lung cancer

Nivolumab plus Ipilimumab in Advanced Non–Small-Cell Lung Cancer

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Abstract

Background

In an early-phase study involving patients with advanced non–small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.

Methods

In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.

Results

Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P=0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.

Conclusions

First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up.

Discussion

In this phase 3, randomized trial, we found that patients with advanced NSCLC and a PD-L1 expression level of 1% or more who received nivolumab plus ipilimumab had a significantly longer duration of overall survival than those who received chemotherapy as first-line treatment. At 2 years, the rate of ongoing response was 49% with nivolumab plus ipilimumab, as compared with 11% with chemotherapy. The safety of nivolumab plus ipilimumab has been improved in patients with NSCLC with the use of a lower dose and frequency of administration of ipilimumab, as was suggested in the phase 1 dose-finding study.10

In addition, the duration of overall survival was longer with nivolumab plus ipilimumab than with chemotherapy in all the trial patients, including in those with a PD-L1 expression level of less than 1%, a population for whom anti–PD-1 monotherapy has been insufficient. Although the relative benefit of nivolumab plus ipilimumab, as compared with chemotherapy, was numerically greater in patients with a PD-L1 expression level of less than 1% than in those with a PD-L1 expression level of 1% or more, this result was mostly due to variations between the PD-L1 subgroups in both the median duration of survival and in survival rates in the chemotherapy group. The median duration of overall survival and rates of overall survival at 1 year and 2 years with nivolumab plus ipilimumab were nearly identical in these two PD-L1 subgroups. This result is consistent with previous reports involving patients with melanoma and renal-cell carcinoma, which also showed a benefit for nivolumab plus ipilimumab regardless of PD-L1 level.8,9 The precise underpinnings of the diminished dependence on PD-L1 expression with a combination of PD-1 and CTLA-4 inhibition, as compared with anti–PD-1 monotherapy, are unknown. However, we hypothesize that the differential immune effects of CTLA-4 versus PD-1 inhibition17,18 may be particularly critical in PD-L1–negative tumors for recruiting effective antitumor immunity from the peripheral compartment, which is increasingly recognized as an important mechanism of response to immunotherapy.19-21

Combining nivolumab with ipilimumab has proved to be effective in melanoma and renal-cell carcinoma in previous studies,8,9,22 yet a key question before this trial was whether the addition of CTLA-4 inhibition to PD-1 blockade contributes to benefit in patients with NSCLC. Although this trial was not powered to compare the two regimens, our findings show better efficacy with nivolumab plus ipilimumab than with nivolumab monotherapy within the same trial. In particular, we observed higher rates of complete response and a longer median duration of response (a difference of >7 months) in the patients who received nivolumab plus ipilimumab. In addition, among the patients with a PD-L1 expression level of less than 1%, those who received nivolumab plus ipilimumab had longer overall survival and a longer duration of response (a difference of nearly 10 months) than did those who received nivolumab plus chemotherapy, although this analysis was not part of the statistical testing hierarchy.

Biomarkers for predicting an enhanced benefit for combination immunotherapy relative to chemotherapy remain elusive. The design of this trial was informed by phase 1 and 2 single-group studies of nivolumab plus ipilimumab that showed increased response rates in patients with PD-L1–expressing tumors or a high tumor mutational burden in patients with NSCLC.10,23 However, in this large, randomized study, the survival benefit with nivolumab plus ipilimumab over chemotherapy was ultimately similar in the two main PD-L1 subgroups on the basis of a cutoff of 1% of tumor cells. Moreover, based on emerging data related to the tumor mutational burden as a biomarker, CheckMate 227 was amended to add a primary end point of progression-free survival with nivolumab plus ipilimumab versus chemotherapy in patients with a high tumor mutational burden.11 In the current report, although absolute survival with nivolumab plus ipilimumab was greatest in patients with a high tumor mutational burden, a similar relative benefit of nivolumab plus ipilimumab, as compared with chemotherapy, was seen in patients regardless of tumor mutational burden. The unexpected effect of the tumor mutational burden on the overall survival of patients who received chemotherapy may have contributed to these results. Before we initiated this trial, some24-27 but not all28 studies had shown that survival was not affected by tumor mutational burden with chemotherapy treatment. Further understanding of the role of the tumor mutational burden, if any, as a biomarker is warranted before the integration of this factor into clinical practice.

In the primary analysis from this trial, the median duration of overall survival was significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with advanced NSCLC who had a PD-L1 expression level of 1% or more. In secondary analyses, the duration of overall survival was also longer with nivolumab plus ipilimumab than with chemotherapy in patients with a PD-L1 expression of less than 1% and in all the trial patients.

Source:NEJM

Exposure to solid fuel for cooking linked to lung cancer mortality risk

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Exposure to household air pollutants, especially solid fuel, appeared linked to lung cancer death among individuals who have never smoked, according to a study published in American Journal of Respiratory and Critical Care Medicine.

Elvin S. Cheng

“Since lung cancer patients can present with a wide range of clinical symptoms before a proper diagnosis is made, ranging from asymptomatic, some common chest symptoms (eg, cough or hemoptysis) or systemic symptoms (eg, lethargy or weight loss), to atypical presentations often due to metastasis, it remains a challenge for clinicians to make a timelier diagnosis,” Elvin S. Cheng, PhD, MPH, BScMed, MBBS, research scientist from the Daffodil Centre at the University of Sydney, told Healio. “As early detection would allow better prospect of curative treatments, a clinical history of strong exposure to solid fuels could be considered as one of the criteria for early diagnostic or screening intervention (using low-dose CT scan) for lung cancer in the never-smoking populations.”

