 G12C–mutant non–small cell lung cancer experienced an overall survival (OS) rate of 32.5% (95% CI, 25.0%-40.2%) following treatment with sotorasib (Lumakras), according to longer follow-up data from the phase 1/2 CodeBreaK 100 trial (NCT03600883) that were presented during the 2022 AACR Annual Meeting.

Additional results showed that the overall response rate (ORR) achieved with sotorasib was 40.7% (95% CI, 33.3%-48.4%) and the disease control rate (DCR) was 83.7% (95% CI, 77.3%-88.9%). Moreover, the median duration of response (DOR) was 12.3 months (95% CI, 7.1-15.0), and 50.6% (95% CI, 37.4%-62.4%) of responders were in response for at least 12 months.

The median progression-free survival (PFS) was 6.3 months (95% CI, 5.3-8.2) and the median OS was 12.5 months (95% CI, 10.0-17.8). At 1-year, the OS rate was 50.8% (95% CI, 42.8%-58.2%).

“In this longest follow-up of patients on any KRAS G12C inhibitor, sotorasib demonstrated very meaningful and durable efficacy, as well as a safety profile [that was] consistent with what had been [previously] reported,” Grace K. Dy, MD, chief of thoracic oncology and professor of oncology at Roswell Park Comprehensive Cancer Center, said in a press conference during the meeting. “We also reported a 2-year [OS rate] of [approximately] 33% in [patients with] pretreated 

 G12C–mutated NSCLC, which compares favorably with what we would expect with historical treatment using docetaxel in this setting.”

for the treatment of patients with locally advanced or metastatic 

 G12C–mutant NSCLC who have not received prior therapy. The regulatory decision was based on earlier findings from the CodeBreaK 100 trial.

The pooled phase 1/2 CodeBreak 100 trial enrolled a total of 174 patients with locally advanced or metastatic 

 G12C–mutant solid tumors. Patients had received at least 1 prior systemic therapy or were ineligible or intolerant for treatment. Those with stable brain metastases were permitted.

In the trial, study participants received oral sotorasib at the FDA-approved dose, which was 960 mg once daily, until disease progression. Radiographic scans were done every 6 weeks up to week 48 and then once every 12 weeks thereafter.

In the phase 1 portion of the research (n = 48), the primary end point was safety and tolerability; key secondary end points were pharmacokinetics, ORR, DOR, PFS, and duration of stable disease. In the phase 2 part of the trial (n = 126), the primary outcome measure was ORR by RECIST v1.1 criteria by blinded independent central review. Key secondary end points were DOR, DCR, PFS, OS, time to response, and safety.

For the updated analysis, the data cutoff was February 22, 2022. The median follow-up time for OS was 24.9 months.

In the updated analysis, investigators analyzed data from the 174 patients who were treated with sotorasib in the combined phase 1 and 2 portions of CodeBreaK 100; these patients received the FDA-approved dose of sotorasib at 960 mg daily. Notably, 82.8% of patients had previously received both platinum-based chemotherapy and anti–PD-1/PD-L1 treatment.

Additional findings showed that the clinical activity with sotorasib was observed regardless of PD-L1 expression and was seen in those with low PD-L1 levels. “Our findings also provide rationale for studies that investigate the incorporation of sotorasib earlier in the treatment course to improve the outcomes for patients [with] NSCLC who are less likely to benefit from immunotherapy,” Dy stated in a press release.

Further analyses were conducted on both tumor and plasma samples to identify biomarker profiles linked with durable clinical benefit. These studies showed that prolonged clinical benefit was observed regardless of tumor mutation burden, PD-L1 expression, and 

In patients with a PD-L1 expression of less than 1% (n = 31), the PFS benefit with sotorasib lasted at least 12 months in 51.6% of patients; in those whose PD-L1 expression was between 1% and 49% (n = 21), this rate was 28.6%. In patients who had PD-L1 expression of at least 50% (n = 4), 25.0% of patients had a PFS benefit of at least 12 months.

 wild-type status (n = 13), the long-term PFS benefit was at least 12 months in 46.2%; this was true for 45.5% of those with 

 wild-type disease (n = 33). In those with 

-mutant disease (n = 12), a PFS benefit of at least 12 months was experienced by 16.7% of patients; this was also true for 14.3% of those with 

“Longer-term follow-up data are important to better define the safety and efficacy of sotorasib, since it is the first-in-class KRAS G12C inhibitor therapy to be approved for this patient population,” Dy added in the press release. “For this particular analysis, we also sought to determine whether there are potential biomarkers that can identify patients who will derive long-term benefit from sotorasib treatment.”

No new safety concerns were observed with long-term treatment with sotorasib. Grade 3/4 treatment-related adverse effects (TRAEs) occurred in 21% of patients, and 1 patient had a new onset grade 3 TRAE of hemolytic anemia after 1 year. Notably, no TRAE-related deaths occurred, nor did any TRAEs lead to discontinuation after 1 year of therapy.

