Retevmo (selpercatinib) demonstrated response improvements in previously treated patients with 

 fusion-positive non-small cell lung cancer (NSCLC), according to findings presented at the virtual 2021 ASCO Annual Meeting.

“However, results should be interpreted with caution, as a limitation of this analysis was that immediate prior response assessment was based on physician-reported best response in patients’ medical history and may not follow RECIST criteria,” the researchers said.

This study consisted of 218 evaluable patients (median age 61 years) who previously received platinum-based chemotherapy. The majority had an ECOG (or the measurement to describe a patient’s level of functioning in terms of ability to care for themselves, daily activity and physical ability; with zero being fully active and four being disabled) of 0/1, with an average of two (range: 1-15) prior systematic therapies, across 89 sites in 16 countries.

The primary endpoint of the study was objective response rate (or the rate of a measurable response to the treatment), with secondary endpoints of progression-free survival (time during and after treatment when the patient lives without disease progression), duration of response (or the length of time that a tumor continues to respond to treatment without the cancer growing or spreading) and safety.

The study compared each patient’s best overall response to their prior therapy to the response elicited from Retevmo.

The objective response rate with Retevmo was 57% which was “markedly higher,” the researchers wrote, than responses for prior treatment at 16%.

A total of 108 patients (50%) did not respond to prior therapy but did respond to Retevmo. There were 16 patients (7%) who responded to both Retevmo and prior therapy, 18 patients (8%) who responded to prior therapy but not Retevmo and 76 patients (35%) who did not respond to either.

Objective response rate was improved regardless of prior therapy, chemotherapy plus immune checkpoint inhibitor (57% versus 14%), single-agent immune checkpoint inhibitor (48% versus 3%) or chemotherapy (58% versus 15%).

Fewer patients had progressive disease with Retevmo best overall response (2%), compared with immediate prior therapy (28%). Median duration of response was also longer compared with prior therapy, with an average of 11.8 months versus 3.4 months.

“A global, randomized, phase 3 trial (LIBRETTO-431; NCT04194944) evaluating (Retevmo) compared with standard frontline therapy (Altima/ carboplatin with or without Keytruda) is ongoing,” the researchers concluded.

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Previously treated patients with non-small cell lung cancer tended to have better responses with Retevmo than they did with prior treatments. 

Retevmo Shows Improvement for Previously Treated Patients With Non-Small Cell Lung Cancer 

Pralsetinib (Gavreto) elicited promising responses and tolerability in patients with 

 fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.

“These data are real important because it supports the importance of early biomarker testing for all patients with metastatic NSCLC prior to treatment initiation to inform optimal healthcare decisions,” said Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano in Italy and head of the division of early drug development at the European Institute of Oncology in Italy, at the 2021 virtual ASCO Annual Meeting about updated data from the ARROW trial.

The phase 1/2 study was conducted at 84 sites in 13 countries. In particular, the safety population for this study included 233 patients with 

 fusion-positive NSCLC and 238 patients with other RET-altered solid tumors. In particular, 216 patients (median age, 60 years; 48% men) with 

fusion-positive NSCLC had measurable disease.

Originally patients who were treatment-naïve were not eligible, which was a requirement that was later removed by a protocol amendment. There were 25 patients who were enrolled after this eligibility revision (median age, 54 years; 44% men).

The study had a primary endpoint of objective response rate (ORR). Follow-up was conducted for a median of 17.1 months.

For the 216 patients who received pralsetinib and were 

 fusion-positive, the ORR was 69% (95%, CI, 62-75), DCR was 92% (95%, CI; 87-95), CBR was 77% (95%, CI; 71-82) and median DoR was 22.3 months (95%, CI; 15.1-not reached).

In the post-eligibility population with 25 patients, the ORR was 88% (95% CI, 69-98), CBR was 88% (95% CI, 69-98), DCR was 96% (95% CI, 80-100). In addition, median DoR and median PFS was not reached.

“The most important observation is that in the expansion cohort of real-world and first-line treatment of (non-small cell lung cancer) patients with 

fusion-positive tumor, the overall response rate was 88%, providing support for RET inhibitor as a first-line standard of care because the response rate was better in this population (with) respect to the previous eligibility criteria population,” Curigliano said.

The median duration of response in patients with prior platinum-based chemotherapy was 22.3 months (95% CI, 15.1-not reached). Curigliano added that it was too early to analyze data regarding the duration of response in treatment-naïve patients.

Overall, 26 patients (6%) out of 471 patients in the entire study discontinued treatment due to treatment-related adverse events. In all tumor types, 15% of patients had treatment-related neutropenia leading to treatment interruption whereas 14% had neutropenia from the treatment which resulted in a dose reduction. Less than 1% of patients discontinued treatment from treatment-related neutropenia.

“It means that pralsetinib was very well tolerated,” Curigliano said.

Curigliano, G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9089.

Pralsetinib elicited promising responses and tolerability in patients with RET fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.  

 Pralsetinib Is Tolerable, Durable in RET Fusion+ NSCLC

The FDA approved sotorasib (Lumakras) for the treatment of patients with non-small cell lung cancer (NSCLC) whose tumor have a KRAS G12C mutation and have received 1 or more prior systemic therapy. The approval marks the first targeted therapy for KRAS-mutant tumors, which account for about 25% of mutations in NSCLC.

