The initiation of immunotherapy at the end of life among patients with advanced cancers is increasing over time, according to findings from a cohort study led by investigators at the Yale School of Medicine.

Data from the study, which were published in 

, demonstrated that among 242,371 patients who were analyzed the percentage of patients who received end-of-life immunotherapy increased over time for all cancers. The study included patients with stage IV melanoma (n = 20,415), non–small cell lung cancer (NSCLC; n = 197,331), or renal cell carcinoma (RCC; n = 24,625). During the study period, the percentage of patients with metastatic disease who started immunotherapy within 1 month of death increased from 0.8% to 4.3% for patients with melanoma, 0.9% to 3.2% for patients with NSCLC, and 0.5% to 2.6% for patients with RCC.

“Immunotherapy has revolutionized the field of oncology over the last decade,” Sajid A Khan , MD, FACS, FSSO, senior author of the study, the codirector of Team Science at the Yale Center for Clinical Investigation, as well as section chief of hepato-pancreato-biliary (HPB) and mixed tumors and an associate professor of surgery (Oncology) at Yale School of Medicine in New Haven, Connecticut, said in a press release. “Because survival is substantially improved for many patients treated with these drugs, its overall application has increased across the United States.”

To conduct their study, investigators used the National Cancer Database to collect data from patients with the 3 cancers with the highest volume and longest longitudinal experience with immunotherapy, stage IV melanoma, NSCLC, and RCC. The beginning of the study period for each cancer type was the year immediately following the FDA approval for the first immune checkpoint inhibitor for the treatment of stage IV disease for that malignancy, which was 2012 for melanoma and 2016 for NSCLC and RCC. The end of each study period was 2019.

The retrospective study included patients with both clear cell and non–clear cell KCC; all patients needed to be at least 18 years old and have stage IV disease. Those with unknown immunotherapy status or unknown timing of immunotherapy and those without reported follow-up data were excluded.

The primary outcome was the rate of initiation of immunotherapy in the last month of life. Independent variables of interest included facility type and hospital volume.

At baseline, the mean age for all patients was 67.9 years (standard deviation, 11.4), 42.5% were older than 70 years, 56.0% were male, and 29.3% received immunotherapy. In the melanoma cohort, most patients did not receive immunotherapy (57%), 41% received immunotherapy and lived longer than 1 month after initiation (non–end of life immunotherapy), and 3% received immunotherapy initiation at the end of life. In the NSCLC cohort, these rates were 72%, 26%, and 3%, respectively. The rates were 73%, 26%, and 2%, respectively, for patients with RCC.

Additional findings from the study showed that end-of-life treatment as a percentage of all immunotherapy and chemotherapy treatments were approximately constant over time among patients with NSCLC or RCC. In the melanoma cohort, the proportion of chemotherapy treatments initiated at the end of life decreased from 8.8% in 2012 to 5.1% in 2019 (

 = .04), and the proportion of immunotherapy treatments that were end-of-life initiated increased slightly from 5.0% to 6.9% (

Treatment at an academic or a high-volume center was associated with a significant decrease in the odds of patients receiving end-of-life initiated immunotherapy; patients treated at these facilities were 31% (OR, 0.69; 95% CI, 0.65-0.74; 

 < .001) and 30% (OR, 0.70; 95% CI, 0.65-0.76; 

 < .001) less likely to die within 1 month of the initiation of immunotherapy compared with those who received treatment at a nonacademic or very-low volume center, respectively.

Additionally, the presence of metastases in at least 3 solid organs was associated with increased odds of end-of-life initiated immunotherapy across all 3 cancer types compared with distant lymph node metastases only. The ORs in the melanoma, NSCLC, and KCC cohorts were 9.98 (95% CI, 4.03-24.67), 3.61 (95% CI, 2.87-4.55), and 3.26 (95% CI, 1.66-6.40), respectively.

In the NSCLC cohort, patients aged 51 to 70 years (OR, 1.36; 95% CI, 1.15-1.62; 

 < .001) and aged older than 70 years (OR, 1.58; 95% CI, 1.31-1.89; 

 < .001) experienced increased odds of receiving end-of-life initiated immunotherapy compared with those 50 years and younger. Burden of comorbidities by Charlson-Deyo Comorbidity Index was also a factor associated with increased use of end-of-life initiated immunotherapy; in the overall population, patients with Charlson-Deyo scores of 2 (OR, 1.36; 95% CI, 1.22-1.50; 

 < .001) or 3 or higher (OR, 1.58; 95% CI, 1.42- 1.76; 

 < .001) experienced increased odds of end-of-life initiated immunotherapy.

