The role of m6A demethylases in lung cancer: diagnostic and therapeutic implications

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small cell lung cancer survival rate with treatment :: Article Creator

Imfinzi Improves Survival Outcomes In Subgroups Of Patients With LS-SCLC

Among patients with limited-stage small cell lung cancer, the benefits of consolidation Imfinzi were seen across a number of subgroups.

Patients with limited-stage (cancer that is only on one side of the chest) small cell lung cancer (LS-SCLC) experienced benefits to both progression-free survival (PFS; the time a patient lives without their disease spreading or worsening) and overall survival (OS; the time a patient lives, regardless of disease status) when treated with consolidation therapy with Imfinzi (durvalumab), research has shown.

Notably, these improvements were seen across subgroups based on factors associated with prior prophylactic cranial irradiation (PCI; radiation therapy to the head) and concurrent chemoradiotherapy (CRT) use, according to findings from the phase 3 ADRIATIC trial presented at the 2024 European Society for Medical Oncology (ESMO) Congress.

Study highlights: Patients with LS-SCLC treated with Imfinzi (durvalumab) experienced significant improvements in both overall survival (OS) and progression-free survival (PFS) compared to placebo. The positive effects of Imfinzi were observed across various subgroups, including those with prior prophylactic cranial irradiation (PCI) and those receiving different types of chemotherapy. The ADRIATIC trial suggests that Imfinzi may be a promising treatment option for patients with LS-SCLC, especially those who have received prior PCI or chemotherapy.

In the ongoing, international ADRIATIC trial, 730 patients with stage 1 to 3 LS-SCLC were randomly assigned to receive Imfinzi monotherapy (264 patients), placebo (266 patients) or Imfinzi plus Imjudo (tremelimumab, 200 patients).

Regarding patients with prior PCI in the Imfinzi (142 patients) and placebo groups (143 patients), the median OS was not reached (meaning more than half of the patients in that group were still alive) and 42.5 months in each group. The 36-month OS rates were 62.1% versus 56.5%, respectively. Among patients who had no prior PCI in the Imfinzi (122 patients) and placebo (123 patients) groups, data showed a median OS of 37.3 months and 24.1 months in each group. After three years, the OS rates were 50.2% with Imfinzi versus 37.3% with placebo.

Among patients with prior PCI in the Imfinzi and placebo groups, the median PFS was 28.2 months versus 13 months, respectively. The 24-month PFS rates in each group were 54.6% and 38.5%. Among those without prior PCI, the median PFS was 9.1 months versus 7.4 months in each group. At two years, the PFS rates were 37.1% versus 29.3% in each group.

Among those who received carboplatin chemotherapy in the Imfinzi (91 patients) and placebo groups (88 patients), the median OS was not reached and 33.4 months in each group. At three years, OS rates were 65.3% versus 46.7% in each group. Regarding patients who received cisplatin chemotherapy in the Imfinzi (173 patients) and placebo groups (178 patients), the median OS was 41.9 months versus 34.3 months in each group. The three-year OS rates were 52.1% and 48.1%, respectively.

Regarding PFS in the carboplatin subgroups, the median PFS was 27.9 months in the Imfinzi group versus 9.2 months in the placebo group. At two years, the PFS rates were 54.8% versus 33.2%, respectively. Among patients who received cisplatin, the median PFS was 11.4 months versus 9.7 months in each group. The two-year PFS rates were 41.8% with Imfinzi and 34.8% with placebo.

Among patients who received 45 grays (Gy) of radiation twice daily over three weeks in the Imfinzi (69 patients) and placebo (79 patients) groups, the median OS was not reached versus 44.8 months in each group. The three-year OS rates were 65.8% versus 57.4% with Imfinzi and placebo, respectively. Regarding those who received radiotherapy at 60 to 66 Gy once daily for six weeks in the Imfinzi (195 patients) and placebo groups (187 patients), the median OS was 41.9 months versus 26.1 months, respectively. At three years, the respective OS rates were 53.1% versus 43.3%.