“[Overall], most toxicities were grade 1/2 in severity; major AEs were [gastrointestinal] in nature [with] nausea, diarrhea, [liver function test] abnormalities, and 22% of patients required dose modifications or dose interruptions; about 6% required dose discontinuation,” Ly said in the presentation, adding that approximately one-quarter of patients remain on treatment after 1 year.

CodeBreaK 100 is a single-arm, non-randomized trial, which investigators noted as a limitation. The randomized, global phase 3 trial CodeBreaK 200 study (NCT04303780) is ongoing and includes a comparator arm of docetaxel in patients with 

“We eagerly await the results of the phase 3 study, which likely will be available later this year, and expect that they will confirm our findings from CodeBreaK 100,” Dy stated in the press release.

Dy GK, Govindan R, Velcheti V, et al. Long-term outcomes with sotorasib in pretreated KRASp.G12C-mutated NSCLC: 2-year analysis of CodeBreaK100. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022, New Orleans, LA. Abstract CT008.

KRAS G12C inhibitor sotorasib may offer long-term clinical benefit in patients with non-small cell lung cancer. News release. American Association for Cancer Research; April 10, 2022. Accessed April 10, 2022. 

FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA; May 28, 2021. Accessed April 10, 2022. 

Articles

Longer follow-up data from the phase 1/2 CodeBreaK 100 trial show that patients with KRAS G12C–mutant non–small cell lung cancer experienced improved prolonged overall survival and encouraging response rates with sotorasib.

2-Year Follow-Up Showcases Sotorasib Benefit in KRAS G12C+ NSCLC

 and Inflamed T-cell signature may indicate that a patient with extensive-stage small cell lung cancer (ES-SCLC) is primed to respond well to immunotherapy with durvalumab (Imfinzi) and chemotherapy, according to an exploratory analysis of the phase 3 CASPIAN study (NCT03043872) which was recently presented at the 2022 AACR Annual Meeting.

An analysis of 2 different RNA sequencing-based SCLC subtyping methods applied within the context of the CASPIAN data demonstrated that patients with these subtypes experienced the longest OS following treatment with the immunotherapy combination compared with patients expressing 

Overall, the highest median OS were observed in patients with 

 or T-cell inflamed signature expression who received durvalumab/EP. In these patients, the median OS were 17.3 months (95% CI, 12.8-NE) and 17.6 months (95% CI, 11.4-NE), respectively.

These data are consistent with previous findings, although further research is warranted to determine the relationship between these biomarkers and immunotherapy response, the study authors noted. 

“When the 2 RNA-based subtyping methods were applied to the CASPIAN data, we found that the 2 methods were consistent in differentiating neuroendocrine from non-neuroendocrine subtypes, and showed highest concordance within the non-neuroendocrine subtypes,” lead study author Yashaswi Shrestha, PhD, director of Oncology Translational Medicine and clinical biomarkers at AstraZeneca, said in a presentation of the findings. “Among the 4 subtypes, the inflamed subtype determined by Gay et al and the 

subtype [determined] by Rudin et al showed the longest overall survival in the durvalumab/[chemotherapy] arm, suggesting that [this] subgroup of patients that have an inflamed phenotype are primed to respond to immunotherapy.”

Investigators on the phase 3 CASPIAN study enrolled 805 patients with treatment-naïve ES-SCLC and a World Health Organization performance status of either 0 or 1, a life expectancy of 12 weeks or greater, and measurable disease per RECIST v1.1 criteria. Patients with asymptomatic or treated and stable brain metastases were permitted to enroll.

The enrolled patients were randomized 1:1:1 to undergo either durvalumab plus etoposide with either carboplatin or cisplatin (EP) for 4 cycles followed by single-agent durvalumab until disease progression, EP for up to 6 cycles followed by optional prophylactic cranial irradiation, or tremelimumab added to durvalumab plus EP for 4 cycles, followed by durvalumab until disease progression.

EP was administered in a dose ranging from 80 to 100 mg/m2 of etoposide along with either area under the curve 5-6 of carboplatin or 75 to 80 mg/m2 of cisplatin. Durvalumab was administered at 1500 mg and tremelimumab was administered at 75 mg.

The coprimary end points of CASPIAN were OS; progression-free survival, overall response rate, safety and tolerability, and patient reported outcomes (PROs) represented secondary end points. Biomarker analysis (tTMB; PD-L1) was an exploratory outcome measure.