“Our study found that in the last 10 years, the initiation of immunotherapy in [what turned out to be] the final month of a patient’s life has significantly increased, accounting for 1 in 14 immunotherapy treatments overall,” Khan said. “The reason we focused on immunotherapy initiation at the end of a patient’s life with cancer metastasis was to see what we could learn about prescribing patterns. What we found we hope will serve as a harbinger for shifts in the clinical approach to patients with advanced cancer.”

Masciadrelli M. Immunotherapy for metastatic cancer on the rise, even near end of life. Yale School of Medicine. January 4, 2024. Accessed January 15, 2024. 

https://medicine.yale.edu/surgery/plastics/news-article/immunotherapy-for-metastatic-cancer-on-the-rise-even-near-end-of-life/

Kerekes DM, Frey AE, Prsic EH, et al. Immunotherapy initiation at the end of life in patients with metastatic cancer in the US. 

. Published online January 4, 2024. doi:10.1001/jamaoncol.2023.6025

Articles

The initiation of immunotherapy at the end of life among patients with advanced cancers is increasing over time.

Rate of End-of-Life Immunotherapy Is on the Rise in Advanced Melanoma, NSCLC, RCC

The FDA has granted fast track designation to SLS009 (formerly GFH009) for use as a potential therapeutic option in patients with relapsed or refractory acute myeloid leukemia (AML), according to an announcement from SELLAS Life Sciences Group, Inc.

The safety and efficacy of the CDK9 inhibitor in combination with venetoclax (Venclexta) and azacitidine (Vidaza) in this population is being explored as part of an ongoing phase1/2 study (NCT04588922).

Of the 9 patients enrolled to the safety cohort who were given SLS009 at 45 mg in combination with the doublet, 8 remain alive and 6 are still on treatment. At a follow-up ranging from 2 to 7 months for those still alive, the median overall survival (OS) had not yet been reached. Seven out of 8 evaluable patients were found to experience significant antileukemia effects defined as having a decrease of at least 50% in bone marrow blasts. To date, no dose-limiting toxicities and no significant safety signals have been observed.

Findings from the phase 1 portion showed that when SLS009 was given as a single agent, it elicited a complete response (CR) that proved to be durable in a patient who had AML and experienced failure with previous venetoclax/azacitidine. Moreover, no minimal residual disease was observed in this patient who continues to be alive at 16 months post-treatment initiation.

“Receiving fast track designation for SLS009 for relapsed or refractory AML, following the recent orphan drug designation for the same indication, underscores the potential for SLS009 and highlights the critical unmet need for patients with AML who face a poor prognosis due to the progressive nature of the disease,” Angelos Stergiou, MD, ScD hc, president and chief executive officer of SELLAS Life Sciences Group, Inc., stated in a press release. “The initial positive topline phase 2a data at the 45-mg [safety] dose level demonstrate that SLS009 in combination with venetoclax and azacitidine exhibits antileukemic effects with a favorable safety profile in AML patients resistant to venetoclax combination therapies.”

The open-label, single-arm, multicenter study enrolled patients with cytologically or histologically confirmed relapsed or refractory hematologic malignancies, including AML, chronic lymphocytic leukemia or small lymphocytic lymphoma, and lymphoma.

They needed to be at least 18 years of age, have at least 1 measurable or evaluable lesion by 2014 Lugano response criteria, and have previously received at least 2 lines of systemic treatment. Those in the phase 2a AML combination cohort needed to be relapsed or refractory to previous venetoclax-containing regimens.

If patients had bulky disease that was at least 10 cm and required receipt of cytoreductive chemotherapy, symptomatic central nervous system metastases or primary lymphoma, or severe cardiovascular disease within 6 months of enrollment, they were excluded.

In the phase 2a portion of the research, SLS009 is under evaluation at 2 doses: 45 mg and 60 mg; both doe cohorts will also receive venetoclax and azacitidine.

 Those included in the 60-mg cohort were randomly assigned into 1 of 2 groups: those who were given a fixed dose of 60 mg once weekly or those given a fixed dose of 30 mg twice weekly. Each group is slated to enroll 5 to 10 participants.