In the twice-daily radiotherapy groups, the median PFS was 38.7 months with Imfinzi versus 14.3 months in the placebo group. The two-year PFS rates were 60.5% versus 42.9% in each group. Among patients who received once-daily radiotherapy, the median PFS was 11.4 months with Imfinzi versus 7.8 months with placebo. At two years, the PFS rates were 41% versus 30.3% with Imfinzi and placebo, respectively.

"The magnitude of benefit with [Imfinzi] versus placebo was consistent within the PCI and radiotherapy subgroups and varied somewhat between the chemotherapy subgroups. Multivariate analyses showed no significant interactions between [Imfinzi] treatment effect and PCI or concurrent [CRT] subgroups," Suresh Senan, a professor of Clinical Experimental Radiotherapy at the Amsterdam University Medical Centers (VUmc location) in The Netherlands, said in a presentation on these data. "[Imfinzi] demonstrated consistent benefit versus placebo irrespective of prior PCI use and concurrent [CRT] components, further supporting consolidation [Imfinzi] as the new standard of care in [LS-SCLC]."

Of note, 35% and 34% of patients in the Imfinzi and placebo groups, respectively, were 65 years or older in the PCI subgroup compared with 45% and 45% in the non-PCI group. Additionally, most patients in each treatment group received radiotherapy once daily in the PCI (66% versus 62%) and non-PCI groups (83% versus 80%). Additionally, a higher proportion of patients were 65 years and older in the carboplatin (49% versus 59%) subgroup compared with the cisplatin subgroup (34% versus 29%) and the intent-to-treat (ITT) population (39% versus 39%). Data also showed that more patients in the twice-daily radiotherapy group received PCI (70% versus 70%) compared with those in the once-daily radiotherapy subgroup (48% versus 47%) and the ITT population (54% versus 54%).

In terms of safety in the Imfinzi and placebo groups, respectively, the rate of grade 3 (severe)/4 (life-threatening) treatment-emergent side effects were higher in the PCI group (28.4% versus 29.6%) versus non-PCI group (19.8% versus 17.9%), higher in the carboplatin (31.5% versus 31.8%) versus cisplatin group (20.8% versus 20.3%), and higher in the once-daily radiation (26.4% versus 24.7%) versus the twice-daily radiation group (18.8% versus 22.8%). Overall, rates of treatment-emergent side effects leading to treatment discontinuation were comparable across subgroups, and investigators reported no meaningful differences in safety outcomes across the once-daily and twice-daily radiotherapy groups.

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Five-Year Data Shows CheckMate 9LA Regimen Maintains Survival In NSCLC

During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses combination therapy with nivolumab plus ipilimumab and chemotherapy for patients with non–small cell lung cancer in the first article of a 2-part series.

Ticiana Leal, MD

Associate Professor

Department of Hematology and Medical Oncology

Director

Thoracic Medical Oncology Program

Emory University School of Medicine

Winship Cancer Institute

Atlanta, GA

Targeted Oncology: Please discuss the long-term data for nivolumab [Opdivo] plus ipilimumab [Yervoy] in non–small cell lung cancer (NSCLC).

Ticiana Leal, MD: We now have 5-year updates from the CheckMate 9LA trial [NCT03215706], which included patients with stage IV NSCLC with no prior systemic therapy, [and] no actionable driver mutation for performance status.

Patients were stratified by PD-L1 [expression of] less than1% and 1% or greater. About 32% of the patients had a PD-L1 of 15% to 49% and then 24% of the patients had a PD-L1 of 50% or greater. There was 32% of the patients who were squamous histology and 68% that were non-squamous. More than one third of the enrolled participants in this study had PD-L1 expression of less than 1%.

These patients were randomly assigned 1:1 to [receive] nivolumab plus ipilimumab. The dose for ipilimumab is a low dose, 1 mg/kg every 6 weeks with only 2 cycles of chemotherapy vs chemotherapy for 4 cycles with optional maintenance in the pemetrexed group of patients with non-squamous histology.