“KRAS mutations have long been considered resistant to drug therapy, representing a true unmet need for patients with certain types of cancer,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, 

The approval is based on findings from a clinical trial including 124 patients with locally advanced or metastatic KRAS G12C-mutant NSCLC whose disease progressed after treatment with a checkpoint inhibitor and/or platinum-based chemotherapy. Patients on sotorasib had a 36% objective response rate, and 58% of them had a duration of response that lasted 6 months or longer.

The FDA approved a 960 mg dose of the drug, and since it was granted an accelerated approval, the agency will conduct a post-marketing trial to determine if a lower dose has a similar clinical effect.

Common adverse events seen in patients taking sotorasib include musculoskeletal pain, nausea, fatigue, liver damage, and cough.

If a patient develops symptoms of interstitial lung disease, sotorasib should be withheld. If interstitial lung disease is confirmed, the drug should be stopped permanently. Additionally, if a patient develops liver damage, sotorasib should be withheld, dose-reduced, or permanently discontinued.

Patients should not take acid-reducing agents, drugs that induce or are substrates for certain liver enzymes, and drugs that are substrates of the P-glycoprotein while they are taking sotorasib.

“Today’s approval represents a significant step towards a future where more patients will have a personalized treatment approach,” Pazdur said

FDA. FDA Approves First Targeted Therapy for Lung Cancer Mutation Previously Considered Resistant to Drug Therapy. May 28, 2021. 

https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug#:~:text=Today%2C%20the%20U.S.%20Food%20and,least%20one%20prior%20systemic%20therapy

Sotorasib is the first targeted therapy approved for KRAS-mutant non-small cell lung cancer. 

FDA Approves Sotorasib for KRAS G12-Mutant NSCLC 

Patients with oncogene-driven non–small cell lung cancer (NSCLC) stand to benefit from the availability of targeted therapy in the clinic, but also in clinical trials, explained Andrea Saltos, MD, making broad molecular testing all the more essential to lung cancer care.

“These are very effective new drugs that were not available a couple of years ago for mutations that may not have been considered standard to test for a couple of years ago. [The availability of these drugs] highlights the importance of broad genomic profiling for every patient with advanced NSCLC,” said Saltos. “It’s always important to know the full genetic makeup of your patient’s cancer, because there really are a lot of new targeted treatments that are being worked on beyond [those for mutations in], 

, and it’s really exciting to see that these drugs are effective in the populations that they’re targeted for.”

® during an Institutional Perspectives in Cancer webinar on lung cancer, Saltos, a medical oncologist and Clinical Research Medical Director in the Department of Thoracic Oncology at Moffitt Cancer Center, provided perspective on the use of targeted therapy across 

®: With regard to the ADAURA trial, is it necessary to wait to see an overall survival (OS) benefit with adjuvant osimertinib (Tagrisso) before you start recommending it to your patients with early-stage

: It’s a key first step to wait for the long-term data, but it’s always going to come down to a patient and physician discussion. As far as the risks and benefits go, it’s very true that OS is not necessarily always found to be significant in a study where [disease]-free survival [DFS] was significant. There are examples with other EGFR-targeted therapies, such as erlotinib [Tarceva], where that was true.

On the other hand, the hazard ratio [for DFS] is very striking. There’s also something to be said of having a markedly improved DFS. Some patients who progress may have brain metastases or very symptomatic events, so sometimes if the therapy can forestall progression, it may have some merits on its own in that context, especially if the therapy is tolerable.

That’s where the tolerability of osimertinib really comes into play. Certainly, there are patients who have a lot of adverse effects [AEs] with osimertinib, but there are some who don’t, and individualization of a plan and careful monitoring are going to be a key part of that anyway.

In a bigger context, when we’re designing these adjuvant therapy clinical trials, we know there’s a tradeoff between having a more readily available outcome for quick readout like DFS vs the gold standard of OS.

What research is being done to build off of the benefit achieved with osimertinib in the advanced

The big ones are the combination of osimertinib and chemotherapy and the combination of osimertinib with anti-VEGF therapy, both of which have some have some pretty good clinical backgrounds to support the hypothesis that those combinations might be of benefit to patients.

The FLAURA 2 study is looking at randomization of osimertinib with or without platinum-based chemotherapy in the first-line setting. Hopefully that trial will answer the question about the chemotherapy combination. As far as the combination in the RELAY trial, which was conducted with erlotinib plus the VEGF inhibitor ramucirumab [Cyramza], this was positive and led to the FDA approval of the combination. Where that exactly fits into first-line therapy compared with osimertinib is not completely clear.

We’re also running a clinical trial at Moffitt Cancer Center looking at combining ramucirumab with osimertinib, taking the next logical step. Hopefully, we’ll have information on whether those [combinations] work [soon].

Poziotinib showed encouraging data in patients with

-exon 20 mutant NSCLC in the ZENITH20 trial. What are your thoughts on the doses that are being tested?

