaries. If a patient has already received chemotherapy, then I also discuss adjuvant nivolumab; if they haven’t, then I discuss adjuvant chemotherapy.”

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab for patients with locally advanced or metastatic UC and who are ineligible for cisplatin chemotherapy. The second indication for the antibody-drug conjugate highlights the role of nectin-4 as a clinically actionable target in this patient population.

The most recent approval was supported by findings from the phase 1/2 KEYNOTE-869 trial (NCT03288545), which showed that the objective response rate in patients that received enfortumab vedotin and pembrolizumab (n = 121) was 68% (95% CI, 59%-76%), including a 12% CR rate.

 The recommended enfortumab vedotin dose given with pembrolizumab is 1.25 mg/kg (up to 125 mg for patients with a body weight ≥ 100 kg) via intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle until disease progression or unacceptable toxicity. The recommended pembrolizumab dose, administered after enfortumab vedotin on the same day, is 200 mg every 3 weeks or 400 mg every 6 weeks.

“We have data in the metastatic setting that enfortumab vedotin is active,” Apolo said. “It’s active on its own as monotherapy and it’s active in combination with checkpoint inhibitor pembrolizumab. This year we saw several trials in progress that are comparing enfortumab vedotin alone with enfortumab vedotin in combination with pembrolizumab. The KEYNOTE-905/EV-303 study [NCT03924895] is evaluating neoadjuvant pembrolizumab alone compared with pembrolizumab plus enfortumab vedotin. KEYNOTE-B15/EV-304 [NCT04700124] is a randomized phase 3 trial comparing enfortumab vedotin plus pembrolizumab with platinum-based chemotherapy in the neoadjuvant setting for patients with muscle-invasive disease. It’s going to be very interesting to move these therapies forward and to see what the outcomes are in these trials.”

The phase 2 TROPHY U-01 trial (NCT03547973) is a multicohort, open-label, study that led to the accelerated FDA approval of sacituzumab govitecan-hziy (Trodelvy) for patients with locally advanced or metastatic UC who previously received a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor.

 Neutropenia and diarrhea are the most frequent toxicities associated with sacituzumab govitecan, an active medication with a controllable safety profile.

“The TROPHY U-01 cohort 5 study investigated sacituzumab govitecan plus zimberelimab, which is a PD1 inhibitor, vs zimberelimab alone vs avelumab [Bavencio],” Parikh said. “It will give us interesting data. It will be challenging for patients to be on that kind of intensified therapy. There are more challenges in terms of weekly infusions, potential for cytopenias, and gastrointestinal [adverse] effects, so we’ll have to see if the tolerability is acceptable. It will be interesting to see the duration of therapy for all these regimens, including with intensified approaches.”

Taking the Whole Patient Into Consideration

Parikh noted that bladder-preserving efforts are something that should be given more focus because patients’ quality of life is greatly affected with radical cystectomies (

 “There are a lot of really exciting things that are around the corner for bladder cancer [and] one thing that’s very inspiring in our field is that we’re listening to the patients about what they want,” she said. “We have heard that cystectomies are [procedures] they would like to avoid, as they are impacting their quality of life. It’s wonderful to see the field listening to that and looking in both the non–muscle-invasive space as well as the muscle-invasive space to find patients for whom we can spare their bladders and looking at approaches that potentially could get us to bladder preservation for all.”

Urothelial Cancer Agents Approved by the FDA Since 2020

Grivas also noted that novel preservation approaches are actively being discussed in the clinic using the tools that are available. “This is a very important and rapidly evolving theme [as] we see a trend toward a higher desire and willingness to go for bladder preservation,” he said. “This has been evolving with our urologist [colleagues] being strong advocates for that in well-selected patients. The way we navigate discussions in a busy multidisciplinary clinic is we try to think about the individual in front of us. What is the best local regional definitive therapy assuming no metastasis of course and curative intent? Is radical surgery or trimodality therapy the best approach for bladder preservation? This has to do with a number of patient-related characteristics but also cancer-related characteristics.”

Counseling the patient on the best course of action is the next step, and keeping the patient part of the decision-making process is paramount. “With this approach I would say that approximately 15% to 20% of patients may undergo bladder preservation using anecdotal statistics and of course it’s a method of selection based on the criteria we use for bladder preservation,” Grivas said.