Primary end points of the study include safety, tolerability, composite CR rate, and duration of response. Investigators will also assess event-free survival, OS, pharmacokinetics, and pharmacodynamics.

 shared in October 2023 indicated that of 5 patients enrolled and treated in the safety 45-mg dose cohort, 1 achieved a CR and had been in the fifth month of treatment following relapse on venetoclax.

 Another patient was still alive and in the fourth month of treatment with the regimen. At that time point, all enrolled patients were still alive and 4 total were still on treatment. All patients were noted to have experienced antileukemic effects without substantial safety concerns.

“We have now also enrolled several patients in the ongoing 60-mg dose cohort,” Stergiou added in the press release.

 “Our team is committed to advancing the development of SLS009 with the goal of providing effective solutions to patients in need of viable treatment options.”

Additional data from the safety 45-mg cohort is anticipated in the first quarter of 2024, as are initial findings from the 60-mg cohort, which is the recommended phase 2 dose of SLS009. The 60-mg cohort will be assessed in the second quarter of this year.

SELLAS Life Sciences receives FDA fast track designation for SLS009 for treatment of relapsed/refractory acute myeloid leukemia and provides updated data for phase 2a study of SLS009 in relapsed/refractory acute myeloid leukemia patients. News release. SELLAS Life Sciences Group, Inc. January 9, 2024. Accessed January 10, 2024. 

https://www.sellaslifesciences.com/investors/news/News-Details/2024/SELLAS-Life-Sciences-Receives-FDA-Fast-Track-Designation-for-SLS009-for-Treatment-of-RelapsedRefractory-Acute-Myeloid-Leukemia-and-Provides-Updated-Data-for-Phase-2a-Study-of-SLS009-in-RelapsedRefractory-Acute-Myeloid-Leukemia-Patients/default.aspx

A study of GFH009 in patients with hematologic malignancies. ClinicalTrials.gov. Updated September 1, 2023. Accessed January 10, 2024. 

https://classic.clinicaltrials.gov/ct2/show/NCT04588922

SELLAS announces positive initial topline phase 2a data of SLS009 in acute myeloid leukemia. News release. SELLAS. October 16, 2023. Accessed January 10, 2024. 

https://www.sellaslifesciences.com/investors/news/News-Details/2023/SELLAS-Announces-Positive-Initial-Topline-Phase-2a-Data-of-SLS009-in-Acute-Myeloid-Leukemia/default.aspx

The FDA has granted fast track designation to SLS009 for use in patients with relapsed or refractory acute myeloid leukemia.

FDA Grants Fast Track Status to SLS009 for Relapsed/Refractory Acute Myeloid Leukemia

Treatment with the anti-CD25 antibody-drug conjugate (ADC) camidanlumab tesirine (ADCT-301) was deemed well tolerated as a monotherapy and produced encouraging responses when administered with pembrolizumab (Keytruda) in select pretreated patients with advanced solid tumors. However, the combination was associated with an increase in immune-related adverse effects (AEs), according to findings from a phase 1 trial (NCT03621982) presented at the 2023 SITC Annual Meeting.

In the monotherapy cohort (n = 44), 25.0% of patients achieved stable disease (SD). No patients achieved an objective response, and the disease control rate (DCR) was 25.0%. Conversely, 30.3% of patients in the combination cohort (n = 34) achieved SD, 3.0% of patients achieved a complete response (CR), and 12.1% of patients achieved a partial response (PR). The DCR in this cohort was 45.5%. Notably, all 5 responders had ovarian or fallopian cancer. 

Among efficacy-evaluable patients with ovarian cancer in the combination arm, who had received a median of 4 prior lines of therapy and were immunotherapy naive (n = 17), the overall response rate (ORR) was 29.4%, and the DCR was 47.0%.

“In terms of safety and tolerability, the drug was very well tolerated as a monotherapy. There were no dose-limiting toxicities observed, and the maximum tolerated dose (MTD) was not reached... [Conversely], there was considerably higher toxicity, particularly immune-related and skin toxicity, noted in the combination cohort,” lead study author Christopher T. Chen, MD, the director of Early Drug Development at Stanford Cancer Institute and an assistant professor of medicine in the Division of Oncology at Stanford University School of Medicine, stated in an oral presentation of the data. 