The tolerability of EGFR TKIs has been kind of a concern, especially in the early days with some of the earlier agents that had more wild-type EGFR inhibition. Some of those same toxicities are emerging with drugs like poziotinib. A lot of clinical experience with these agents and knowing what supportive care to institute and when can maximize the ability to tolerate the drug for many patients. Early institution of things like topical steroids, topical antibiotics, or oral antibiotics for dermatologic toxicities [can help]. I even often institute things like oral non-absorbable steroids, such as budesonide, for patients who have severe diarrhea. There are a lot of different tricks that can help.

 exon 20 mutations, historically, have been very difficult to target, but there are a few drugs [in development]. There’s also amivantamab, which is a bispecific antibody targeting 

fusions, how do the data seen with pralsetinib (Gavreto) and selpercatinib (Retevmo) stack up against the data with next-generation EGFR and ALK inhibitors?

 fusions are proving to be like a true driver mutation that is highly targetable, much in the same way of 

. The clinical benefit rates and response rates to both of these drugs, from the LIBRETTO[-001] and ARROW studies, are phenomenal. Patients who had no prior therapy on the selpercatinib trial had an 85% response rate, and only 3% of patients had confirmed progression of disease on the drug. That’s pretty much in line with what we see with the ALK and EGFR next-generation TKIs. It’s a very similar story with pralsetinib. The treatment-naïve patients had about a 75% response rate, but these are small trials.

It’s difficult to do cross-trial comparison, but clearly, most of these drugs are highly effective and fairly well tolerated. The incidence of grade 3 toxicity with both of these drugs is very acceptable. With both drugs, a majority of patients with central nervous system (CNS) metastases had a significant response, which means that patients with asymptomatic brain metastases, who have historically been treated with whole brain radiation, can maybe be spared that [approach] up front, which can be very meaningful for quality of life.

amplification, how have capmatinib (Tabrecta) and tepotinib (Tepmetko) affected the paradigm? Where do you see research headed?

 amplification is its own entity in lung cancer, and sometimes it goes hand in hand with exon 14 skipping, but clearly the patients who are more sensitive to these drugs are the ones who have the exon 14 skipping mutations.

The response rates are not quite as high as what we see with the EGFR, ALK, and RET inhibitors, but still a majority of patients have a response to both of these drugs in the frontline setting, somewhere in the 50% to 60% range. Both agents are quite well tolerated and also have good CNS activity.

We know how to target patients who have these high-level 

 amplifications. Both of these drugs do show activity in that amplification setting. There certainly are some patients who have 

 amplification, independent of any driver mutations, but there are also some patients with EGFR-mutant lung cancer who progress on osimertinib. It’s a very common scenario where they become resistant to osimertinib through 

 amplification. Many clinical trials are looking at these drugs in combination with EGFR inhibitors for those patients, as well as those who have 

The second area of important research will be novel drugs to target 

 and what the resistance mechanisms might end up being for patients who progress on these drugs. Some patients may progress through resistance mutations within the 

 gene, but a lot of patients may progress through alternate pathways, which is what we see with the other driver mutations in NSCLC. Being able to characterize and develop more targeted strategies beyond the first line will be important, but for now, these 2 new drug approvals represent a nice milestone for those patients.

This article was originally published on OncLive as, "

Targeted Therapies Continue to Make Strides in Oncogene-Driven NSCLC

Molecular testing is more essential than ever, thanks to the targeted therapy options for non-small cell lung cancer.

Targeted Therapies Move Forward in Oncogene-Driven Lung Cancer

The FDA approved amivantamab-vmjw (Rybrevant) for the treatment of adults with non-small cell lung cancer (NSCLC) whose tumors have EGFR exon 20 insertion mutations. This is the first targeted therapy approved for this subset of lung cancers.

The agency also approved a companion diagnostic — Guardant360 CDx.

“Advances in precision oncology continue to facilitate drug development, allowing diseases like lung cancer to be subset into biomarker-defined populations appropriate for targeted therapies,” said Julia Beaver, MD, chief of medical oncology in the FDA’s Oncology Center of Excellence and acting deputy director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in a statement.

The approval was based on findings from a clinical trial that included 81 patients with NSCLC with EGFR exon 20 insertion mutations whose disease progressed on or after receiving platinum-based chemotherapy. The overall response rate in patients who received amivantamab-vmjw was 40%, and average duration of response was 11.1 months. Sixty-three percent of patients had a response that lasted 6 months or longer.

Common adverse events of the targeted agent include: rash, skin infections around the finger and toenails, infusion-related reactions, muscle and joint pain, nausea, fatigue, shortness of breath, swelling in the lower legs or hand or face, mouth sores, constipation, cough, vomiting, and changes in some blood tests.

If patients start to show symptoms of interstitial lung disease, treatment with amivantamab-vmjw should be stopped; if interstitial lung disease is confirmed, treatment with the drug should be discontinued permanently.

Nurses should also talk to patients about sun exposure, which should be limited for 2 months after treatment with amivantamab-vmjw, as well as the possibility of vision problems occurring. Before prescribing the drug, clinicians should be sure that women are not pregnant.

“With today’s approval, for the first time, patients with non-small cell lung cancer with EGFR exon 20 insertion mutations will have a targeted treatment option,” Beaver said.

FDA. FDA Approves First Targeted Therapy for Subset of Non-Small Cell Lung Cancer. May 21, 2021. https://content.govdelivery.com/accounts/USFDA/bulletins/2da97ee

This is the first targeted therapy regimen approved for this patient population. 