Cooking fuel
Researchers observed that the most frequently reported household air pollutant was solid fuel use for cooking at 67%. Source: Adobe Stock

In a prospective cohort study, Cheng and colleagues analyzed 323,794 individuals (mean age, 51.5 years; 89% women) who never smoked from the China Kadoorie Biobank between 2004 and 2008, to determine if household air pollution and secondhand tobacco smoking were related to death due to lung cancer.

Researchers used participants’ reports of domestic fuel use — including whether they used gas, coal, wood, electricity or other fuel and how often — to calculate the total time of household air pollution exposure. They assessed secondhand smoke exposure according to the participants’ exposure at home, the workplace or in public.

In order to find associations, researchers used Cox regression and adjusted for confounders.

Of the total cohort, 84.8% reported ever exposure to household air pollutants and 91% reported ever exposure to secondhand smoke, with 78.2% exposed to both and 2.4% to neither.

Researchers additionally observed that the most frequently reported household air pollutant was solid fuel use for cooking at 67%, followed by a “coal-smoky home” at 27%, which researchers defined as visible or smellable air pollution from use of coal burning for heating.

Individuals were studied until Dec. 31, 2016, with a median follow-up of 10.2 years. In that time, 979 individuals from the cohort died of lung cancer.

Although researchers did not find a significant association between household air pollution ever exposure and lung cancer mortality, they did find a significant log-linear positive relationship between cumulative duration of exposure and lung cancer death. Researchers observed that per every 5-year increment of exposure duration, risk for death due to lung cancer increased by 4% (HR = 1.04; 95% CI, 1.01-1.06).

Researchers also found that the highest risk for lung cancer mortality occurred among individuals who experienced 40.1 years to 50 years of exposure to household air pollution (HR = 1.53; 95% CI, 1.13-2.07). The hazard ratio for individuals who experienced more than 50 years of exposure was 1.27 (95% CI, 0.93-1.73).

Peter Ka Hung Chan

The latter hazard ratio was likely lower due to survivor bias, as people who used solid fuels for a long time tended to be elderly but healthy enough to survive without major disease, according to study researcherPeter Ka Hung Chan, DPhil, MSc, BSc, research fellow from the Oxford British Heart Foundation Centre of Research Excellence at the University of Oxford.

“Elderly who were already affected by the exposure would have a lower chance of being included in the study,” Chan told Healio.

When looking at individual factors such as sex, age, area (urban vs. rural), past history of respiratory disease and self-rated poor health in subgroup analysis of household air pollution exposure and lung cancer death, researchers observed no significant differences between the groups, except for a borderline significant difference between “poor” health (HR = 0.97; 95% CI, 0.91-1.04) and “not poor” health (HR = 1.05; 95% CI, 1.02-1.08; P for heterogeneity = .047).

In terms of secondhand tobacco smoking and lung cancer mortality, researchers found no significant association between the two factors, which Chan said is “consistent with the more recent prospective studies (as opposed to earlier retrospective studies).”

“We need more large prospective studies with more accurate assessment of solid fuel use and secondhand smoke exposure, examining not only risk of lung cancer death but also risk of developing newly diagnosed lung cancer,” Chan told Healio. “For example, we could combine questionnaire data with direct measurement of harmful chemicals in solid fuel and secondhand smoke within a prospective study, so we can potentially tease out the specific pollutants that are most relevant to lung cancer risk.”

The populations in most developed countries have seen an increase in the proportion of never-smokers due to stringent tobacco control, according to Cheng.

“However, the etiology of lung cancer among never-smokers is still largely unknown,” Cheng told Healio. “Research to study the major risk factors for lung cancer unrelated to tobacco smoke is greatly warranted to combat the impact of lung cancer as the leading cause of cancer mortality globally.”

Chan also told Healio about how these findings impact clinicians.

“Generally, I’d hope clinicians advise their patients to avoid solid fuel or secondhand smoke — eg, don’t stay too close to a barbecue for too long,” Chan said. “Often patients would get respiratory symptoms well before any other respiratory diseases like lung cancer, and those are warning signals about the potential harm on their lungs.”

This study by Cheng and colleagues adds to the literature indicating that exposure to household air pollutants needs to be studied further and global organizations need to take action on this issue to improve public health, according to an accompanying editorial byOm P. Kurmi, PhD, associate professor in epidemiology and health care research at Coventry University, U.K.

“It is too early to understand the full spectrum of diseases associated with exposure to HAP,” Kurmi wrote. “Some of these large, prospective cohorts have tried to provide better estimates; however, they often have raised some serious public health concerns, which suggests that we need to develop policies for prevention rather than waiting to understand the full spectrum of diseases and mechanisms of how some of the HAP and SHS act. Cardiorespiratory diseases and lung cancer control should be targeted to improve global health. This is important if we are serious about reducing one-third of premature mortality from noncommunicable diseases by 2030, one of the key goals of the United Nations Sustainable Development Goals.”

Lung Cancer Growth Suppressed in Mice Using Japanese Fruit

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Actinidia arguta, also known as Sarunashi, is an edible fruit cultivated in Japan’s Okayama Prefecture. Researchers from Okayama University, led by Sakae Arimoto-Kobayashi, PhD, associate professor in the faculty of pharmaceutical sciences, have demonstrated in a mouse model, that Sarunashi juice (Sar-j) and its key constituent, isoquercetin (isoQ) can help prevent and reduce lung cancer. The team reported the findings in Genes and Environment, in a paper titled, “ Chemopreventive effects and anti-tumorigenic mechanisms of Actinidia arguta, known as sarunashi in Japan toward 4 (methylnitrosoamino)‑​1‑( 3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in a/J mouse.”