CD25-positive, FOXP3-positive regulatory T cells (Tregs) are known to be key drivers of an immunosuppressive tumor microenvironment, and studies with preclinical animal models have shown that effectively depleting CD25-positive Tregs can inhibit tumor growth and improve survival across solid tumor histologies and lymphomas.

Camidanlumab tesirine consists of a CD25-directed antibody linked via a cleavable linker to a PBD toxin payload. Prior phase 2 research has shown activity and manageable toxicity with camidanlumab tesirine when used as a single agent in patients with relapsed/refractory Hodgkin lymphoma. The agent may also have synergy when used with the anti–PD-(L)1 inhibitor pembrolizumab.

“Unlike most ADCs designed to deplete tumor cells, camidanlumab tesirine is designed to deplete Tregs highly potently,” Chen explained during the presentation. “By doing so, the hope is that we see improvement in the cytotoxic T lymphocyte [CTL]:Treg intratumoral ratio, leading to greater to antitumor activity.”

Based on these data, investigators assessed the clinical, pharmacokinetic, and biomarker data from a phase 1a/b trial of camidanlumab tesirine both as a monotherapy and in combination with pembrolizumab. The multicenter, open-label trial enrolled patients 18 years of age or older with locally advanced or metastatic solid tumors, measurable disease, and an ECOG performance status of 0 or 1. Patients were also required to be refractory or intolerant to existing therapies, including prior immunotherapy or anti–PD-(L)1 therapy. Exclusion criteria included prior anti-CD25 therapy, prior solid organ transplant, autoimmune disease, or recent infection.

The trial utilized a 3+3 design in the dose escalation phase (part 1). Patients in part 1 who were enrolled onto the monotherapy arm received 20 µg/kg to 300 µg/kg of camidanlumab tesirine intravenously (IV) on day 1 of each 3-week cycle. Patients enrolled onto the combination arm received an IV infusion of camidanlumab tesirine at 30 µg/kg to 300 µg/kg on day 1 of each 3-week cycle for 2 cycles on and 2 cycles off. Every 3 weeks, these patients also received 200 mg of pembrolizumab 1 hour after camidanlumab tesirine infusion.

The study’s primary end points were safety and tolerability, with key secondary end points of antitumor activity and pharmacokinetics. The study also evaluated exploratory end points of biomarker data and paired biopsy immune cell profile.

Across both cohorts, most patients were heavily pretreated, having received a mean of at least 4 prior lines of therapy. In the monotherapy cohort, 40.9% of patients were female, and 90.9% of patients were White. The mean age of patients was 60.8 years (standard deviation [SD], 11.35), and the most common tumor types were pancreatic cancer (38.1%) and colorectal cancer (34.1%). Patients received a mean of 2.1 cycles of therapy (SD, 1.06), with a median treatment duration of 27.1 days (SD, 30.80).

In the monotherapy cohort, 67.6% of patients were female, and 82.4% of patients were White. The mean age of patients was 64.1 years (SD, 8.46), and the most common tumor type was ovarian/fallopian cancer (52.9%). Patients received a mean of 3.0 cycles of therapy (SD, 2.88), with a median treatment duration of 49.4 days (SD, 69.29).

As of the data cutoff of December 21, 2022, all patients discontinued the study. Reasons for treatment discontinuation included progressive disease (81.8% with monotherapy; 58.8% with combination), unacceptable toxicity, (2.3%; 20.6%), withdrawal by patients (11.4%; 11.8%), death (4.5%; 5.9%), or study termination by sponsor (0.0%; 2.9%).

Assessment of pharmacokinetics revealed that the maximum serum concentration and area under the curve of the camidanlumab tesirine/PBD–conjugated antibody increased linearly with escalating doses of camidanlumab tesirine. Moderately higher exposures were observed with the combination cohort vs the monotherapy cohort. Moderate interpatient variability was also observed. There was no accumulation of camidanlumab tesirine up to cycle 2, and no clinically relevant antidrug antibody induction effects were observed.

Regarding safety, grade 3 or greater adverse effects (AEs) were seen in 70.5% of patients treated with camidanlumab tesirine monotherapy, the most common of which were anemia (9.1%), abdominal pain (6.8%), pulmonary embolism (PE; 6.8%), and rash (6.8%). Serious AEs occurred in 40.9% of patients. AEs led to death, dose delay, dose reduction, and treatment discontinuation in 11.4%, 22.7%, 0.0%, and 4.5% of patients, respectively.