FDA Approves Amivantamab-vmjw for EGFR Exon 20-Mutant NSCLC

A biologics license application (BLA) for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer (NSCLC) has been accepted for FDA review, according to an announcement from Innovent Biologics, Inc.1

The application, which was submitted to the regulatory agency in March 2021, was based on data from the phase 3 ORIENT-11 trial (NCT03607539), which demonstrated that the regimen significantly improved progression-free survival vs chemotherapy alone in the frontline treatment of patients with locally advanced or metastatic nonsquamous NSCLC.2

At a median follow-up of 8.9 months, the median PFS with sintilimab was 8.9 months (95% CI, 7.1-11.3) per an independent radiologic review committee (IRRC) vs 5.0 months (95% CI, 4.8-6.2) with chemotherapy alone; this translated to an estimated 52% reduction in the risk of disease progression or death (HR, 0.482; 95% CI, 0.362-0.643; 

Under the Prescription Drug User Fee Act, the FDA is slated to make a decision on the BLA in March 2022. The regulatory agency did not identify any potential review issues in its acceptance letter, and it will be holding an Advisory Committee meeting to further discuss the application.

“The acceptance of this application – the first for sintilimab in the United States and outside of China – is an important milestone in Innovent’s global commercialization strategy and in our collaboration with Lilly,” Yongjun Liu, MD, PhD, president of Innovent, stated in a press release. “We look forward to working closely with the FDA to potentially bring this sintilimab/pemetrexed/platinum chemotherapy combination as a treatment option in the United States, following the regimen’s regulatory approval in China earlier this year.”

phase 3 ORIENT-11 study examined the safety and efficacy of sintilimab in combination with pemetrexed and platinum-based chemotherapy

 as a frontline treatment in a total of 397 patients with nonsquamous NSCLC.

To be eligible for enrollment, patients had to have stage IIIB/C or IV disease and not be candidates for surgery or local therapy. They also needed to have an ECOG performance status of 0 or 1 and have a provision of a tumor sample for PD-L1 assessment. Stratification factors included gender, type of platinum therapy (cisplatin vs carboplatin) and PD-L1 expression level (tumor proportion score [TPS] less than 1% vs 1% or higher).

In the trial, study participants were randomized 2:1 to receive either sintilimab at 200 mg (n = 266) or placebo (n = 131) in combination with pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin area under the curve (AUC) 5, every 3 weeks for 4 cycles.

Patients in the investigative arm were given sintilimab at 200 mg every 3 weeks for up to 2 years plus pemetrexed at 500 mg/m2 every 3 weeks, while those in the control arm were given placebo every 3 weeks for up to 24 months plus pemetrexed at the 500 mg/m2 every-3-week dosing schedule. Following this time point, patients on the control arm were allowed to cross over to receive sintilimab at 200 mg every 3 weeks for up to 24 months.

The primary objective of the trial was PFS per IRRC, while secondary end points comprised overall survival (OS), response rate, duration of response (DOR), time to response, and safety. Efficacy was evaluated in the intent-to-treat population and safety data included all patients who were given at least 1 dose of the study treatment.

The median age of study participants was 61 years (range, 32.5-75.0) and the majority (76.2%) were male. Moreover, 72.7% had an ECOG performance status of 1, 90.3% had stave IV disease, and about 15% had brain metastases. More patients received carboplatin (74.1%) vs cisplatin, and 65.4% were either current or former smokers. More than half, or 67.2%, of patients had a PD-L1 TPS of 1% or higher.

At a median follow-up of 8.0 months, a total of 198 PFS events were reported. Moreover, 31.3% (n = 35) of patients who were on the control arm crossed over to receive sintilimab. Additional data indicated that the PFS benefit achieved with sintilimab was noted across key subgroups analyzed, including age, performance status, platinum-based therapy, smoking status, and presence of brain metastases.

Notably, PFS benefit was found to correlate with level of PD-L1 expression. The median PFS in patients with a TPS of less than 1% was 7.3 months (95% CI, 6.2–not reached [NR]) and 5.1 months (95% CI, 4.6-7.8) with sintilimab and chemotherapy alone, respectively (HR, 0.664; 95% CI, 0.406-1.086). In the subgroup of patients with a TPS of 1% to 49%, the median PFS in the sintilimab and chemotherapy-alone arms was 7.1 months (95% CI, 6.2-9.2) and 4.8 months (95% CI, 2.5-8.0), respectively (HR, 0.503; 95% CI, 6.2-9.2). In the subset of patients with the highest PD-L1 TPS of 50% or greater, the median PFS had not yet been reached (95% CI, 9.2–NR) with sintilimab vs 5.0 months (95% CI, 4.3-6.8) with chemotherapy alone (HR, 0.310; 95% CI, 0.197-0.489).

Moreover, sintilimab resulted in an approximate 40% reduction in the risk of death compared with chemotherapy alone, and this was determined to be nominally significant (HR, 0.609; 95% CI, 0.400-0.926; 

 = .01921). The OS rates at 6 months in the investigative and control arms were 89.6% and 80.4%, respectively.

The sintilimab regimen elicited an objective response rate (ORR) of 51.9% vs 29.8% with chemotherapy alone. The disease control rates achieved in the investigative and control arms were 86.8% and 75.6%, respectively. The median OR had not yet been reached (95% CI, 8.0-NR) with sintilimab vs 5.5 months (95% CI, 4.1-10.9) with chemotherapy alone. Time to response also proved to be shorter in the sintilimab arm vs the chemotherapy-alone arm, at 1.5 months and 2.6 months, respectively.