Prior findings from CASPIAN revealed that durvalumab/EP significantly improved OS vs EP alone in this patient population, a benefit that was sustained for over 3 years of median follow-up. In the intent-to-treat population, the median OS was 12.9 months (95% CI, 11.3-14.7) with durvalumab/EP and 10.5 months (95% CI, 9.3-11.2) with EP alone (HR, 0.71; 95% CI, 0.60-0.86; 

These results established durvalumab/EP as the global standard of care in ES-SCLC.2 The combination is FDA approved for the first-line treatment of patients with ES-SCLC.

Notably, the association between predictive biomarkers and improved outcomes with immune checkpoint inhibitors are still not well understood for patients with SCLC. However, investigators recently identified 4 SCLC molecular subtypes with distinct therapeutic vulnerabilities using 2 different differential gene expression methods.

Investigators in the exploratory analysis therefore evaluated the concordance between the 2 methods and their link to improved OS using RNA sequencing data from the phase 3 CASPIAN study.

Formalin-fixed paraffin-embedded (FFPE) tumor samples previously collected at baseline were used to create whole-transcriptome RNA sequencing data.

Overall, the biomarker-evaluable population (BEP) consisted of 57 out of 268 patients on durvalumab/EP and 47 out of 269 patients on EP monotherapy arm.

For the BEP population, the data cutoff date was March 2021, and the median number of months follow-up was 39.4 months (range, 0.1–47.5). In the BEP population, the median OS was 11.8 months (95% CI, 8.6-14.9) with durvalumab/EP and 9.1 months (95% CI, 7.7-11.3) with EP alone (HR, 0.61; 95% CI, 0.40-0.92).

The Rudin et al. 2019 SCLC subtyping method3 found that 

 was commonly expressed in all subtypes, though at a relatively low level. Therefore, a sample was labeled as 

. Among the 4 transcription factors determined to be a subtype of the sample, 

 were classified as neuroendocrine while 

The Gay et al. 2021 SCLC subtyping method4 used a 1300 gene signature to arrange the subtypes into 4 hierarchical clusters, each of which were assigned a subtype based on the highest expressed gene of 

 The fourth cluster, which had a low expression of all 3 of the gene signatures was designated as the inflamed subtype because of its inflamed gene signature.

The T-cell inflamed signature was identified through assessment of RNA baseline tumor samples from pembrolizumab (Keytruda)-treated patients. The 18-gene T-cell inflamed gene expression signature comprised IFN-γ–responsive genes related to antigen presentation, chemokine expression, cytotoxic activity, and adaptive immune resistance.

The methods revealed high agreement in distinguishing neuroendocrine tumors from non-neuroendocrine subtypes. The highest levels of concordance were identified between non-neuroendocrine subtypes: the prevalence of Rudin 

 was 8% and the prevalence of Gay inflamed was 11%.

An OS analysis of the Rudin et al method revealed that, among patients treated with durvalumab/EP, the median OS with 

was 17.3 months. In patients treated with EP alone, the median OS with 

An analysis of the Gay et al. method showed that, among patients treated with durvalumab/EP, the median OS with 

was 17.6 months. In patients treated with EP alone, the median OS with 

Specifically, patients with high T-cell inflamed signature had numerically longer OS when receiving durvalumab/EP treatment than with EP alone. Patients in the former arm had a median top quartile OS of 15.8 months (10.4-NE), and a low median OS of 11.3 months (7.3-14.6; HR, 0.64; 95% CI, 0.31-1.32). Patients receiving EP alone had a median top quartile OS of 9.4 months (95% CI, 7.3-15.9), and a low median OS of 8.3 month (95% CI, 6.1-11.4), leading to a 13% reduction in the risk of disease progression or death (HR, 0.87; 95% CI, 0.45-1.66).

“This finding is consistent with previous observations,” Shrestha concluded. “[However], further analysis is necessary for us to gain confidence on the response and resistance biomarkers for immunotherapy and small cell lung cancer.”

Because of the limited sample size of eligible RNA sequencing data, these findings should be considered hypothesis generating, Shrestha noted.

Xie M, Chugh P, Broadhurst H, et al. Durvalumab + platinum-etoposide in first-line extensive-stage small cell lung cancer (ES-SCLC): exploratory analysis of SCLC molecular subtypes in CASPIAN. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT024.

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

. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6.

Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data [published correction appears in 

. 2019;19(5):289-297. doi:10.1038/s41568-019-0133-9.

Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. 

. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014.

Patients with YAP1 and inflamed T-cell expressing extensive-stage small cell lung cancer experienced superior overall survival following treatment with durvalumab and etoposide. 

Certain Biomarkers Tied to Superior Durvalumab/Chemo Performance in Extensive-Stage SCLC

Frontline treatment with carboplatin/etoposide and atezolizumab (Tecentriq) plus the anti-TIGIT immunotherapy tiragolumab did not significantly improve progression-free survival in patients with extensive-stage small cell lung cancer (ES-SCLC), according to updated findings form the phase 3 SKYSCRAPER-02 trial (NCT04256421).