The MTD was also not reached in the combination cohort. In this cohort, grade 3 or greater AEs were seen in 79.4% of patients, the most common of which were macropapular rash (17.6%), anemia (14.7%), hyponatremia (11.8%), and decreased lymphocyte count (11.8%). Serious AEs occurred in 70.6% of patients. AEs led to death, dose delay, dose reduction, and treatment discontinuation in 5.9%, 41.2%, 0.0%, and 23.5% of patients, respectively.

Two DLT events of grade 3 pneumonitis and pancreatitis were reported in 1 patient each at the 45 µg/kg and 100 µg/kg dose levels, respectively. Additionally, 1 patient treated with 60 µg/kg of camidanlumab tesirine experienced grade 3 encephalitis in cycle 1 with concomitant COVID-19 infection. This event was determined to be treatment-related rather than a DLT, and the patient recovered without sequalae after discontinuing treatment.

Notably, there was an increase in the frequency of skin and soft tissue AEs with the combination (61.8%) vs monotherapy (36.4%). The incidence of autoimmune-related AEs also increased with the combination (55.9%) vs monotherapy (11.4%). One patient experienced Stevens-Johnson syndrome and toxic epidermal necrolysis that was considered related to study treatment more than 30 days after their last dose.

“There was no Guillain-Barre syndrome reported during the study. That is of particular note because in the lymphoma study [of camidanlumab tesirine], there were Guillain-Barre syndrome events [that were] thought to be drug related,” Chen notes. 

Responses with the combination regimen according to baseline biopsy biomarker status were assessed in 16 patients with ovarian cancer with available baseline biopsy biomarker data. In this population, patients with baseline CTL infiltration levels in the tumor epithelium that were higher than the median experienced numerically higher response rates. Investigators noted that interpretation of these data should be treated with caution due to the small sample size and different camidanlumab tesirine doses administered. Additionally, the CTL:Treg ratio increased from baseline in approximately half of patients in the monotherapy cohort, and 10 out of 15 patients in this cohort experienced a decrease in Treg infiltration.

Similarly, most patients in the combination cohort experienced an increase in CTL:Treg ratios from baseline. Ten out of 16 patients experienced a decrease in Treg infiltration, although none experienced a concomitant decrease in CTL infiltration. Paired biopsies were available for 10 patients with ovarian cancer treated with the combination. Of these patients, 3 experienced a PR, 1 experienced SD, and 6 had disease progression. All 3 responders had Treg and CTL infiltration levels in the tumor epithelium in the post-treatment biopsy that were higher than the median.

“To point out a notable clinical phenomenon about the kinetics of responses on this study, delayed and prolonged responses were [also] observed in a number of patients… The durability [of response] and fact that several patients showed sustained responses without drug dosing is a striking factor…” Chen added. 

 Chen discloses the following relationships: consulting/advisory roles for Boxer Capital and Guidepoint Global; and research funding from ADC Therapeutics, Gilead, Kinnate Biopharma, Mersana Therapeutics, ORIC Pharmaceuticals, Palleon, Rain Oncology, Riboscience, and Takeda.

Chen C, Hamilton E. LoRusso P, et al. Results of a phase 1 study investigating camidanlumab tesirine as monotherapy and in combination with pembrolizumab in patients with select advanced solid tumors. Presented at: 2023 SITC Annual Meeting; November 1-5, 2023; San Diego, CA. Abstract 608.

Camidanlumab tesirine was well tolerated as a monotherapy and elicited responses when given with pembrolizumab in patients with advanced solid tumors.

Camidanlumab Tesirine Plus Pembrolizumab Produces Responses But Increases Immune Toxicities in Select Solid Tumors

Dostarlimab-gxly (Jemperli) plus chemotherapy elicited a higher objective response rate (ORR) and showcased a numerical improvement in overall survival (OS) compared with pembrolizumab (Keytruda) and chemotherapy in patients with treatment-naïve, nonsquamous non–small cell lung cancer (NSCLC), according to data from a preplanned updated OS analysis of the phase 2 PERLA trial (NCT04581824) presented at the 

With a median follow-up of 20.7 months (95% CI, 19.3-22.3) in the dostarlimab arm (n = 121) and 21.6 months (95% CI, 19.6-23.1) in the pembrolizumab arm (n = 122), and OS data maturity at 55.1% (n = 134/243), the median OS was 19.4 months (95% CI, 14.5-not reached [NR]) and 15.9 months (95% CI, 11.6-19.3), respectively (HR, 0.75; 95% CI, 0.53-1.05).