Rates of adverse effects (AEs) were comparable between the 2 treatment arms, with grade 3 to 5 toxicities experienced by 61.7% and 58.5% of those on the investigative and control arms, respectively. Serious AEs were reported by 28.2% of those given the sintilimab regimen vs 29.8% of those who received chemotherapy alone. Six patients on the investigative arm experienced AEs that resulted in death vs 9 patients on the control arm.

Toxicities that led to discontinuation of treatment were reported in 6.0% and 8.4% of those on the investigative and control arms, respectively. Moreover, slightly more immune-related AEs were experienced by those who received the sintilimab regimen vs chemotherapy alone, at 43.2% and 36.6%, respectively; these effects were grade 3 to 5 in 5.6% and 6.1% of patients, respectively.

The most frequently experienced toxicities included anemia, reduced neutrophil count, reduced white blood cell count, reduced platelet count, increased aspartate aminotransferase, increased alanine aminotransferase, nausea, reduced appetite, asthenia, vomiting, constipation, and pyrexia.

Currently, 2 indications for sintilimab have been approved in China, while 3 regulatory submissions remain under review.

US FDA accepts regulatory submission for sintilimab in combination with pemetrexed and platinum chemotherapy for the first-line treatment of people with nonsquamous non-small cell lung cancer. News release. Innovent Biologics, Inc. May 18, 2021. Accessed May 18, 2021. 

Zhang Li, Yang Y, Wang Z, et al. ORIENT-11: sintilimab + pemetrexed + platinum as first-line therapy for locally advanced or metastatic non-squamous NSCLC. 

. 2020;15(10). doi:10.1016/j.jtho.2020.08.002

This article was originally posted on OncLive as, "

Sintilimab/Pemetrexed Regimen in Frontline Nonsquamous NSCLC Accepted for FDA Review

A biologics license application for sintilimab injection plus pemetrexed and platinum-based chemotherapy for the frontline treatment of patients with nonsquamous non–small cell lung cancer has been accepted for FDA review.

FDA Grants Sintilimab/Pemetrexed Review for Frontline Nonsquamous NSCLC

The phase 3 IMpower133 trial (NCT02763579), which examined atezolizumab (Tecentriq) plus platinum-based chemotherapy and etoposide in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) helped lay the foundation for the exploration of other novel immunotherapy combinations, according to Ravi Salgia, MD, PhD.

In the phase 3 CASPIAN trial (NCT03043872), investigators examined the use of first-line durvalumab (Imfinzi) plus the same chemotherapy backbone in patients with ES-SCLC.

 The combination yielded a durable improvement in overall survival, but the addition of tremelimumab (formerly ticilimumab; CP-675,206) did not appear to elicit any further statistically significant improvement.

Now, a phase 1 study (NCT04560972) will further build off of the IMpower133 regimen by examining the safety of the novel agent LB-100 in combination with carboplatin, etoposide, and atezolizumab in patients with untreated ES-SCLC.

Further exploration of immunotherapy regimens will be necessary, Salgia said.

“It is important for us to realize that the tumor mutational burden for SCLC is very high,” Salgia said. “We need to be able to [consider whether] immunotherapy [may] work even better [when used] in combination with chemotherapy or other therapeutic strategies.”

® during an Institutional Perspective in Cancer webinar on lung cancer, Salgia, a medical oncologist and Arthur & Rosalie Kaplan Chair in Medical Oncology at City of Hope, discussed pivotal trials that have shaken up the small cell lung cancer treatment paradigm, novel immunotherapy regimens under investigation, and next steps for research.

®: What is your approach for selecting treatment for patients with limited-stage SCLC [LS-SCLC] vs ES-SCLC?

: SCLC is a difficult disease to treat. We have come a long way in terms of thinking about [the disease] and we know that there are 2 varieties of [the disease] that we consider in terms of the staging: LS-SCLC and ES-SCLC. For [patients with] LS-SCLC, we still [administer] chemotherapy and radiation therapy [with consideration] for prophylactic cranial radiation. For those with [ES-SCLC], we are changing the paradigm. Currently, we are using chemotherapy with immunotherapy. After the first line of therapy fails, [we have a] second-line option, which is lurbinectedin [Zepzelca]. Of course, we really try to emphasize [enrollment to] clinical trials, as well.

Starting in the frontline setting, how are you applying the findings from the pivotal phase 3 IMpower133 trial to clinical practice?

Results have [demonstrated] that platinum-based chemotherapy with etoposide in combination with atezolizumab does [yield] better survival. That is revolutionary for us and we are using that [agent] in our clinical practice. It is important to realize that the severity of the adverse effects were not worse than [what was reported in] the chemotherapy arm.

An ongoing study that is open at City of Hope is building off of the success seen with the IMpower133 regimen. Could you highlight this research and its potential implications?

For ES-SCLC, we are using carboplatin and etoposide with atezolizumab, as an example. However, we know patients can recur and relapse, so we wanted to make that better. In our laboratory, we had discovered that the PP2A pathway in SCLC is very important. We can inhibit that pathway with a drug called LB-100. We are using a backbone of the IMpower133 regimen—carboplatin and etoposide with atezolizumab—and combining it with LB-100. We are going to be publishing [these data] relatively soon. It is important to realize it is a phase 1 study, but we are quite hopeful that this [research] will [result in] revolutionary breakthroughs.