It is important to note that adding the short course of chemotherapy was to help patients through a challenging phase for when they do not do well with immunotherapy alone in the first 3 months of treatment. You can synergize with immunotherapy to get a more rapid response, minimize toxicity of chemotherapy by reducing the number of cycles of chemotherapy, and then keep patients on maintenance immuno-oncology [IO].

The primary end point [for the trial] was overall survival [OS] and secondary end points were progression-free survival [PFS], overall response rate, efficacy by PD-L1 expression, and safety.

What was the efficacy with the combination in the CheckMate 9LA trial?

The results from CheckMate 9LA, which is [now] an approved regimen, led to improved OS for nivolumab/ipilimumab/chemotherapy vs chemotherapy [alone]. Now we have 5-year OS data that showed a median OS of 15.8 months vs 11.0 months for nivolumab/ipilimumab/chemotherapy vs chemotherapy, respectively, with an HR of 0.73. The 5-year OS rates are 18% vs 11% and this was in the all-comer population.

When examining the data related to PD-L1 expression, what stands out is the excitement surrounding the PD-L1 negative group. Traditionally, this population has experienced shorter survival rates, but they do show positive responses to combinations of chemotherapy with immunotherapy or dual immune-oncology treatments. Comparatively, they are receiving benefit from this combination strategy. We saw a median OS of 9.8 months with chemotherapy vs 17.7 months with combination therapy, and with a HR of 0.63. Then we saw a median OS that is translating now into this durable benefit at the 5-year update: 22% vs 8%, respectively, with the PD-L1 positive group also deriving benefit. It was 18% vs 11% for the PD-L1 negative group, 18% for the all comers [group], 22% for PD-L1 negative [group], and 18% for the PD-L1 positive [group].

Regarding histology with this regimen, a subgroup of patients showed benefit in the squamous and in the non-squamous population with a median OS of 9.1 [months with chemotherapy] vs 14.5 [with the combination], and an HR of 0.63 [in the squamous group]. The 5-year OS rates were 18% vs 7% [in the squamous group], and in the non-squamous group 19% vs 12%, [respectively].

For all patients who were randomly assigned by PD-L1 expression, the overall response rate was also higher in the PD-L1 greater than 1% group of patients. Importantly, the duration of response [DOR] was higher, with a median DOR of 4.3 [months with chemotherapy] vs 17.5 [with the combination]. This was also seen in the DOR in the PD-L1 negative group. When you look at the survival curve at the 5-year update, there was a DOR of 25% for nivolumab/ipilimumab vs 0% for chemotherapy, and then in the PD-L1 positive it is 15% vs 10%, respectively.

Regarding the main end points, we saw improvement in OS across all subgroups, even subgroups who have been known to have worse outcomes, including the PD-L1 negative and the squamous subgroup.

We also see meaningful improvement in the median DOR, and importantly, as a 5-year update. This combination led to long-term, durable survival benefit compared with chemotherapy, and in patients with historically poor outcomes. The other end points were improved PFS and improved treatment-free interval.

How did this patient population do in terms of safety with the nivolumab/ipilimumab regimen?

For toxicities, we know that when you use combination immunotherapy with dual checkpoint inhibition, you see greater incidence of adverse events [AEs], which can have an earlier onset. However, in terms of the time of the toxicity, it is reassuring to see over time and [with] more exposure to ipilimumab, we are not seeing higher rates of [grade] 3 or 4 toxicities.

The toxicities in terms of incidence are rash, which certainly has been the most common, but also pneumonitis, hepatitis, and certainly grade 3/4 toxicities can occur. Some of them can be life threatening and fatal, and this is something we monitor very closely.

One important aspect in the CheckMate 9LA [trial] is that for the patients who come off treatment because of toxicity from the CheckMate 9LA regimen, they did not see a negative impact on survival. In fact, it showed an impressive 5-year OS update for those patients despite having to come off therapy.

For brain metastasis, we have the 3-year follow up, and in the study, they did require treatment of brain metastasis at study entry. At the 3-year follow up, patients with baseline brain metastasis or without brain metastasis had improved outcomes with the addition of nivolumab/ipilimumab/chemotherapy vs chemotherapy alone. In the patients with brain metastasis, the 3-year update showed a survival rate of 16% vs 6%, and for patients without brain metastasis it was 13% vs 5%, respectively.