In their paper, the team concluded, “Sar-j targets both the initiation and growth/progression steps in carcinogenesis, specifically, via anti-mutagenesis, stimulation repair of alkyl-DNA adducts, suppression of Akt-mediated growth signaling.”

Lung cancer is the leading cause of death in Japan and across the globe, and has one of the lowest five-year survival rates of all cancers. Smoking tobacco and using tobacco-based products is known to heavily contribute to the development of lung cancer. As the authors explained, “The relationship between lung cancer and tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), has been investigated via molecular epidemiological studies … NNK effectively induces lung tumors in mice, rats, and hamsters, and is believed to play a significant role in the development of lung cancer in smokers.”

It is a clinically established fact that the active ingredients in various fruits can minimize the risk of chronic diseases including cancer, the authors suggested. “Epidemiological data support the association between high fruit intake and a low risk of chronic diseases. The bioactive properties of fruits have long been the focus of investigations.”

A. arguta is one of the richest sources of polyphenols and vitamin C, the researchers further stated. They had previously demonstrated the inhibitory effect of Sarunashi juice on mutagenesis, inflammation, and mouse skin tumorigenesis, and identified the components of A. arguta responsible for the anti-mutagenic effects as water-soluble and heat-sensitive phenolic compounds. Subsequently, the researchers proposed the major polyphenolic compound in A. arguta, isoQ as a constituting component with anticarcinogenic potential.

As Arimoto-Kobayashi explained, for their newly reported study, “… we sought to investigate the chemopreventive effects of A. arguta juice and its constituting component isoQ on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice, and identify the possible mechanisms underlying the anti-tumorigenic effects of A. arguta.”

The investigators studied the effects of sar-j and isoQ on lung tumorigenesis in mice injected with the cancer-causing compound NNK. The results were encouraging, and showed that the number of tumor nodules per mouse lung in the cohort that received NNK injections and oral doses of A. arguta juice was significantly lower than in the group injected with NNK only. “Of note, sar-j reduced NNK-induced pulmonary nodules by
25.4% on average and completely inhibited the tumor formation in 5 out of 9 mice,” the investigators stated. Oral administration of isoQ also reduced the number of nodules in mouse lungs.

Next, the team investigated the likely mechanism of action of sar-j. NNK and 1-methyl-3-nitro-1-nitrosoguanidine (MNNG) are known mutagens. The team designed a series of experiments to study the effect of sar-j and isoQ on NNK- and MNNG-mediated mutagenesis using Salmonella typhimurium TA1535, a bacterial strain commonly used for detecting DNA mutations. As expected, the mutagenicity of NNK and MNNG detected using S. typhimurium TA1535 decreased in the presence of sar-j. However, when similar tests were conducted using S. typhimurium YG7108, a strain lacking key enzymes responsible for DNA repair, sar-j was unable to decrease the mutagenic effects of NNK and MNNG. Based on this key observation, the researchers concluded that sar-j seems to mediate its antimutagenic effect by accelerating DNA repair.

Finally, using cell-based experiments, the team also showed that sar-j suppressed the action of Akt, a key protein involved in cancer signaling. Akt and associated protein Pi3k are known to be over-activated in several human cancers.

As Arimoto-Kobayashi, co-author Katsuyuki Kiura, PhD, a professor in the department of allergy and respiratory medicine, Okayama University Hospital, and colleagues, concluded in their paper, “ Sar-j and isoQ reduced NNK-induced lung tumorigenesis. Sar-j targets both the initiation and growth/progression steps during carcinogenesis, specifically via anti-mutagenesis, stimulation of alkyl DNA adduct repair, and suppression of Akt-mediated growth signaling. IsoQ might contribute in part to the biological effects of sar-j via suppression of Akt phosphorylation, but it may not be the main active ingredient.”

The team believes that the constituting components of sar-j, including isoQ, may be attractive candidates for chemoprevention.

Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer

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Abstract

EGFR-TKI targeted therapy is one of the most effective treatments for lung cancer patients harboring EGFR activating mutations. However, inhibition response is easily attenuated by drug resistance, which is mainly due to bypass activation or downstream activation. Herein, we established osimertinib-resistant cells by stepwise dose-escalation in vitro and an osimertinib-resistant patient-derived xenograft model through persistent treatment in vivo. Phosphorylated proteomics identified that MEK1 and AKT1/2 were abnormally activated in resistant cells compared with parental cells. Likewise, EGFR inhibition by osimertinib induced activation of MEK1 and AKT1/2, which weakened osimertinib sensitivity in NSCLC cells. Consequently, this study aimed to identify a novel inhibitor which could suppress resistant cell growth by dual targeting of MEK1 and AKT1/2. Based on computational screening, we identified that costunolide could interact with MEK1 and AKT1/2. Further exploration using in vitro kinase assays validated that costunolide inhibited the kinase activity of MEK1 and AKT1/2, which restrained downstream ERK-RSK2 and GSK3β signal transduction and significantly induced cell apoptosis. Remarkably, the combination of osimertinib and costunolide showed synergistic or additive inhibitory effects on tumor growth in osimertinib-resistant cell lines and PDX model. Hence, this study highlights a potential therapeutic strategy for osimertinib-resistant patients through targeting of MEK1 and AKT1/2 by costunolide.