The treatment regimen, therefore, did not reach its co-primary endpoint.

In addition, the other co-primary endpoint of the study was also not met at the interim analysis and is not anticipated to reach statistical significance by the planned final analysis. Although overall survival (OS) and PFS data were not positive, the combination was associated with acceptable tolerability and no new safety signals.

A more extensive analysis of the interim findings will be presented at an upcoming medical conference, according to Roche.

“Today’s outcome is disappointing as we had hoped to continue building on the advances of [atezolizumab] in ES-SCLC, which remains difficult to treat,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release.

An immune checkpoint inhibitor with an intact Fc region, tiragolumab was designed to selectively bind to TIGIT, which is known to suppress the response of the immune system to cancer. Preclinical data have indicated that the agent can serve as an immune amplifier when paired with other immunotherapeutic agents.

Although the TIGIT pathway is distinct to the PD-L1/PD-1 pathway, it is also complementary. Investigators have hypothesized that the combination of tiragolumab and an immunotherapy like atezolizumab could serve to overcome immune suppression and essentially restore response.

The global, placebo-controlled, double-blinded SKYSCRAPER-02 trial enrolled patients with histologically or cytologically confirmed ES-SCLC who have not previously received systemic treatment.

To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, acceptable hematologic and end-organ function, and they needed to be treatment free for at least 6 months since their last chemoradiation.

If patients had symptomatic or actively progressing central nervous system metastases, malignancies other than SCLC within 5 years before randomization, active or a history of autoimmune disease or immune deficiency, or human immunodeficiency virus, active hepatitis B or C virus, or severe infection at the time of randomization, they were excluded.

A total of 490 patients were enrolled to the trial, and they were randomized 1:1 to receive intravenous (IV) tiragolumab at 600 mg on day 1 of each 21-day cycle plus atezolizumab and carboplatin/etoposide or placebo plus atezolizumab and carboplatin/etoposide. All patients received IV atezolizumab at 1200 mg on day 1 of each 21-day cycle, IV carboplatin on day 1 of each 21-day cycle for 4 cycles followed by etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for 4 cycles.

The co-primary end points of the trial were OS and PFS in the primary analysis set, which was comprised of all randomized patients whose cancer had not spread to the brain. Important secondary end points included OS and PFS in all randomized patients and safety.

Previously, tiragolumab was granted a breakthrough therapy designation from the FDA for use in combination with atezolizumab in the first-line treatment of patients with metastatic NSCLC whose tumors are PD-L1 high and do not harbor any 

The phase 2 CITYSCAPE trial (NCT03563716) enrolled treatment-naïve patients with stage IV non–small cell lung cancer (NSCLC) who had 

 wild-type disease. To participate, patients needed to have a PD-L1 tumor proportion score (TPS) of 1% or higher per 22C3 immunohistochemistry and local or central assay.

A total of 135 patients were randomized 1:1 to receive IV tiragolumab at 600 mg every 3 weeks in combination with IV atezolizumab at 1200 mg every 3 weeks (n = 67), or IV placebo at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 68). Treatment was administered until progressive disease or clinical benefit was lost. Key stratification factors included PD-L1 TPS (1% to 49% vs more than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no).

The co-primary end points of this research were objective response rate (ORR) and PFS. Secondary end points included duration of response, OS, and safety.

At a median follow-up of 30.4 months, the combination produced a median PFS of 5.6 months (95% CI, 4.2-10.4) per investigator assessment vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone in the intention-to-treat (ITT) population. The median OS in the investigative and control arms was 23.2 months (95% CI, 14.1-31.5) and 14.5 months (95% CI, 9.6-20.4), respectively.

At the time of the primary analysis, which had a data cutoff date of June 30, 2019, and a median follow-up of 5.9 months, the tiragolumab combination produced a clinically meaningful improvement in ORR and PFS in the ITT population vs atezolizumab monotherapy. That benefit was maintained with the additional follow-up, with a greater magnitude of improvement noted in the patient subset who had a PD-L1 TPS of 50% or less.

The phase 3 SKYSCRAPER-01 trial (NCT04294810) is currently ongoing to confirm the results yielded in CITYSCAPE. Here, the safety and efficacy of tiragolumab plus atezolizumab is being compared with atezolizumab alone in patients with previously untreated locally advanced, unresectable or metastatic PD-L1–selected NSCLC without an 

“We look forward to seeing additional data from the upcoming phase 3 trial in PD-L1–high NSCLC based on encouraging results from the CITYSCAPE study,” Garraway added.

Ad hoc announcement pursuant to Art. 53 LR Roche provides update on phase III SKYSCRAPER-02 study in extensive-stage small cell lung cancer. News release. Roche; March 30, 2022. Accessed March 30, 2022. 