Dostarlimab plus chemotherapy induced an ORR of 45% (95% CI, 36.4%-54.8%) vs 39% (95% CI, 30.6%-48.6%) with pembrolizumab plus chemotherapy, which translated to a difference of 6.04% (95% CI, –6.17% to 18.24%). In the dostarlimab arm, the complete response rate was 3%, the partial response rate was 42%, and the stable disease rate was 40%; in the pembrolizumab arm, these rates were 5%, 34%, and 39%, respectively. Twelve patients in each arm experienced progressive disease (PD).

“Results are consistent with the study hypothesis that dostarlimab and pembrolizumab have similar efficacy,” Solange Peters, MD, ESMO past president, full professor and chair of medical oncology and the Thoracic Malignancies Program in the Department of Oncology at the University Hospital of Lausanne in Switzerland, said in a presentation of the data. “…These results support further investigation of dostarlimab as a treatment backbone in combination with standard-of-care treatments and future novel cancer therapies in patients with NSCLC.”

It is known the PD-1/PD-L1 inhibition improves outcomes in patients with metastatic nonsquamous NSCLC, both as single agents and when paired with chemotherapy compared with chemotherapy alone. Dostarlimab binds to PD-1 at distinct binding sites with different binding orientations from other PD-1 inhibitors, Peters noted.

FDA granted accelerated approval to dostarlimab

 for use in adult patients with mismatch repair–deficient (dMMR) recurrent or advanced solid tumors that have progressed on or after prior treatment and who have no satisfactory alternative options.

 for use in dMMR recurrent or advanced endometrial cancer that has progressed on or following a platinum-based regimen in any setting and who are not eligible to undergo curative surgery or radiation.

 followed by single-agent dostarlimab was FDA approved for use in adult patients with primary advanced or recurrent endometrial cancer that is dMMR or microsatellite instability high.

PERLA, the first global, randomized, double-blind, head-to-head study of 2 PD-1 inhibitors, enrolled patients with histologically or cytologically confirmed metastatic nonsquamous NSCLC without known targetable oncogenic driver mutations.

 Patients were required to have documented PD-L1 status, an ECOG performance status of 0 or 1, and acceptable organ function. They could not have previously received systemic treatment for metastatic disease.

Study participants were randomly assigned 1:1 to receive 500 mg of dostarlimab plus chemotherapy every 3 weeks or 200 mg of pembrolizumab plus chemotherapy every 3 weeks. Chemotherapy consisted of pemetrexed at 500 mg/m

 every 3 weeks for up to 35 cycles and carboplatin at area under the curve 5 mg/mL/min or cisplatin at 75 mg/m

 every 3 weeks for up to 4 cycles. Treatment continued until PD, intolerable toxicity, death, or up to 35 cycles.

Key stratification factors included PD-L1 expression (tumor proportion score [TPS] of <1% vs 1% to 49% vs ≥50%) and smoking status (never vs former/current).

Confirmed ORR by blinded independent central review (BICR) and RECIST v1.1 criteria served as the trial’s primary end point. Secondary end points included OS; progression-free survival by RECIST v1.1 criteria and investigator assessment; and safety. Duration of response by RECIST v1.1 criteria and BICR represented an exploratory end point of interest.

“The primary analysis was allowed to confirm that the ORR was met, with equivalence of the 2 compounds, and I’m sure you have the question in mind, it meant that the study could detect this equivalence in response rate with an 85% power, enabling us to detect the 15% difference in response rate between the 2 arms at a 10% one-sided type I error rate, [when the true ORR is] 45% [for] both arms,” Peters said.

, the combination of dostarlimab and chemotherapy showed numerical trends in ORR and PFS compared with pembrolizumab plus chemotherapy, meeting the primary end point.

 The ORR in the dostarlimab arm was 46% (95% CI, 37.2%-55.6%) vs 37% (95% CI, 28.3%-46.1%) in the pembrolizumab arm.

 showed similar ORRs across the subsets of patients with nonsquamous NSCLC for both combinations, with responses numerically favoring the dostarlimab combination in most subgroups.