Background

Based on the Global Cancer Statistics of 2020, lung cancer ranks the second most frequently diagnosed cancer (11.4% of total cases) and is the leading cause of cancer-related death (18% of total cancer deaths)[1]. At present, therapeutic regimens for lung cancer include surgery, chemotherapy, immunotherapy, and targeted therapy[2]. Despite the continuous refinement of treatment options, the 5-year survival rate still remains below 20%[3]. Therefore, further investigation is needed to optimize therapeutic strategies.

Of the diverse therapeutic schemes, targeted therapy showed significant preponderance with lower side effects, stronger pertinence, and more convenience for patients[4]. Epidermal Growth Factor Receptor (EGFR)-focused targeted therapy is one of the most widely used treatments for non-small cell lung cancer (NSCLC) patients that harbor EGFR mutations, with more than 60% object response rate[5]. Osimertinib is a third generation EGFR- tyrosine kinase inhibitor (TKI) that has been approved by the FDA as a second-line treatment of EGFR acquired mutant(T790M) NSCLC patient, a first-line treatment for EGFR activating mutant (L858R or exon 19 deletion) NSCLC patients, and as a postoperative adjuvant therapy approved by National Medical Products Administration in China[6]. However, drug resistance is an inevitable issue. Due to tumor heterogeneity, mechanisms of drug resistance vary among different populations and are mainly caused by acquired EGFR mutations, activation or tetraploidization of bypass signal molecules, or phenotypic transformation[5]. Bypass activation, such as Erb-B2 receptor tyrosine kinase 2 (HER2) activation could abnormally activate the mitogen-activated protein kinase (MAPK) or protein-serine-threonine kinase- glycogen synthase kinase 3 beta (AKT-GSK3β) pathways, leading to increased cell proliferation and drug resistance[7]. Currently, EGFR-TKI combined with other drugs are popular regimens for managing drug resistance.

To further explore strategies that could overcome osimertinib resistance, we established osimertinib-resistant cells through a stepwise dose-escalation method and performed phosphorylated proteomics analysis to identify the aberrant activated pathways in resistant cells. In the present study, we identified that mitogen-activated protein kinase kinase 1 (MEK1) and AKT1/2 were abnormally activated in resistant cells. Knockdown of MEK1 and AKT1/2 inhibited the growth of osimertinib-resistant cells and partially restored osimertinib sensitivity. Moreover, we found that costunolide functions as a dual inhibitor of MEK1 and AKT1/2 that significantly induces cell apoptosis in the osimertinib-resistant cell pool. Combination of costunolide with osimertinib showed synergistic or additive inhibitory effect on osimertinib-resistant cells and a resistant patient-derived xenograft (PDX) model. These data demonstrated that costunolide may be considered as a promising strategy for osimertinib-resistant patients with activated MEK1 and AKT1/2.

Discussion

EGFR targeted therapy has achieved prominent performance for NSCLC treatment; however, acquired drug resistance inevitably limits long-term effects[7]. An appropriate drug resistant model is rather important for preclinical studies. Consequently, we generated osmertinib-resistance in cell lines harboring EFGR mutations through a step-wise dose escalation method, which showed a remarkably higher IC50 of osimertinib compared with parental cells. The lower drug susceptibility was further confirmed by foci formation and cell apoptosis assays in the resistant cells. To establish a more comprehensive resistance mechanism in vivo, we also generated an osimertinib-resistant PDX model through continuous induction using lung cancer tissue harboring an EGFR mutation. These long-term inducted resistant models are effective tools to realistically simulate the process of drug resistance in a laboratory setting.

Due to tumor heterogeneity, the reported mechanisms of osimertinib resistance may vary depending on the terms of different regimens. Acquired EGFR mutation, c-MET amplification, HER2 amplification or mutation, PIK3CA mutation, BRAF and KRAS mutation have been reported as the dominant factors contributing to osimertinib resistance in response to first-line treatment. Acquired EGFR mutation, c-MET amplification, cell cycle gene alteration, HER2 amplification, PIK3CA amplification or mutation have been reported as contributors to osimertinib resistance in response to second-line treatment. Obviously, most of the dysregulated proteins highlighted above can activate PI3K/AKT and MAPK-ERK pathways. As reported, AKT is a key modulator in regulating multi-drug resistance[12]. One mechanism occurs through AKT-triggered activation of NFκB, which can inhibit cell apoptosis and promote tumor growth. Furthermore, activated AKT also modulates cell proliferation through the phosphorylation of GSK3β, which can facilitate resistance by promoting the evasion of EGFR-targeted therapy. Besides, MEK also plays a profound role in regulating drug resistance. The paradoxical activation of MEK stimulates ERK to promote cell proliferation and drug resistance[13]. Most often, activation of MEK or AKT also play crucial roles during the drug resistance process. As reported, combination of gefitinib with MEK1/2 inhibitor synergistically inhibited gefitinib-resistant NSCLC cell growth[14]. Dual blockade of PI3K/AKT and MEK/ERK pathways potentiated gefitinib sensitivity in gefitinib resistant NSCLC and breast cancer cells. Accordingly, AKT/GSK and MEK/ERK are the most frequently dysregulated signaling pathways in acquired drug resistance. However, individually targeting AKT or MEK may facilitate active bypass or downstream signaling which will limit the success of therapies. Thus, the rational to inhibit PI3K/AKT and MAPK pathways simultaneously seems logical to produce a more robust inhibitory response that may prevent further resistance. In present study, we identified that costunolide is an effective inhibitor capable of suppressing the kinase activity of MEK1 and AKT1/2, thereby inducing significant cell apoptosis and inhibition of cell growth. Costunolide is a natural bioactive sesquiterpene lactone with antioxidant, anti-inflammatory and anticancer effects that is extracted from the roots of Saussurea lappa. Recent studies have shown that costunolide can inhibit the proliferation of various cancer cells. In ovarian cancer cells, costunolide promotes the expression of apoptosis signals, such as caspase 3, caspase 8 and caspase 9 by enhancing the production of ROS, thereby inhibiting the growth of cisplatin-resistant cells[15]. In addition, costunolide can inhibit the growth of colorectal cancer and melanoma cells by inhibiting the kinase activity of AKT[10]. Costunolide also showed a similar inhibitory effect compared with the combination of AKTi and MEKi, but at a higher dose. Our data suggested that, costunolide could act as a safe and effective inhibitor to suppress osimertinib-resistant cell growth.