A study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer (SKYSCRAPER-02). ClinicalTrials.gov. Updated March 17, 2022. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04256421

Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche; January 5, 2021. Accessed March 30, 2022. 

Cho BC, Rodriguez-Abreu S, Hussein M, et al. LBA2 updated analysis and patient-reported outcomes (PROs) from CITYSCAPE: a randomised, double-blind, phase II study of the anti-TIGIT antibody tiragolumab + atezolizumab (TA) versus placebo + atezolizumab (PA) as first-line treatment for PD-L1+ NSCLC. 

. 2021;32(suppl 7):S1428. doi:10.1016/j.annonc.2021.10.217

A study of tiragolumab in combination with atezolizumab compared with placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (SKYSCRAPER-01). ClinicalTrials.gov. Updated December 7, 2021. Accessed March 30, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04294810

This article was published on OncLive as “Tiragolumab Plus Atezolizumab/Chemo Misses PFS End Point in Extensive-Stage SCLC"

An update from the phase 3 SKYSCRAPER-02 trial found that tiragolumab to atezolizumab did not significantly improve progression-free survival in extensive-stage small cell lung cancer. 

Tiragolumab/Atezolizumab Fails to Improve PFS in Extensive-Stage SCLC 

 fusion–positive non–small cell lung cancer (NSCLC) experienced favorable response rates following treatment with selpercatinib (Retevmo), according to data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) presented during the 2022 European Lung Cancer Congress.

Following treatment, the 247 patients who had previously received platinum chemotherapy experienced a confirmed objective response rate (ORR) of 61.1% (95% CI, 54.7%-67.2%). Among the 69 treatment-naïve patients, the confirmed ORR was 84.1% (95% CI, 73.3%-91.8%). In addition, the 26 patients with measurable central nervous system (CNS) at baseline achieved an ORR of 84.6%. Among this group, 22 patients experienced complete or partial response as their confirmed best response to treatment.

At a 20.3-month median follow-up, patients in the treatment-naïve population were found to have an estimated duration of response (DOR) of 20.2 months (55.2% censoring rate). In the pretreated population, at a median follow-up time of 21.2 months, the median DOR was 28.6 months (60.9%).

Furthermore, the agent is anticipated to elicit a median progression-free survival (PFS) in the treatment-naïve and pretreated populations of 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. Patients with measurable CNS disease experienced a median intracranial PFS of 19.4 months; however, these median estimated are not yet mature.

With a median follow-up of 20.3 months in the treatment-naïve population, the median duration of response (DOR) was estimated to be 20.2 months (55.2% censoring rate). At a median follow-up of 21.2 months in the platinum-pretreated population, the median DOR was estimated to be 28.6 months (60.9%).

The estimated median progression-free survival (PFS) in the treatment-naïve and pretreated populations were 22.0 months (53.6% censoring rate; median follow-up of 21.9 months) and 24.9 months (55.9% censoring rate; median follow-up of 24.7 months), respectively. In those with measurable CNS disease, the median intracranial PFS with selpercatinib was 19.4 months. However, the median estimates remain immature.

“The LIBRETTO trial provides the largest set of clinical data for a RET inhibitor and these results continue to demonstrate evidence of meaningful clinical outcomes for patients with metastatic 

 fusion–positive NSCLC treated with [selpercatinib], including those with difficult-to-treat brain metastases,” David Hyman, MD, chief medical officer of oncology at Eli Lilly and Company, stated in a press release.

In May 2020, the FDA granted an accelerated approval to selpercatinib for the treatment of patients with 

 alteration–positive NSCLC, medullary thyroid cancer, and other thyroid cancers based on earlier data from LIBRETTO-001.

 The regulatory decision is contingent upon data from a confirmatory trial.

The multicenter phase 1/2 LIBRETTO-001 trial enrolled patients with a diagnosis of advanced or metastatic solid tumors harboring 

 alterations.3 Patients needed to have an ECOG performance status ranging from 0 to 2, a QTc of ≤470 msec, and acceptable organ function. Notably, those with asymptomatic CNS metastases were allowed to participate.

A total of 355 patients were eligible for the efficacy analysis; of these patients, 247 patients were previously treated with at least 1 line of platinum chemotherapy and 69 were treatment naïve. Those who received prior treatment had received a median of 2 prior regimens (range, 1-15); 58% of these patients had received anti–PD-1/PD-L1 agents.

The primary end point of the trial was ORR per RECIST v1.1 criteria by independent review, and secondary end points included DOR, PFS, and safety.

The safety findings observed in the cohort proved to be consistent with what is known about selpercatinib. A total of 356 patients who had received at least 1 dose of the agent comprised the safety population. The adverse effects that were experienced by 25% or more of patients included dry mouth, diarrhea, hypertension, increased alanine/aspartate aminotransferase levels, peripheral edema, constipation, rash, headache, and fatigue.