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Advances Across Urothelial Carcinomas Highlight Need for Shared Decision-making

Although emerging strategies are expanding options for treating patients with early-stage non–small cell lung cancer (NSCLC), stage IIIB disease continues to pose challenges. A multimodality approach may help overcome current barriers to care.

The paradigm for treating patients with stage IIIB disease was among the topics discussed by a panel of experts participating in a recent 

® program. The discussion spanned the spectrum of care for patients with stages I to III NSCLC. “There are so many different trials coming forward, I’m really excited about where we are in the management of NSCLC,” moderator Heather A. Wakelee, MD, said.

In general, staging patients with NSCLC is clinically challenging. Although the sensitivity and specificity of individual diagnostic modalities are high, the accuracy of comparing the clinical stage and pathological stage is typically low, ranging from 50% to 60%. Nevertheless, correct clinical staging is crucial because it affects initial therapy options and, potentially, treatment outcomes. A multidisciplinary team should classify patients into 1 of 3 categories before beginning any treatment: potentially resectable, potentially resectable with a higher risk of incomplete resection, or definitely unresectable.

Stage III NSCLC is defined as a locally advanced lung cancer within the primary tumor (T) based on size and location and/or metastatic disease present only in regional lymph nodes (N), and no distant metastasis (M), according to the American Joint Committee on Cancer TNM staging system, which was updated in 2017.

The stage III classification encompasses a heterogenous group of tumors characterized as stage IIIA, IIIB, and IIIC.

 Whereas surgery with neoadjuvant and/or adjuvant therapy is frequently an option for patients with stage IIIA disease, most patients with stage IIIB or stage IIIC NSCLC are not candidates for surgery.

An estimated 17.6% of patients have received diagnoses of stage IIIB NSCLC. The estimate 5-year survival rate ranges from 3% to 7% for most patients, although it has reached 20% for selected patients with T4, N0-1 disease (

. Illustration of Lung Cancer at Stage IIIB

Within stage IIIB, there are 2 unresectable subgroups: T1 to T2, N3 tumors; and T3 to T4, N2 tumors. For patients with confirmed N3-positive disease, the standard of care is definitive concurrent chemoradiation (cCRT) followed by durvalumab (Imfinzi), a PD-L1 inhibitor, according to National Comprehensive Cancer Network guidelines. The immunotherapy agent also is recommended as consolidation therapy for eligible patients with unresectable stage III NSCLC whose disease has not progressed after definitive cCRT.

Although surgery is not advised for patients with T4, N2 to N3 disease (stages IIIB and IIIC), the N3 and N2 nodes are biopsied during the initial work-up. The same treatment options as for stage IIIA (T4, N0-1) disease may be considered if these biopsies are negative. Durvalumab is recommended for patients with unresectable tumors who have received definitive cCRT if either the contralateral or ipsilateral mediastinal node is positive.

 program, panelists discussed which patients with early-stage NSCLC should be considered for neoadjuvant chemoimmunotherapy, including some patients whose tumors might be downstaged for subsequent surgery with earlier intervention.

“For stage III disease, it’s clear—nodal disease, that patient who is at high risk of occurrence, over 50% to 70%, depending on which literature you read, in 5 years,” Joshua K. Sabari, MD, said. “So that’s the patient population, and there’s no argument in our tumor boards. I would even argue the stage II patients should get neoadjuvant therapy. It’s the IB/IIAs that become controversial in tumor board. I think that’s going to be an ongoing discussion until we see real survival benefit that’s long term.

“Patients with stage IIIA NSCLC are the ones to be resected,” Sabari added. “With stage IIIB NSCLC patients, I’m on the fence.”

Billy W. Loo Jr, MD, PhD, FASTRO, FACR, sounded a note of caution about embracing neoadjuvant approaches too quickly. In answer to a question about patients with stage IIIB NSCLC, he said he was concerned about “trying to expand the indications [to] patients who really would not have been considered resectable up front, and the idea is that now we’re going to try and make them resectable with induction therapy. That’s a risky extrapolation.”