Another critical finding of our study is that costunolide reversed osimertinib resistance in vivo. Due to the stable biological characteristics of patient derived tissues, we used an EGFR mutant PDX model to further evaluate the combination effects of costunolide and osimertinib. Based on the data, costunolide inhibited tumor growth and a significant synergistic effect was observed in the model. Moreover, downstream signaling effectors of MEK and AKT were markedly inhibited in the combination treatment group. Additionally, we did not observe obvious changes in total body weight, ALT or AST level between the different groups, indicating a well-tolerated dose of costunolide plus osimertinib. However, it should be noted that costunolide did not show a growth inhibitory effect in the HLG57-DMSO model. This observation is mainly because p-MEK and p-AKT protein expression levels are lower in the HLG57 relative to other lung tumor tissues. Based on this in vivo study, we concluded that the efficiency of costunolide is dependent on the levels of activated MEK1 and AKT1/2. Additional studies are required to further characterize suitable strategies for managing osimertinib-resistant cell populations deficient in active MEK and AKT.

Conclusion

Our study demonstrated that MEK1 and AKT1/2 are critical for the development of osimertinib resistance. Moreover, costunolide reversed osimertinib resistance through direct targeting of MEK1 and AKT1/2. A synergistic or additive effect was observed with the combination treatment of costunolide and osimertinb both in vitro and in vivo, which might offer a candidate strategy in the clinic.

Abbreviations

EGFR:

epidermal growth factor receptorNSCLC:

non-small cell lung cancerTKI:

tyrosine kinase inhibitorHER2:

Erb-B2 receptor tyrosine kinase 2BRAF:

B-Raf Proto-OncogenePIK3CA:

phosphatidylinositol-4,5-Bisphosphate 3-kinase catalytic subunit alphaAKT:

protein-serine-threonine kinaseGSK3β:

glycogen synthase kinase 3 betaMEK1:

mitogen-activated protein kinase kinase 1PDX:

patient-derived xenograft

source: Molecular Cancer

Herb Can Help Avoid Drug Resistance in Treating Lung Cancer: New Study

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Lung cancer ranks as the No.1 killer of all cancers globally. (Kateryna Kon/Shutterstock)

Lung cancer ranks as the No.1 killer of all cancers globally.

0:002:41

Lung cancer ranks as the No.1 killer of all cancers globally. The main treatment method of Western medicine for non-small cell lung cancer, the most common type of lung cancer, is targeted therapy.

However, a thorny problem with targeted therapy is the development of drug resistance in patients.

Lee Mi-hyun, a pre-Korean medicine professor at Dongshin University in South Korea, announced on Nov. 14 that the extract of a herb “costustoot” could solve the problem of patients’ resistance to the targeted drug Osimertinib.

Lung cancer can be pathologically divided into small lung cancer and non-small cell lung cancer (NSCLC). More than 80 percent of lung cancer patients have non-small cell lung cancer, and about 50 percent of non-small cell lung cancers have mutations in the epidermal growth factor receptor (EGFR).

In treating the gene mutation, if the patient is injected with the targeted anti-cancer agent Osimertinib for a long period of time, the body will develop resistance to the drug, reducing the effectiveness of the treatment.

Osimertinib is a third-generation epidermal growth factor receptor inhibitor (EGFR-tyrosine kinase inhibitors, EGFR-TKIs), a targeted drug.

It was approved by the Food and Drug Administration and the European Union in 2017 for the treatment of non-small cell lung cancer and by the China Food and Drug Administration in 2018 for the treatment of advanced or metastatic non-small cell lung cancer.

Epoch Times Photo
A study shows that the extract of the herb “costustoot” could solve the problem of patients’ resistance to the targeted drug Osimertinib.

Lee found that this resistance is due to the over presence of MEK and AKT proteins that affect cancer cell proliferation and survival.

Based on this, Lee confirmed that costunolide, extracted from the roots of costustoot, was able to target MEK and AKT proteins, effectively blocking cancer appreciation and inducing death in oxitinib-resistant cells and animal models.

From the perspective of Korean medicine (traditional Chinese medicine), costustoot is mainly used to treat thoracic or epigastric abdominal distension, jaundice, lack of appetite, diarrhea, tenesmus, and food stagnation.

Modern pharmacological studies have shown that costustoot has the functions of protecting gastric mucosa, anti-inflammatory, analgesic, regulating gastrointestinal motility, improving gallbladder, inhibiting pathogenic microorganisms, and anti-tumor.