Thirty four percent of patients needed to discontinue treatment with selpercatinib, with 10% doing so because of toxicity. Eleven of these cases were determined to be associated with the study agent.

“We are continuing to build on the robust body of evidence supporting [selpercatinib], including through an ongoing randomized phase 3 confirmatory study, with a planned readout in 2023,” Hyman added.

The phase 3 LIBRETTO-431 (NCT04194944), which is comparing the safety and efficacy of selpercatinib with standard treatment in patients with 

 fusion–positive nonsquamous NSCLC that has spread to other parts of the body, is currently recruiting.

Lilly presents updated data on Retevmo (selpercatinib) in advanced RET fusion-positive non-small-cell lung cancer (NSCLC) at the 2022 European Cancer Congress. News release. Eli Lilly and Company; April 1, 2022. Accessed April 1, 2022. 

FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. New release. FDA; May 8, 2020. Accessed April 1, 2022. 

Besse B, Drilon AE, Solomon BJ, et al. Updated overall efficacy and safety of selpercatinib in patients (pts) with 

 fusion+ non-small cell lung cancer (NSCLC). 

. 2021;39(suppl 15):9065. doi:10.1200/JCO.2021.39.15_suppl.9065

A study of selpercatinib (LY3527723) in participants with advanced or metastatic RET fusion-positive non-small cell lung cancer (LIBRETTO-431). ClinicalTrials.gov. Updated March 23, 2022. Accessed April 1, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04194944

This article was originally published on OncLive as “Selpercatinib Continues to Provide Clinically Meaningful Benefit in Advanced RET Fusion–Positive NSCLC”

Patients with metastatic RET fusion–positive non–small cell lung cancer experienced encouraging responses with selpercatinib.

Selpercatinib Shows Promise in Advanced RET Fusion-Positive NSCLC

Adjuvant pembrolizumab (Keytruda) following complete resection demonstrated statistically significant and clinically meaningful improvements in disease-free survival (DFS) among patients with stage IB to IIIA non–small cell lung cancer, according to findings of the phase 3 EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study (NCT02504372) that were recently presented at the 2022 ESMO Plenary.

In an analysis of all study populations, regardless of PD-L1 expression, the median DFS was 53.6 months in the pembrolizumab group vs 42.0 months in the control group (HR, 0.76; 95% CI, 0.63-0.91; 

= .0014). However, the DFS data did not reach the significance threshold among patients with a tumor proportion score (TPS) of at least 50% (median not reached in either arm; HR, 0.82; 95% CI, 0.57-1.18; 

Similarly, the significance threshold for overall survival (OS) was not reached in the all-comers population (HR, 0.87; 95% CI 0.67-1.15; 

= .17); only 209 events were reported. The 18-month OS rate was 91.7% with pembrolizumab vs 91.3% with the control arm.

Moreover, the safety profile associated with the PD-1/PD-L1 inhibitor was consistent with previously reported profiles. Further analyses will seek to assess DFS and OS among the PD-L1–specific population.

“Even when [NSCLC] is early-stage and caught in time, only about 50% of patients are actually cured [post-surgery], which means [that for the remaining patients], the disease either comes back, or the disease was more advanced than was initially thought,” Mary O’Brien, PhD, a medical oncologists at the Royal Marsden in London, and professor of practice medical oncology at Imperial College London, said in an interview with 

. “These are the patients that are high risk…but this immunotherapy seems to do twice as much and decreases the risk of [recurrence] by about 24%. Ultimately, we are ‘nibbling’ away at this cancer and increasing the number of patients who are cured by their surgery.”

The randomized, triple-blind, phase 3 EORTC-1416-LCG/ETOP 8-15–PEARLS/KEYNOTE-091 study randomized 1177 patients with stage IB, II, or IIIA NSCLC to receive either pembrolizumab (n = 590) at 200 mg or placebo n = (587) every 3 weeks for 18 doses following complete resection (T ≥4 cm) and adjuvant chemotherapy, ad indicated per guidelines. Overall, the median number of doses that patients received was 17 doses in the pembrolizumab arm and 18 in the placebo arm.

Of note, 168 patients in the pembrolizumab arm and 165 patients in the placebo arm also had a TPS of at least 50%. The baseline characteristics were reportedly similar between the 2 arms and the median time from randomization to data cutoff was 35.6 months (range, 16.5-68.0).

The primary objective of the trial was DFS in both the all-comers and PD-L1 TPS 50% or higher populations. The secondary objectives included DFS in the TPS ≥1% population, OS in the all-comers, TPS at least 50% and at least 1% populations, and safety. The data recently reported at the 2022 ESMO Plenary were collected at the protocol-specified second interim analysis data cutoff in September 2021.