Does LB-100 have a safety profile that makes it amenable for use in a 4-drug combination?

The initial LB-100 study [that examined the] drug by itself was done here, at City of Hope, and that [research] was published by Vincent Chung, MD, and colleagues. The safety profile [of LB-100] was really good. [However], we do not know yet [what this will look like] in combination [with other agents] because this is a phase 1 study. Once we start the study, we are very much hoping that the toxicity is no different than [what we saw in] the IMpower133 study.

What has been learned from the phase 3 CASPIAN trial? How do you select which patients should receive this regimen vs the IMpower133 regimen in practice?

The CASPIAN study also gives us another [option] for our patients. Instead of utilizing atezolizumab, we utilize durvalumab. The study looked at durvalumab [plus platinum/etoposide and] with tremelimumab [vs platinum/etoposide alone]. However, the issue became that the [the addition of tremelimumab] did not [provide more benefit] than durvalumab [with platinum/etoposide]. We are using a platinum-based backbone, with etoposide and durvalumab. The difference is that in the context of the maintenance study, durvalumab was given once a month [while] atezolizumab was given once every 3 weeks. At the same time, we use it in our practice either way. I do believe [the decision] is really dependent on [factors like] tolerability. Both of the regimens are very reasonable.

In February 2021, the FDA approved trilaciclib (Cosela) to reduce chemotherapy-induced bone marrow suppression in adult patients with ES-SCLC who were receiving certain chemotherapy agents. How did this decision impact the paradigm?

Growth factor support has been always important for SCLC, especially [because of] the cytotoxic therapies that we give [to our patients]. We have used granulocyte colony-stimulating factor, and now, we have another option [in the form of] this new CDK4/6 inhibitor.

It was nice to see that [that the agent] did not affect the survival [of the patients who received it] in a negative way. We are very happy with that and [we will] be utilizing that [option] in our clinical practice. The more choices we have, the better it is for patients.

Shifting to the second-line setting, in June 2020, lurbinectedin was also approved by the FDA for use in patients with metastatic SCLC following progression on a platinum-based chemotherapy. How does the agent compare with standard topotecan?

We know that in the first-line setting of SCLC, many of our patients relapse and/or recur. [Therefore], it is important to have [options in the] second-line setting. We have always said that clinical trials are incredibly important and lurbinectedin provides a potential [option] beyond topotecan. As we know, topotecan has been approved as a second-line therapy; however, lurbinectedin seems to be better tolerated and is showing [good] efficacy. [Moreover], topotecan is given on days 1 through 5, whereas [lurbinectedin] is really much easier to give. Having another choice makes a huge difference in practice.

How would you approach choosing between the 2 options?

Lurbinectedin is probably going to become the standard of choice; it has been in our practice. It is because of convenience—instead of days 1 through 5, it is [administered every] 21 days—as well as tolerability. I do think it has a huge role for us, and we will continue to utilize it. It [will be] important for us to explore this [agent] in the first-line setting [and learn] how we can overcome resistance in the second line.

The indication for pembrolizumab (Keytruda) in patients with metastatic SCLC who experienced disease progression on or after platinum-based chemotherapy and at least 1 prior line of treatment was recently withdrawn by the FDA. How do you foresee this impacting the use of the agent in this disease?

We has been excited about the approval of pembrolizumab, but it has since been withdrawn by the FDA, and very reasonably so— the end points [of the confirmatory trial] have not been met. If it does not help our patients, it is not worth it. [It begs the question], is pembrolizumab important? It could be very important in terms of early-stage disease, in the first-line setting, [and] in combination in other settings. We do not [currently] know and, clearly, we need to do more clinical trials.

Bispecific antibodies are going to be important, as well as bispecific T-cell engagers. Potentially even CAR T-cell therapies will be significant. All of those [options] will lead to significant advances in SCLC. Can one use immunotherapeutics with small molecule inhibitors? Can one [leverage] the genomics or alterations in SCLC [to improve outcomes]? That is to be determined, and that is where we need to [focus our] attention in [terms of] clinical trials.

Lung cancer is still a very tough disease to treat. We have some therapeutics that have revolutionized our way of thinking, but it is not good enough; we need to do better. We need to continue to [conduct] clinical trials [and encourage enrollment] so we can make a difference. It is important to do research in, and fund research [for], SCLC as we have done for non–small cell lung cancer, [where] many of the codes are being broken. We need to break the code even better for SCLC.

Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. 

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

LB-100, carboplatin, etoposide, and atezolizumab for the treatment of untreated extensive-stage small cell lung cancer. ClinicalTrials.gov. Updated March 15, 2021. Accessed April 29, 2021. https://clinicaltrials.gov/ct2/show/NCT04560972

Future of SCLC Treatment Lies in Innovative Immunotherapy Combos

New immunotherapy combinations are being explored in the small cell lung cancer space.

Next Up in SCLC: Immunotherapy Combinations

The EGFR TKI osimertinib (Tagrisso) has shaken up the treatment paradigm of advanced non–small cell lung cancer (NSCLC), and now the agent is under exploration in earlier-stage settings in an effort to further prevent recurrence and prolong survival, according to Edward S. Kim, MD, who added that the key to reaching patients earlier is to test for biomarkers earlier.