Wakelee agreed that the prospect of surgery for these patients could be problematic. “That’s what we always say—the tumor never really shrinks away from the mediastinum; it always shrinks into it.”

Spicer noted promising findings for patients who participated in the INCREASE trial (NL8435), a small study conducted in the Netherlands, with results reported at the European Society for Medical Oncology Congress 2022 in September 2022. Patients with T3 to T4, N0 to 2, M0 NSCLC were treated with combination immunotherapy with ipilimumab (Yervoy), a CTLA-4 inhibitor, plus nivolumab (Opdivo), a PD-1 inhibitor, along with platinum-doublet chemotherapy and radiotherapy, followed by surgical resection.

Among 24 participants who received induction therapy and subsequent surgery, 15 patients (63%) had a pathological complete response and 19 (79%) had a major pathological response, defined as residual viable tumor cells of 10% or less. The pathological complete response compared favorably (

 < .001) with a historical reference point of 30%, investigators said.

Wakelee noted that most INCREASE participants had Pancoast tumors, defined as tumors of the superior sulcus that occur infrequently but are sometimes tackled with curative therapy.

 She also pointed out that patients received chemoradiation plus immunotherapy.

“They were mostly Pancoast [tumors], but there was some invasion of the mediastinum,” Sabari agreed. “It’s a controversial study, don’t get me wrong, but [there was] 100% resection in that sampling. So, again, we need prospective trials to drive this.”

During 2022, new data were reported for durvalumab therapy in patients with unresectable stage III NSCLC that solidify its place in the treatment paradigm and suggest a broader role in this population.

PACIFIC Study: Durvalumab Following cCRT 

In February 2018, the FDA approved durvalumab for patients with unresectable stage III NSCLC whose disease had not progressed following concurrent platinum-based chemotherapy and radiation therapy.

The agency based its decision on an interim analysis of data from the phase 3 PACIFIC trial (NCT02125461), in which 713 patients who had completed at least 2 cycles of cCRT were randomly assigned 2:1 to receive durvalumab at 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months. In all, 476 patients were treated with durvalumab and 237 were given placebo; 53% of the participants had stage IIIA disease and 45% had stage IIIB.

After a prespecified number of events, the findings showed that median overall survival (OS) was not reached (NR) for patients who received durvalumab (95% CI, 34.7 months-NR) compared with 28.7 months (95% CI, 22.9-NR) for participants treated with placebo (HR, 0.68; 95% CI, 0.53-0.87; 

 = .0025). Median progression-free survival (PFS) also was longer with durvalumab at 16.8 months (95% CI, 13.0-18.1) vs 5.6 months (95% CI, 4.6-7.8) with placebo (HR, 0.52, 95% CI, 0.42-0.65).

Five-year data from PACIFIC show “robust and sustained OS and durable PFS benefit” with durvalumab therapy, investigators reported in the 

 in February 2022. The median OS was 47.5 months (95% CI, 38.1-52.9) for patients who received durvalumab compared with 29.1 months (95% CI, 22.1-35.1) for those on placebo (HR, 0.72; 95% CI, 0.59-0.89). The median PFS was 16.9 months (95% CI, 13.0-23.9) with durvalumab vs 5.6 months (95% CI, 4.8-7.7) with placebo (HR, 0.55; 95% CI, 0.45-0.68).

In a subgroup analysis, the benefit with durvalumab therapy was greater for patients with stage IIIA disease (HR, 0.61; 95% CI, 0.470.80) than for participants with stage IIIB (HR, 0.86; 95% CI, 0,63-1.17).

Overall, the estimated 5-year OS rate was 42.9% (95% CI, 38.2%-47.4%) with durvalumab and 33.4% (95% CI, 27.3%-39.6%) with placebo. The corresponding PFS rates were 33.1% (95% CI, 28.0%-38.2%) and 19.0% (95% CI, 13.6%-25.2%), respectively.

The objective response rate also was higher with durvalumab therapy compared with placebo (29.8% vs 18.3%, respectively), and approximately half of the durvalumab respondents had continuing responses at 5 years.