In terms of adverse events (AEs), 34.1% of patients in the investigational arm experienced a grade 3 or higher AE compared with 25.8% of patients in the placebo arm. Discontinuation because of severe grade AEs occurred in 19.8% vs 5.9% of patients in the 2 arms, respectively, and treatment-related fatal AEs occurred in 0.7% vs 0% of patients in the 2 arms.

O’Brien noted that investigators have yet to determine the extended benefit of this treatment, but the current data are promising.

“Would 2 years [with pembrolizumab] do more [in terms of benefit]? Would 2 years combined with another drug do even more?” she said. “The research going forward will be addressing all of these things; we have opened a whole new world now after surgery.”

She also acknowledged that, historically, clinical trials did not always assess patients post-surgery because approximately half of patients did not experience recurrence. However, research is now aimed to find a durable treatment plan for the remaining 50% of patients.

“We have got over that hurdle and we are focusing on the half that are not cured,” she said. “We can make a difference, so, we will be doing more trials in this spot. We will be asking all these questions.”

Paz-Ares L, O’Brien MER, Mauer M, et al. Pembrolizumab (pembro) versus placebo for early-stage non-small cell lung cancer (NSCLC) following complete resection and adjuvant chemotherapy (chemo) when indicated: randomized, triple-blind, phase 3 EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study. 

. 2022;33(4):451-453. doi:10.1016/j.annonc.2022.02.224

Findings from the KEYNOTE-091 trial showed that patients with non–small cell lung cancer who were treated with pembrolizumab following complete resection and chemotherapy had a 24% decreased risk of recurrence compared with a control arm. 

Adjuvant Pembrolizumab Reduces Recurrence Risk in Resectable NSCLC

Patients with non–small cell lung cancer (NSCLC) and HER2 exon 20 insertion mutations benefited from receiving 16 mg daily doses of frontline poziotinib, according to data from cohort 4 of the ongoing phase 2 ZENITH20 trial (NCT03318939) presented during the 2022 ESMO Targeted Anticancer Therapies Meeting.

Among 70 patients who received the agent, the confirmed objective response rate (ORR) was 41% (95% CI, 30%-54%). In the 58 patients determined to be evaluable, the ORR with poziotinib was 50% (95% CI, 37%-63%). The study met its primary end point, as the observed lower bound of 30% exceeded the prespecified lower bound of 20%.

Moreover, the median duration of response (DOR) was 5.7 months (range, 1.2-19.1+), and the disease control rate (DCR) was 73% (95% CI, 61%-83%) with the agent in this population. Poziotinib resulted in a median progression-free survival (PFS) of 5.6 months (range, 0.0-20.2+).

“Cohort 4 from our ZENITH20 study demonstrated positive results for treatment-naïve lung cancer patients harboring 

 exon 20 insertion mutations,” Francois Lebel, MD, chief medical officer of Spectrum Pharmaceuticals, stated in a press release.

 “There is currently no approved treatment for NSCLC patients with these mutations. We are encouraged by these findings and look forward to further discussions with the FDA on the regulatory path forward.”

The multicenter, multicohort, open-label phase 2 ZENITH20 trial is composed of 7 cohorts of patients with NSCLC.3 Those with previously treated NSCLC and 

 exon 20 mutations comprise cohort 1; those with 

 exon 20 mutations comprise cohort 2; those with treatment-naïve NSCLC and 

 exon 20 mutations comprise cohort 3; and those with treatment-naïve NSCLC and 

Cohort 5 is enrolling previously treated or treatment-naïve patients with 

 exon 20 insertion mutations; cohort 6 is enrolling those with NSCLC and classical 

 mutations who progressed on frontline osimertinib (Tagrisso) and developed an additional 

 mutation; and cohort 7 is enrolling those with NSCLC who have a variety of less common mutations in 

 exons 18 through 21 or the extracellular or transmembrane domains.

In cohort 4 of the trial, poziotinib was evaluated at a once- or twice-daily dosing strategy in patients with NSCLC and 

 exon 20 insertion mutations. The oral drug was given once daily at 16 mg for the first 48 patients, and then at a twice-daily dose of 8 mg in an additional 22 patients. Both regimens allowed for dose reductions or interruptions if patients experienced toxicity.

The primary end point was ORR per central evaluation and by independent image review committee utilizing RECIST v1.1 criteria. Key secondary end points included DCR, DOR, and PFS, as well as safety and tolerability.

Those in cohort 4 had a median age of 60 years (range, 27-88), and 37% were female. Twenty percent of the 70 total patients were still receiving treatment at the time of data cutoff, and the median duration of treatment was 4.5 months (range, < 1-21).

Additional findings presented during the meeting revealed that 73% of patients achieved disease control and experienced a clinically meaningful reduction in tumor size.

Regarding safety, 90% of those who received the once-daily dose required a dose interruption with a median of 19 days to first interruption, vs 68% of those who were given the twice-daily dose. The median time to first interruption among those who received the twice-daily dose was slightly longer, at 26 days.