Select treatment-related AEs [TRAEs] with nivolumab/ipilimumab/chemotherapy were skin and endocrine [related], which is not surprising. The majority were grade 1 and 2, but certainly grade 3 and 4 AEs require frequent monitoring or potential intervention.

We saw greater incidents and earlier onset [with the combination], but when you look at the treatment discontinuation rates, they are similar across the trial [cohorts]. Many of the AEs are commonly related to the chemotherapy backbone, such as, anemia and neutropenia and there are only 2 cycles of chemotherapy.

The percentage of patients that discontinued was 41%, which is a small number of patients, [and] with a total population of 61 patients. These are the patients that discontinued [treatment] due to TRAEs at 48 months, and 35% [of patients] at 60 months, which is reassuring for the patients who had to discontinue all components due to TRAEs. Even after discontinuation, these patients had a median DOR at 14.5 months, and they had ongoing response for a year or greater after discontinuation, which is about half of the patients.

REFERENCE: Reck M, Ciuleanu TE, Schenker M, et al. Five-year outcomes with first-line (1L) nivolumab + ipilimumab + chemotherapy (N + I + C) vs C in patients (pts) with metastatic NSCLC (mNSCLC) in CheckMate 9LA. J Clin Oncol. 2024;42(16_suppl):8560-8560. Doi:10.1200/jco.2024.42.16_suppl.8560

Lung Cancer Treatment

Pulmonary nodules smaller than two centimetres can be cured if detected early

  • Thanks to the minimally invasive approach assisted by Da Vinci robotic surgery, lung cancer procedures can now be performed in a nearly outpatient manner.
  • Smokers over the age of fifty are advised to have a lung CT scan every two years.
  • Immunotherapy has significantly improved survival rates in lung cancer patients, even in cases of advanced disease.

    • As part of European Lung Cancer Week, Dr Joseba Rebollo, an oncology specialist at Quirónsalud Hospital in Torrevieja and Quirónsalud Alicante, reminds us that lung nodules smaller than two centimetres are often curable with surgery if detected early. Therefore, he recommends that smokers over the age of fifty undergo a lung CT scan every two years in order to detect these mostly asymptomatic pulmonary nodules at an early stage.

    Types of lung cancer and their treatment

    Lung cancer is classified into two main types: small cell and non-small cell. Small cell lung cancer, which accounts for 30% of cases, is highly related to smoking and tends to spread quickly. "It can be treated with chemotherapy, immunotherapy, and radiotherapy, achieving cure rates of around 20% in cases of limited disease, which is when the disease can be contained within a radiotherapy field," states Dr Manuel Sureda, an oncologist at Quirónsalud Hospital in Torrevieja and an expert in oncological immunology.

    On the other hand, non-small cell lung cancer is the most common type, and its treatments greatly benefit from genetic tumour studies. "Approximately 50% of these tumours have specific genetic alterations that allow the use of targeted therapies for that specific alteration. Moreover, immunotherapy, which has revolutionised the treatment of this type of lung cancer, has significantly improved survival rates in patients eligible for it, even in cases of advanced disease," Dr Sureda adds.

    Early lung cancer recovery thanks to Da Vinci

    Thanks to the minimally invasive approach assisted by Da Vinci robotic surgery, interventions that once required open surgery and long hospital stays for lung cancer patients can now be performed in a nearly outpatient manner, with shorter hospital stays in any case.

    "In addition," notes Dr José Belda, head of the Thoracic Surgery Department at Quirónsalud Torrevieja and specialist in robotic surgery, "the great precision of Da Vinci surgeries allows us to address both benign and malignant lung conditions, including lobectomies and sublobar resections, all without compromising oncological thoroughness." Other advantages noted by the specialist at Quirónsalud Torrevieja include less blood loss and a reduced risk of postoperative infections.

    For more information about robotic lung cancer surgery, watch this video: https://www.Youtube.Com/watch?V=AZ0EPpsaUE0&t=1s





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