At the 2023 ESMO Congress, Peters shared insights from the preplanned updated OS analysis.

“[When looking at the] demographics and baseline characteristics, you can see in bold what has been seen to be different between the 2 treatment arms in favor of the pembrolizumab plus chemotherapy,” Peters said. “There were more males, more patients with brain metastases, more patients with liver metastases, and more patients with an ECOG performance status of 1 in the dostarlimab plus chemotherapy arm. In favor of the dostarlimab plus chemotherapy arm, there were more patients [who were over] 60 years old in the pembrolizumab plus chemotherapy arm. Of interest, if you look at PD-L1 [expression,] it was, of course, a stratification factor and well balanced. But more than 40% of the patients are negative for PD-L1, which is a bit more than what would be expected based on all the data we have and recent clinical trials.”

At the data cutoff date of July 7, 2023, 48% of patients in the dostarlimab arm were still receiving treatment vs 34% of those on the pembrolizumab arm.

“Importantly, more patients had died due to any reason in the pembrolizumab plus chemotherapy arm, at 61%, as compared with 49% in the dostarlimab plus chemotherapy arm,” Peters noted.

Patients in the dostarlimab arm received a median of 13 treatment cycles (range, 1-35) vs 7.5 cycles (range, 1-35) in the pembrolizumab arm. The median duration of exposure was 9 months (range, 0.3-26.8) and 6 months (range, 0.2-25.3) in the dostarlimab and pembrolizumab arms, respectively.

Investigators also examined OS by PD-L1 TPS status. “This numerical difference in OS [with dostarlimab vs pembrolizumab] was seen in all patients with positive PD-L1 assessment, as you can see in the strata of [TPS of] more than 1%, 1% to 49%, and more than 50%,” Solange said.

In the group of patients with a PD-L1 TPS of 1% or higher, the median OS was 18.0 months (95% CI, 12.7-NR) and 15.9 months (95% CI, 7.8-NR) with dostarlimab and pembrolizumab, respectively. In the subset of patients with a PD-L1 TPS ranging from 1% to 49%, the median OS with dostarlimab was 17.6 months (95% CI, 10.5-NR) vs 14.5 months (95% CI, 6.5-NR) with pembrolizumab. In those with a PD-L1 TPS of 50% or higher, the median OS in the dostarlimab arm was 19.4 months (95% CI, 9.9-NR) vs 17.6 months (95% CI, 6.2-22.2) in the pembrolizumab arm.

In those with a PD-L1 TPS of less than 1%, the median OS in the dostarlimab and pembrolizumab arms was 20.8 months (95% CI, 11.4-NR) and 16.1 months (95% CI, 11.6-20.1), respectively. “In the negative PD-L1 patients, the Kaplan-Meier curves cross more than once, making the difference difficult to assess,” she noted. “However, the drug seems equivalent, and if anything, the median OS is still numerically superior for dostarlimab plus chemotherapy as compared with pembrolizumab plus chemotherapy.”

Regarding safety, the proportion of patients experiencing adverse effects (AEs), including grade 3 or higher AEs, proved to be comparable between the treatment arms. Any-grade AEs were experienced by 98% of those who received dostarlimab and 98% of those given pembrolizumab; 71% vs 57% of patients experienced immunotherapy (IO)-related AEs, and 64% of patients in both arms had grade 3 or higher AEs. The most common IO-related AEs occurring in at least 10% of patients of either arm included anemia, asthenia, and rash.

The proportion of patients who experienced AEs that led to treatment discontinuation proved to be lower in the dostarlimab arm vs the pembrolizumab arm, at 29% and 38%, respectively; this was also true with regard to IO-related AEs resulting in discontinuation (17% vs 24%).

Moreover, immune-related AEs occurred in 31% and 39% of patients in the dostarlimab and pembrolizumab arms, respectively. Serious toxicities were observed in 41% of those in the dostarlimab arm vs 48% of those in the pembrolizumab arm, with IO-related serious AEs occurring in 12% and 14% of patients, respectively. Twelve percent of patients in the dostarlimab arm had a fatal AE vs 10% of those in the pembrolizumab arm; fatal IO-related AEs occurred in 2% of patients in both arms.

“Safety profiles were similar and consistent with the primary analysis and other published data,” Peters concluded.