In terms of adverse events (AEs), safety data from PACIFIC were not updated beyond the March 2018 data cutoff because no patients were treated as per trial protocols beyond the 12-month study period. At the time of the primary analysis, the incidence of AEs of grade 3/4 severity was 30.5% among patients who received durvalumab and 26.1% for participants in the placebo group, with fatal events of 4.4% and 6.4%, respectively. AEs that most frequently led to discontinuation of therapy included pneumonitis, radiation pneumonitis, and pneumonia.

DOLPHIN Study: Durvalumab Plus Concurrent Radiation Therapy

Although PACIFIC marks a milestone in the use of immunotherapy with curative intent in NSCLC,

 approximately 30% of patients with stage III unresectable disease would not be eligible to receive durvalumab consolidation therapy following definitive chemoradiotherapy because of pneumonitis or disease progression.

Investigators in Japan sought to determine whether introducing durvalumab earlier in the treatment algorithm would be beneficial. The DOLPHIN study (JapicCTI-194840) was the first phase 2 trial to assess the efficacy of immunotherapy plus concurrent curative radiation therapy in patients with PD-L1–positive unresectable locally advanced NSCLC (stage III or postoperative recurrent) without chemotherapy.

The study enrolled 35 patients with a median age of 72 years; 54.3% had an ECOG performance score of 0 and 25.7% had postoperative progression, investigators reported at the IASLC World Conference on Lung Cancer in August 2022. Participants were required to have a PD-L1 expression level of 1% or greater. The treatment involved concurrent curative radiation therapy (60 Gy) plus durvalumab (10 mg/kg every 2 weeks), followed by maintenance durvalumab for up to 12 months until disease progression or intolerable toxicity.

After a median follow-up of 18.7 months, the 12-month PFS rate, the primary end point, was 72.1% (90% CI, 59.1%-85.1%) in 33 evaluable patients. That result exceeded the prespecified threshold for the study of 28%.

The confirmed overall response rate was 90.9% (95% CI, 75.5%-98.1%), including complete and partial response rates of 36.4% and 54.5%, respectively. The median PFS was NR by independent central review and 24.1 months (95% CI, 16.0-NR) by investigator assessment.

In terms of toxicities, 47.1% of 34 safety-evaluable patients experienced grade 3 or grade 4 AEs, most frequently lung infection and pneumonitis (11.8% each). Two patients (5.9%) experienced grade 5 AEs from any cause; 1 patient had lung infection and 1 had a broncho-esophageal fistula because of tumor progression. Thirteen patients (39.4%) discontinued durvalumab; 6 because of disease progression and 7 because of AEs.

The therapeutic approach is a “promising” strategy for patients with unresectable locally advanced NSCLC suitable for exploration in phase 3 studies, investigators concluded.

Moving forward, treatment considerations for patients with stage IIIB NSCLC likely will go beyond the current TNM staging system, 

 panelists noted. Ignacio I. Wistuba, MD, anticipates that “pro-molecular targets” will factor into decision-making. “That’s going to be not just staging but more molecular testing,” he said.

In general, panel members said, the introduction of immunotherapy and targeted therapies into the treatment paradigm in several earlier stages of NSCLC is creating a need for biomarker testing beyond the advanced and metastatic settings currently recommended in National Comprehensive Cancer Network guidelines.

“I think as much information as possible is useful even for stage I [disease],” Jonathan Spicer, MD, PhD, BSc (Hon), FRCS, said. “The landscape is changing enormously fast, and more and more targets are coming into play even for those very early-stage patients. It's helpful for clinical trial enrollment, but in standard practice, I’d say the bare minimum [for testing] is 

, and PD-L1 [tumor proportion score] to get moving, particularly for any tumor that’s over 4 cm or if you have positive lymph nodes.”

Spicer, a surgeon, said he likes to have cases involving any locally advanced NSCLC, which he defines as stages IB to III disease, discussed at tumor board. “It’s a much more fruitful discussion if we have as much molecular data as possible,” he said.

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Although emerging strategies are expanding options for treating patients with early-stage non–small cell lung cancer, stage IIIB disease continues to pose challenges. A multimodality approach may help overcome current barriers to care.

Sandra Toogood

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Advances Across Urothelial Carcinomas Highlight Need for Shared Decision-making

Multifaceted Approach Remains a Linchpin for Stage IIIB NSCLC Therapy