“We are conducting various studies to solve the problem of drug resistance in the treatment of lung cancer by Western medicine, and we will try to make these studies an opportunity for the development of Korean medicine,” Lee said.

Lung Cancer, ‘Silent Killer’, Still Curable If Detected Early

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Adenocarcinoma often begins along the outer parts of the lungs and is the most common type of cancer in people who have never smoked. (Shutterstock)

Adenocarcinoma often begins along the outer parts of the lungs and is the most common type of cancer in people who have never smoked. (Shutterstock)

Lung cancer is often called “the silent killer,” because it can go unnoticed until reaching advanced stages when death is inevitable.

According to National Cancer Institute, 65.8 percent of lung cancer cases were diagnosed at a late stage, surpassing other common cancers like colon cancer, breast cancer, and prostate cancer.

Epoch Times Photo
(Data Source: National Cancer Institute)

“Other cancers give you signs and symptoms,” Raja M. Flores, MD, thoracic surgeon, and Chief of the Division of Thoracic Surgery at Mount Sinai Hospital., told The Epoch Times.

Lung cancer is different.

According to the American Lung Association (ALA), lung cancer is now the leading killer for both men and women in the U.S., and in 1987, it surpassed breast cancer to become the leading cause of cancer deaths in women.

Some Lung Cancer Patients Have Signs While Most Do Not

Many of the symptoms of lung cancer depend on location.

“When you have a tumor that’s closer to your trachea, you may cough up a little blood in early stage,” Flores said. “You may have a wheeze.”

However, the majority of lung cancers don’t occur centrally, near the trachea. Instead, they occur on the outer parts of the lung.

When it’s curable, you don’t know it’s there. Until it has spread.

That’s the biggest thing. “I think everybody tries to ask what signs should I look for—you’re not going to have signs,” said Flores. 

A 2020 Spainish study published in the European Society for Medical Oncology Open analyzed the symptoms of non-small cell lung cancer (NSCLC)—the most common type of lung cancer. The study involved nearly 10,000 patients. The result showed that at stage I, the most common symptom was coughing, however, only 1.8 percent of the patients showed this symptom. As the cancer progressed to stage IV, 17.9 percent of patients showed cough symptoms.

Epoch Times Photo
(Data Source: European Society for Medical Oncology Open)

The other main type of lung cancer is small cell lung cancer. There are treatments for both types that carry relatively high survival rates if the disease is caught early.

Small cell is usually treated with chemotherapy unless it’s in its very early stage, called a small nodule stage one, when it can be removed surgically.

“But they usually do chemotherapy in addition to that and they’ll get a brain scan to make sure there’s nothing that’s spread to the brain,” Flores said.

Non-small cell lung cancer can be split into two categories—adenocarcinoma and squamous cell carcinoma. They make up about 80 to 85 percent of lung cancers.

“These tend to grow and spread more slowly,” said Aimee Strong, DNP, Nurse Practitioner, University of Virginia Thoracic Surgery, Lung Cancer Screening Program

Adenocarcinoma often begins along the outer parts of the lungs and is the most common type of cancer in people who have never smoked. However, squamous cell cancer can begin near the middle of the lungs.  

Small cell lung cancer is almost always related to smoking. “It is fast growing and spreads quickly,”  said Strong.

Smoking Is Not the Only Risk Factor

The degree of risk depends from person to person, and it’s not only smoking but also secondhand smoke that increases the odds of developing lung cancer.

“Let’s say you grew up in a household where mom and dad were smoking like chimneys, especially back in the seventies, you’re at risk,” Flores said.

Flores has had patients who were DJs back when clubs were full of cigarette smoke, who eventually developed lung cancer.

This isn’t the only problem.

“People from 9/11 who were exposed to the asbestos in the pulverized dust down there [are also at risk],” he said. 

Besides, research published in European Respiratory Review, finds that there is a significant genetic component to lung cancer risk.

In China, lung cancer has been increasing over the past decades. 

“There are some people who believe there’s a genetic component to it, [and] that you see [it] in the Chinese population,” said Flores. At the same time, “when you go there you realize that pollution is out of control.”

He noted it’s hard to say whether genetic or environmental factors play a bigger role, but tends to think this is due to the environmental conditions in China.

“I do believe that if you develop cancer, you got it from some external insult that caused the mutation in your system, that’s given you this cancer,” said Flores. “I don’t think it’s just bad luck.”  

Early Detection Is ‘Very Curable’, Screening Is Essential

There are significantly more treatment options for lung cancer than were available even five years ago, and more sophisticated forms of radiation therapy to treat the disease. 

When caught early, especially with the low-dose CAT scan, lung cancers are “very curable,” said Flores. 

This even includes fast growing small cell lung cancers. 

The problem is not that we don’t have a cure. 

“We have a cure, 80 percent of the people with stage I will be cured,” Flores said. “The problem is that we don’t catch it early enough.”

He said the best solution is screening, and people who should be screened for lung cancer include:

  • Current and former smokers
  • People exposed to asbestos or radon gas
  • Those with a family history of lung cancer

People who are at risk can see a lung physician, whether it’s a surgeon, a pulmonologist, a radiologist, or an internal medicine doctor.

Flores observed that many at risk due to previous smoking, now have families.

“They have this guilt that they smoked and how can you fix that guilt?” Flores asked. “Get a screening CAT scan.”