“In the early-stage setting, it is devastating when [patients experience] recurrence. Hopefully, [with osimertinib,] we can do something about it and treat them. Too many times, because of the nihilism that has built up over the years, we are just waiting for the recurrence to occur,” Kim said. “I hope we get to a point where recurrence is less common, and we are treating more patients with earlier-stage disease. Our paradigm has changed. We will continue to study other drugs and targets in these settings, as well.”

 during an Institutional Perspectives in Cancer webinar on lung cancer, Kim, physician-in-chief of City of Hope Orange County and vice physician-in-chief of City of Hope National Medical Center, highlighted the impact of osimertinib in the treatment of patients with 

-mutant NSCLC, next steps with the agent, and the importance of early genetic testing to provide personalized care.

: How has the emergence of osimertinib impacted the management of patients with

 has really been one of the pioneering biomarker pathways in lung cancer. Osimertinib is the preferred drug because it has very strong efficacy and a [favorable] safety profile. The newer-generation drugs penetrate the brain and the central nervous system much more predictably than older-generation agents; this has changed the paradigm of how we approach patients who have initially been diagnosed with brain metastases. If they are stable, then we do not jump right to radiation. Instead, we treat them [with these drugs] if they have a mutation and watch them in case we need the radiation. [However,] it is great to see even our radiation colleagues embrace these data.

What are some areas of focus in the realm of

Throughout our investigations, we have also found other mutations in 

; some are sensitizing, some are resistant, and some we are not sure about yet. We are developing drugs [to target] these specific mutations, which is exciting. That is what we dream [to do with] cancer [treatment]: identify a marker in the tumor that is unique to an individual and finding a [targeted] therapy that [that is efficacious and] will not cause many adverse effects [AEs].

 moving into the earlier-stage setting; this [development,] indeed, follows what we have seen in the breast cancer paradigm. You have drugs that [are initially used in the] metastatic [setting], like tamoxifen, that are now moving into the earlier-stage setting. [Patients] can take [these agents] for several years and [they are effective]. We are seeing that now with osimertinib, [which is under examination] in the early-stage setting, in patients who have stage IB through IIIA [disease].

 mutations. If you find one, then after you finish the surgery and/or give chemotherapy, [you can] then treat the patient with osimertinib for 3 years; this has been shown to greatly improve disease-free survival [DFS]. We are still waiting for overall survival [OS] data [with this approach]. However, the trial [that examined this strategy] was unblinded early because of its effectiveness, and patients are still being treated.

[Treatment has] really cascaded in the direction [where] we want to reach patients earlier—especially those who have curable disease or curative intent disease. [We want to] try to keep disease away as long as possible. I am really happy that biomarkers have made it into the clinic. I urge everyone out there to test [for] biomarkers. Ensure that you are testing for these before you initiate any treatment. It does not matter if you are using smaller panels or larger panels; just ensure that you are getting that information and utilizing it to inform decisions.

Looking more closely at the use of osimertinib in the adjuvant setting, how did the agent perform in the phase 3 ADAURA trial (NCT02511106)? What does this information mean for practice?

The primary end point of ADAURA was DFS, specifically in [patients with] stage II and IIIA [disease], although the trial did enroll [those with] IB through IIIA [disease]. DFS was the first reported outcome because you get those outcomes earlier. Data were revealed early because of the effectiveness [of the agent]; this [runs] parallel to what happened with tamoxifen.

The hazard ratios for DFS were unprecedented. We had not seen that magnitude [of benefit] in lung cancer [previously], although we should; this is a curative intent population. We are asking patients to take a drug for up to 3 years and need to show that there is some benefit. Some would say we need to wait for OS and, of course, our due diligence has to be to wait for [those data].

However, you have to ask yourself, if this was a friend or family member, and they had gone through lung cancer resection, would you prescribe them osimertinib if they have an 

 mutation? My answer is a very clear yes. I do believe that DFS is an important end point, and it is one that we use quite often in earlier stages [of disease]. If you consider any patient who has had early-stage breast cancer and they get a recurrence, it is just devastating.

How are the AEs associated with osimertinib being managed? Are there any challenges to using this agent in the clinic?

What has been really helpful is that osimertinib was first approved [for use] in the advanced metastatic setting. Clinicians gathered quite a bit of experience with not only this drug, but also with drugs that were similar in class. We all remember using gefitinib [Iressa], erlotinib [Tarceva], afatinib [Gilotrif], and now, we have osimertinib. There is a comfort level [with these agents]. Again, the parallels [to what has been seen in the] breast cancer [paradigm] are there. Tamoxifen was first used in the metastatic setting and [people felt comfortable] dealing with those AEs.

On the whole, osimertinib has a very [safe] toxicity profile, when considering other classes of drugs [that are used] in the metastatic setting. Upon conducting the study and reporting out, we really did not see any new safety [signals]. As we consider primary end points and focus on the [patients with] stage II and IIIA disease, even in the total analysis of [those with] IB through IIIA [disease], we saw a benefit across the board. [Osimertinib] is [an agent] that people are comfortable with and we [have] quite a bit of experience [with its use].