Additionally, 79% and 64% of patients who received the once- and twice-daily doses of poziotinib, respectively, experienced dose reductions. The median time to first dose reduction in the once-daily dosing group was 36 days vs 33 days in the twice-daily dosing group.

Treatment-related adverse effects (TRAEs) that were grade 3 or higher were experienced by 69% of those who received poziotinib at a once-daily dose vs 68% of those who received it at a twice-daily dose. The most common TRAEs reported across the dosing groups included rash (30%), stomatitis/mucosal inflammation (19%), diarrhea (14%), paronychia (7%), and pneumonitis (3%).

Grade 4 TRAEs were experienced by 2 patients who received the twice-daily dose of poziotinib; these patients had hypokalemia and hyponatremia.

“[The] safety profile was consistent with the TKI class and tolerability, dose reductions, and interruptions were improved with [twice-daily] dosing,” study author Sophie Sun, MD, FRCPC, of the Division of Medical Oncology at British Columbia Cancer, said in the presentation on the data. “[The] incidence of grade 3 or higher pneumonitis was low.”

In December 2021, a new drug application seeking the approval of poziotinib in patients with previously treated locally advanced or metastatic NSCLC with 

 exon 20 insertion mutations was submitted to the FDA.4 The application is supported by data from cohort of ZENITH20, where the agent elicited an ORR of 27.8% (95% CI, 18.9%-38.2%) in this population. Moreover, in this cohort, the median DOR with the agent was 5.1 months (95% CI, 4.2-5.5) and the median PFS was 5.5 months (95% CI, 3.9-5.8).

Sun S. Efficacy and safety of poziotinib in treatment-naïve 

 exon 20 insertion mutated non-small cell lung cancer: ZENITH20-4. Presented at: 2022 ESMO Targeted Anticancer Therapies; March 7-8, 2022; virtual. Accessed March 7, 2022. 

Spectrum Pharmaceuticals presents positive data for poziotinib in first-line NSCLC patients with HER2 exon 20 insertion mutations. News release. Spectrum Pharmaceuticals; March 7, 2022. Accessed March 7, 2022. 

Le X, Cornelissen R, Garrassino M, et al. Poziotinib in non–small-cell lung cancer harboring 

 exon 20 insertion mutations after prior therapies: ZENITH20-2 trial. 

. Published online November 29, 2021. doi:10.1200/JCO.21.01323

Spectrum Pharmaceuticals submits new drug application for poziotinib. News release. Spectrum Pharmaceuticals; December 6, 2021. Accessed March 7, 2022. 

This article was originally published on OncLive as “Frontline Poziotinib Produces Clinically Meaningful Efficacy in NSCLC Harboring HER2 Exon 20 Insertion Mutations”

Frontline treatment with poziotinib yielded promising overall response rates in patients with non–small cell lung cancer and HER2 exon 20 insertion mutations.

Poziotinib Linked With Promising Response Rates in HER2 Exon 20 Insertion-Mutated NSCLC

Patients with lung cancer showed less depression and anxiety compared with the general population during the COVID-19 pandemic, according to data recently published in

 the Journal of the National Comprehensive Cancer Network.

Notably, the number of people in the general population who experienced clinical levels of anxiety and depression during the pandemic was double the number of people who experienced similarly high levels. These findings suggest that the general population might look to this population to learn resilience and coping skills, according to investigators.

“We were astounded at how resilient these patients [with lung cancer] were in coping with the threat of COVID-19, given they were already under very difficult health circumstances,” study co-author Barbara Andersen, PhD, professor of psychology at The Ohio State University, stated in a press release.

 “That’s not to say patients [with lung cancer] were unfazed by the pandemic—they did show concern. But, they seemed better able to handle the stress than similar people without cancer.”

The study assessed the responses of 76 patients with advanced non–small cell lung cancer (NSCLC). All participants had previously been enrolled in the stage IV NSCLC cohort in the Beating Lung Cancer in Ohio Study (NCT03199651), which predated the COVID-19 pandemic.

At diagnosis, all patients were asked to complete surveys about their psychological health, which was at least 1 year before the pandemic began. Patients submitted similar surveys again between April 2020 through July 2020—these surveys included additional questions querying about COVID-19–related concerns.

The mean age of participants was 62.5 years. All patients resided in Ohio, had low education (high school education or less), and income levels (≤$75,000 annual income). In addition, 91.4% had a smoking history. Between May 8, 2020, and June 19, 2020, 67 control individuals also enrolled in the study and completed similar surveys.

Psychological Position at Diagnosis Vs During Pandemic

The general population experienced nearly double the amount of anxiety and depression that patients with non–small cell lung cancer reported during the COVID-19 pandemic.  

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