Exposure to solid fuel for cooking linked to lung cancer mortality risk

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Exposure to household air pollutants, especially solid fuel, appeared linked to lung cancer death among individuals who have never smoked, according to a study published in American Journal of Respiratory and Critical Care Medicine.

Elvin S. Cheng

“Since lung cancer patients can present with a wide range of clinical symptoms before a proper diagnosis is made, ranging from asymptomatic, some common chest symptoms (eg, cough or hemoptysis) or systemic symptoms (eg, lethargy or weight loss), to atypical presentations often due to metastasis, it remains a challenge for clinicians to make a timelier diagnosis,” Elvin S. Cheng, PhD, MPH, BScMed, MBBS, research scientist from the Daffodil Centre at the University of Sydney, told Healio. “As early detection would allow better prospect of curative treatments, a clinical history of strong exposure to solid fuels could be considered as one of the criteria for early diagnostic or screening intervention (using low-dose CT scan) for lung cancer in the never-smoking populations.”

Cooking fuel
Researchers observed that the most frequently reported household air pollutant was solid fuel use for cooking at 67%. 

In a prospective cohort study, Cheng and colleagues analyzed 323,794 individuals (mean age, 51.5 years; 89% women) who never smoked from the China Kadoorie Biobank between 2004 and 2008, to determine if household air pollution and secondhand tobacco smoking were related to death due to lung cancer.

Researchers used participants’ reports of domestic fuel use — including whether they used gas, coal, wood, electricity or other fuel and how often — to calculate the total time of household air pollution exposure. They assessed secondhand smoke exposure according to the participants’ exposure at home, the workplace or in public.

In order to find associations, researchers used Cox regression and adjusted for confounders.

Of the total cohort, 84.8% reported ever exposure to household air pollutants and 91% reported ever exposure to secondhand smoke, with 78.2% exposed to both and 2.4% to neither.

Researchers additionally observed that the most frequently reported household air pollutant was solid fuel use for cooking at 67%, followed by a “coal-smoky home” at 27%, which researchers defined as visible or smellable air pollution from use of coal burning for heating.

Individuals were studied until Dec. 31, 2016, with a median follow-up of 10.2 years. In that time, 979 individuals from the cohort died of lung cancer.

Although researchers did not find a significant association between household air pollution ever exposure and lung cancer mortality, they did find a significant log-linear positive relationship between cumulative duration of exposure and lung cancer death. Researchers observed that per every 5-year increment of exposure duration, risk for death due to lung cancer increased by 4% (HR = 1.04; 95% CI, 1.01-1.06).

Researchers also found that the highest risk for lung cancer mortality occurred among individuals who experienced 40.1 years to 50 years of exposure to household air pollution (HR = 1.53; 95% CI, 1.13-2.07). The hazard ratio for individuals who experienced more than 50 years of exposure was 1.27 (95% CI, 0.93-1.73).

Peter Ka Hung Chan

The latter hazard ratio was likely lower due to survivor bias, as people who used solid fuels for a long time tended to be elderly but healthy enough to survive without major disease, according to study researcherPeter Ka Hung Chan, DPhil, MSc, BSc, research fellow from the Oxford British Heart Foundation Centre of Research Excellence at the University of Oxford.

“Elderly who were already affected by the exposure would have a lower chance of being included in the study,” Chan told Healio.

When looking at individual factors such as sex, age, area (urban vs. rural), past history of respiratory disease and self-rated poor health in subgroup analysis of household air pollution exposure and lung cancer death, researchers observed no significant differences between the groups, except for a borderline significant difference between “poor” health (HR = 0.97; 95% CI, 0.91-1.04) and “not poor” health (HR = 1.05; 95% CI, 1.02-1.08; P for heterogeneity = .047).

In terms of secondhand tobacco smoking and lung cancer mortality, researchers found no significant association between the two factors, which Chan said is “consistent with the more recent prospective studies (as opposed to earlier retrospective studies).”

“We need more large prospective studies with more accurate assessment of solid fuel use and secondhand smoke exposure, examining not only risk of lung cancer death but also risk of developing newly diagnosed lung cancer,” Chan told Healio. “For example, we could combine questionnaire data with direct measurement of harmful chemicals in solid fuel and secondhand smoke within a prospective study, so we can potentially tease out the specific pollutants that are most relevant to lung cancer risk.”

The populations in most developed countries have seen an increase in the proportion of never-smokers due to stringent tobacco control, according to Cheng.

“However, the etiology of lung cancer among never-smokers is still largely unknown,” Cheng told Healio. “Research to study the major risk factors for lung cancer unrelated to tobacco smoke is greatly warranted to combat the impact of lung cancer as the leading cause of cancer mortality globally.”

Chan also told Healio about how these findings impact clinicians.

“Generally, I’d hope clinicians advise their patients to avoid solid fuel or secondhand smoke — eg, don’t stay too close to a barbecue for too long,” Chan said. “Often patients would get respiratory symptoms well before any other respiratory diseases like lung cancer, and those are warning signals about the potential harm on their lungs.”

This study by Cheng and colleagues adds to the literature indicating that exposure to household air pollutants needs to be studied further and global organizations need to take action on this issue to improve public health, according to an accompanying editorial byOm P. Kurmi, PhD, associate professor in epidemiology and health care research at Coventry University, U.K.