Research Efforts Focus on Reducing Recurrence in Early-Stage EGFR-Mutant NSCLC

Edward S. Kim, MD, highlights the impact of osimertinib in the treatment of patients with EGFR-mutant non–small cell lung cancer, next steps with the agent, and the importance of early genetic testing to provide personalized care.

Reduce Recurrence in Early-Stage NSCLC

The optimal treatment of patients with early-stage and locally advanced non–small cell lung cancer (NSCLC) in 2021 consists of multidisciplinary management, 

 gene testing, and consolidation treatment with durvalumab (Imfinzi) in addition to clear pathways that enable the successful delivery of such care to all patients, explained Jacob Sands, MD.

“We’ve discussed all these best ways to treat patients based upon the data that we have, and one element of this in the real world that then becomes a challenge is the logistics,” said Sands. “One of the things within our health care system and within our hospital systems to start really recognizing more and doing a better job of is how to help make [high level care] feasible for everybody.”

®, Sands, a physician at Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed current approaches to the treatment of patients with early-stage and locally advanced NSCLC.

®: How would you define the multidisciplinary treatment of patients with early-stage NSCLC?

: In early-stage disease, treatment can involve a few different things. Often patients end up with surgically resectable disease, so there’s surgery, and then there’s the postoperative pathology that we look at, which really defines what we do after surgery. That pathology gives us a lot more information. If the size [of the tumor] is greater than 4 cm, particularly if there are lymph nodes involved, we are talking about adjuvant chemotherapy in the case of NSCLC. In the case of small cell lung cancer, we really give adjuvant chemotherapy to anybody.

What is your optimal approach to molecular testing?

In early-stage disease, when we’re talking about something that has been resected and there’s no evidence of disease, those individuals often end up getting adjuvant chemotherapy. If [the tumor is] greater than 4 cm, if there’s any lymph node involvement, that becomes a stage in which adjuvant chemotherapy is important.

As far as genomic testing, we have the recent ADAURA publication that showed a substantial improvement in [disease-]free survival. The overall survival data are going to [require] more [time to mature], but [the results] led to [the] approval [of osimertinib in the adjuvant setting]. Now [the results of] 

 testing, in particular, on the pathology of these patients [is important]. 

As far as doing genomic testing for other potential targets, the data are really compelling [in the metastatic setting] and given how osimertinib [Tagrisso] works for patients with 

 mutations, what about alectinib [Alecensa] for patients with 

 fusions, or some of these other really effective targeted therapies that we use as a standard of care in stage IV disease? Should we be using those agents in earlier-stage disease as well? Those [questions] have led to a number of other trials that are ongoing and now getting started.

Would you say that, if not for standard practice, but for clinical trials, that next-generation sequencing should be ordered rather than a single-gene panel for

Right now, we really don’t have a number of different approved therapies. In the earlier-stage setting, we just have osimertinib right now as an approved adjuvant therapy. It is really important for those patients to also be offered chemotherapy, assuming that they qualify for it. In the ADAURA publication, I was a little surprised by the number of people that actually didn’t get chemotherapy, so it’s important to highlight that these patients should get offered adjuvant chemotherapy, and then, if appropriate, osimertinib.

We don’t really have other approved therapies, so testing for 

 alone right now as far as what you’re clinically going to do is meaningful. Other agents we don’t really have a defined role for, but consideration of enrollment to these various other trials, I would really encourage. In that sense, getting genomic testing to drive enrollment to some of these other studies is really compelling.

What is the role of postoperative radiation in treatment?

For patients who get surgical resection and have N2 mediastinal node involvement, there is really kind of a question now about radiation. There was a recent trial that was negative for inclusion of postoperative radiation. That being said, there are still patients where I would expect postoperative radiation to provide some potential benefits. This is really a population that requires interaction with radiation oncologists and discussion about each individual case, and whether you think that someone is going to really benefit from radiation in that setting.

What are your thoughts on immunotherapy entering the early-stage treatment paradigm?

We have seen great results with immunotherapy in metastatic disease. We have seen also really impressive results after chemoradiation. Now the question is: In resectable disease, do these checkpoint inhibitors have a potential role to play? There are multiple studies that are being done or have enrolled [to that end]. These are studies that enroll after chemotherapy, but a study that is currently open within the ALCHEMIST portfolio is a study called ACCIO. This is a study I’m running, and I would love for people to enroll and to be aware of this. It’s a 3-arm study [that is enrolling patients] after surgical resection, an R0 resection, who are 

 negative, wild-type. Patients need PD-L1 testing for stratification, but all-comers with any level of PD-L1 can enroll, and all [patients with] NSCLC can enroll, [be it] squamous [or] nonsquamous [histology].

The [treatment arms will consist of] standard chemotherapy, followed by observation standard of care vs chemotherapy, followed by pembrolizumab [Keytruda] in a sequential arm, and then the third arm consists of concurrent chemotherapy plus pembrolizumab. Both the sequential and the concurrent arm [will administer] the same duration [of pembrolizumab], which is 1 year, just [at] different starting [points]. This trial is currently open throughout the country, and we certainly welcome enrollment.

Shifting to the stage III setting, what are some of the best practices for ensuring that patients receive durvalumab after concurrent chemoradiation?

An expert gives an overview of recent advancements in the lung cancer space.

Lung Cancer