Subsequently, Noemi Reguart, MD, PhD, of the Hospital Clinic in Barcelona, Spain, shared her thoughts on the PERLA study, stating that the data “confirm the efficacy of dostarlimab plus chemotherapy in nonsquamous NSCLC, [and are] overall comparable with other landmark trials.” She stressed that the “subgroup outcomes and numerical trends must be taken with caution,” that it is important to remember that PERLA had a “randomized phase 2 design” and that there is “limited interpretation of subgroups.”

She agreed that the findings do support the examination of dostarlimab as part of novel combinations and mentioned that the phase 2 GALAXIES LUNG-201 study (NCT05565378) is recruiting and will examine the safety, efficacy, pharmacokinetics, and pharmacodynamics of novel IO combinations vs single-agent IO drugs in patient with PD-L1–high, previously untreated, unresectable, locally advanced or metastatic NSCLC.

 Dostarlimab is one of the drugs that will be evaluated in the trial.

Editor’s Note: Dr Peters disclosed that she serves in an advisory role for AbbVie, AiCME, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GlaxoSmithKline, Illumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Medtoday, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Novocure, OncologyEducation, Pharma Mar, Phosplatin Therapeutics, PER, Peerview, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody.

She is also an invited speaker for AiCME, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, ecancer, Eli Lilly, Foundation Medicine, Illumina, Imedex, Medscape, Merck Sharp and Dohme, Mirati, Novartis, PER, Peerview, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, and Takeda. She disclosed that institutional research grants were received from Amgen, AstraZeneca, Beigene, Bristol Myers Squibb, GlaxoSmithKline, Merck Sharp and Dohme, and Roche/Genentech.

Peters S, Granados ALOO, de Marinis F, et al. LBA64 overall survival from a phase II randomised double-blind trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC. 

. 2023;34(suppl 2):S1309. doi:10.1016/j.annonc.2023.10.065

GSK receives FDA accelerated approval for Jemperli (dostarlimab-gxly) for adult patients with mismatch repair-deficient (dMMR) recurrent or advanced solid tumors. News release. GlaxoSmithKline. August 17, 2021. Accessed October 20, 2023. 

https://www.gsk.com/en-gb/media/press-releases/gsk-receives-fda-accelerated-approval-for-jemperli-dostarlimab-gxly-for-adult-patients-with-mismatch-repair-deficient-dmmr-recurrent-or-advanced-solid-tumours/

FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. News release. FDA. February 9, 2023. Accessed October 20, 2023. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-dostarlimab-gxly-dmmr-endometrial-cancer

Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed October 20, 2023. 

https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/

Peters S, Lim SM, Granados ALOO, et al. 57O randomized double-blind phase II trial (PERLA) of dostarlimab (dostar) + chemotherapy (CT) vs pembrolizumab (pembro) + CT in metastatic non-squamous NSCLC: primary results. 

. 2022;16(suppl 1):100162. doi:10.1016/j.iotech.2022.100162

Ortega Granados ALO, Lim SM, Schenker M, et al. Dostarlimab (dos) or pembrolizumab (pem) + chemotherapy (CT) in previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC): patient (Pt) and disease characteristics subgroup analyses from the PERLA trial. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Poster 44P.

A platform study of novel immunotherapy combinations in participants with previously untreated, advanced/metastatic non-small-cell lung cancer. ClinicalTrials.gov. Updated September 7, 2023. Accessed October 20, 2023. 

https://clinicaltrials.gov/study/NCT05565378

Dostarlimab plus chemotherapy elicited a higher objective response rate and showcased a numerical improvement in overall survival compared with pembrolizumab and chemotherapy in patients with treatment-naïve, nonsquamous non–small cell lung cancer.

Contemporary Oncology®: Biomarkers, Pathways, and Targeted Therapies® - January 2024 | Contemporary Oncology®

Rate of End-of-Life Immunotherapy Is on the Rise in Advanced Melanoma, NSCLC, RCC

FDA Grants Fast Track Status to SLS009 for Relapsed/Refractory Acute Myeloid Leukemia

Camidanlumab Tesirine Plus Pembrolizumab Produces Responses But Increases Immune Toxicities in Select Solid Tumors

Dostarlimab Plus Chemo Continues to Demonstrate Strong Clinical Efficacy in Advanced NSCLC