“It is too early to understand the full spectrum of diseases associated with exposure to HAP,” Kurmi wrote. “Some of these large, prospective cohorts have tried to provide better estimates; however, they often have raised some serious public health concerns, which suggests that we need to develop policies for prevention rather than waiting to understand the full spectrum of diseases and mechanisms of how some of the HAP and SHS act. Cardiorespiratory diseases and lung cancer control should be targeted to improve global health. This is important if we are serious about reducing one-third of premature mortality from noncommunicable diseases by 2030, one of the key goals of the United Nations Sustainable Development Goals.”

Source: http://www.healio.com

Some Smokers Don’t Get Lung Cancer; Genetics Might Explain It

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https://www.medscape.com/viewarticle/974299?src=soc_tw_220522_mscpedt_news_onc_dna&faf=1

Blood Pressure Meds May Prolong Life in Pancreatic Cancer

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Popular blood pressure medications may add years to the lives of patients with pancreatic cancer, a notoriously tough-to-treat cancer with low survival rates, new research suggests.

These drugs, known as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), lower blood pressure by relaxing veins and arteries and allowing the heart to pump blood more easily.

Studies in animals have shown that these medications might slow the growth of pancreatic cancer. Several small studies in people suggest the same thing, but the numbers of patients included were too small to draw firm conclusions.

In the new study, researchers examined data on 3.7 million adults from Italy, and identified 8,158 people diagnosed with pancreatic cancer between 2003 and 2011.

The study, published last month in the journal BMC Cancer, found that the vast majority of these patients (86%) died within about 6 months of their diagnosis.

But patients who took ARBs after their pancreatic cancer diagnosis had a 20% lower risk of dying, compared to similar patients who did not take ARBs.

In a smaller group of patients who had surgery for their cancer, ARB users had a 28% lower risk of dying.

Also, patients with pancreatic cancer who took ACE inhibitors had a 13% lower risk of dying in the first 3 years after diagnosis, but this benefit shrank later.

But “ARBs and ACE inhibitors still need to be considered experimental treatments for pancreatic cancer,” cautions study investigator Scott Keith, PhD, of Thomas Jefferson University in Philadelphia.

Timothy Pawlik, MD, PhD, also cautions not to jump to firm conclusions based on this study.

“While provocative, the data cannot be considered conclusive,” says Pawlik, with the Ohio State University Comprehensive Cancer Center.

“The study is retrospective, which makes it susceptible to selection and treatment bias. In addition, the data were derived from an administrative health care database, which can be notorious for lacking granular clinical data,” he points out.

Pawlik also notes that studies evaluating the benefits of blood pressure medications on cancer risk and outcomes is mixed. Several previous studies, for instance, suggest ACE inhibitors and ARBs may protect against malignancies such as colorectal cancer, while other data suggests a possible link between ACE inhibitors and a higher risk for certain cancers, such as lung cancer.

First Neoadjuvant Immunotherapy OK’d in Lung Cancer

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FDA approves nivolumab plus chemotherapy in resectable, non-small cell lung cancer

FDA APPROVED nivolumab (Opdivo) over a computer rendering of a tumor in the lungs.

The FDA approved nivolumab (Opdivo) in combination with chemotherapy as neoadjuvant treatment for adults with resectable non-small cell lung cancer (NSCLC), Bristol Myers Squibb announced.

According to the company, the approval marks the first for an immunotherapy-based treatment prior to surgery in NSCLC, and was granted for use irrespective of patients’ PD-L1 status based on findings from the CheckMate-816 trial.

“Given the rates of disease recurrence in patients with resectable NSCLC, additional treatment options are needed that can be given before surgery to help improve the chance of successful surgical treatment and support the goal of reducing the risk of cancer returning,” said trial investigator Mark Awad, MD, PhD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, in a release.

“The approval of nivolumab with platinum-doublet chemotherapy marks a turning point in how we treat resectable NSCLC and it enables us to use immunotherapy and chemotherapy as neoadjuvant treatment for patients before surgery,” he added. “Today’s announcement reinforces the need to increase the rates of NSCLC screening and early detection, and for patients to discuss treatment options with their providers.”

In CheckMate-816, 358 patients with resectable NSCLC (tumors ≥4 cm or node positive) were randomized 1:1 to receive either nivolumab combined with platinum-doublet chemotherapy or platinum-doublet chemotherapy alone before surgery.

Investigators found that the immunotherapy-based combination resulted in a statistically significant improvement in event-free survival (EFS), with a 37% reduction in the risk of progression, recurrence, or death (HR 0.63, 95% CI 0.45-0.87, P=0.0052) compared with chemotherapy alone.

The nivolumab group had a median EFS of 31.6 months (95% CI 30.2-not reached) compared with 20.8 months (95% CI 14.0 to 26.7) for patients treated with chemotherapy alone. In addition, a pathologic complete response rate of 24% was observed in the nivolumab group compared with 2.2% with chemotherapy alone (P<0.0001).

A prespecified interim analysis for overall survival resulted in an HR of 0.57 (95% CI 0.38-0.87), which Bristol Myers Squibb noted “did not cross the boundary for statistical significance.” Data from the trial are expected to be presented at the American Association for Cancer Research meeting in April.

As for safety, serious adverse reactions occurred in 30% of patients receiving nivolumab plus chemotherapy. Serious adverse reactions occurring in more than 2% of patients included pneumonia and vomiting, with no fatal adverse reactions occurring in patients who received the combination therapy.

The most common adverse reactions included nausea (38%), constipation (34%), fatigue (26%), decreased appetite (20%), and rash (20%).

Adverse reactions leading to the discontinuation of the combination therapy occurred in 10% of patients, and 30% had at least one treatment withheld for an adverse reaction.