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Highlights of World Conference on Lung Cancer 2020

Dr. Venkata Pradeep Babu Koyyala1, Dr. Venkata Lakshmi Anusha Konakalla 2

1MD, DNB Medical Oncology, Consultant, Medical Oncology, Assam Cancer Care Foundation, Assam

2MD, Radiotherapy, Assistant Professor, Radiotherapy, GSL Medical College, Andhra Pradesh

Email: pradeepbabu.koyyala@gmail.com

World Conference on Lung Cancer (WCLC) is the largest gathering of about 7000 clinicians, researchers, scientists working in the field of thoracic and lung oncology across the globe from over 100 countries, learning and sharing their knowledge and work with each other. This year, this event was organized virtually like all other international conferences amid pandemic and second waves emerging in various countries. As much as the killer is Lung cancer globally, it is one of the few cancers, where personalized oncology is already in vogue and still evolving each year. Such highlights were presented in this Virtual WCLC and we tried to present the highlights of this conference in brief. For convenience, the article is divided into abstracts related to resectable and metastatic non-small-cell lung carcinoma (NSCLC), Small cell lung cancer, Mesothelioma and screening.

Resectable NSCLC:
1. ADAURA[1]

A randomized Phase III trial comparing adjuvant Osimertinib with placebo in patients with surgically resected stage IB to IIIA [American Joint Committee on Cancer (AJCC) 7th edition; pathologic stage] NSCLC with activating Epidermal growth factor receptor (EGFR) mutation either an exon 19 deletion or exon 21 L858R substitution. Osimertinib is a third-generation, irreversible, central nervous system-active, EGFR-tyrosine kinase inhibitor (TKI). A total of 682 patients were randomized 1:1 and treated with osimertinib 80 mg once-daily oral tablets or placebo for three years or until disease recurrence. Adjuvant chemotherapy was allowed.

Primary endpoint: Investigator-assessed DFS in patients with stage II/ IIIA disease.

Health-Related Quality of Life (HR QOL) was assessed with the short form-36 (SF-36) health survey, which consisted of eight domains and two aggregated summary scores, physical (PCS) and mental (MCS) component summary, and was completed by patients at randomization, 12 weeks, 24 weeks and then every 24 weeks until treatment completion or discontinuation.Osimertinib arm demonstrated a significant improvement in DFS vs placebo in patients while maintaining HRQOL.

About 80% of patients in both arms experienced no clinically meaningful deterioration in PCS or MCS while they remained disease-free.SF-36 component scores maintained over time in the Osimertinib arm, with no clinically meaningful differences compared with placebo.

Thoughts:

As much as the excitement ADAURA results have aroused in the oncology community, the eternal debate on ADAURA continues from oncologists’ perspective, regarding which is a better endpoint – Relapse or Death. For the patient, every event is important that can be prevented. Although relapse can occur far before death, relapse can result in a severe decline in performance status and quality of life. A difference of relapse rates 88% vs 32% [HR 0.12] in Osimertinib vs placebo arms is something to think about offering this option to patients. However, one major shortcoming is that the control arm is placebo and we have seen better DFS outcomes even with first-generation TKI like Erlotinib in the Radiant trial.[2] Had there been a comparative arm with first-generation TKI in one of the control arms, we would have got better answers, particularly for developing countries who hardly can afford Osimertinib, which is not possible in practical situations, atleast in Pharma driven trial. As of now, the Osimertinib option should be given to at least stage III patients and large mediastinal lymphadenopathy based on these early data, to prevent relapse in the first two years.

2. ITACA[3]: Tailored vs Standard Adjuvant Chemotherapy in Completely Resected Stage II-IIIA NSCLC

Randomized, multi-national, open-label, active-controlled phase III trial in adults with completely resected (R0) stage II-IIIA NSCLC, ECOG PS 0/1, the interval of 45-60 days between surgery and start of chemotherapy (N = 690)

In the tailored treatment arm, tumours with high Excision Repair Cross Complementation 1 (ERCC1) and high thymidylate synthase (TS) were treated with single-agent paclitaxel (T1; 148 patients), tumours with high ERCC1 and low TS were treated with single-agent pemetrexed (T2; 43 patients), tumours with low ERCC1 and high TS were treated with cisplatin and gemcitabine (T3; 101 patients); and tumours with low ERCC1 and low TS, with cisplatin and pemetrexed (T4; 92 patients). The cut-off value for ERCC1 was 1.42 unitless ratio and was 0.50 unitless ratio for TS.

Primary endpoint: OS

Secondary endpoints: Relapse free survival (RFS), toxicity, treatment compliance and correlation of ERC1 and TS mRNA with protein Grade 3/4 toxicity significantly less likely to occur with tailored vs standard treatment OR: 0.57 (95% CI: 0.42-0.78; P < .001)

With a median follow-up of 28.2 months, there was no significant difference in OS between the tailored treatment arms (96.4 months) and the control arms (83 months) (HR = 0.76; 95% CI: 0.55-1.04).

Thoughts:

Many efforts are ongoing in various cancers, lung cancer in particular, to know “How much is too much and how much is enough?”. ITACA trial tried to answer this question by stratifying patients based on the variable RNA expression of these markers in tumour tissues. There is no benefit in terms of overall survival by customizing chemotherapy versus standard chemotherapy in this trial. However, toxicity is significantly less in tailored arms. This pharmacogenomically driven trial paved the way for personalized therapy to reduce toxicities in the adjuvant setting.

3. LCMC3[4]trial:

The LCMC3 study is a phase II trial of a checkpoint inhibitor in resectable NSCLC stage IB-III in the neoadjuvant and adjuvant setting. A total of 181 patients with no targetable mutations received 1200 mg Atezolizumab three weekly for two cycles followed by surgical resection in 30-50 days. Adjuvant Atezolizumab was continued for 12 more months in patients with response to neoadjuvant therapy.

Primary endpoint: Major pathological response (MPR) defined as < 10% viable cells at the surgery.

Secondary endpoint: MPR associated with Programmed Death Ligand-1(PDL1) status, tumour mutation burden and adverse events.

A total of 159 patients underwent resection and 144 were suitable for efficacy analysis. Resection was performed with low perioperative morbidity and mortality and high complete resection (R0) rate (92%). A total of 30 (21%) patients had MPR and 10 (7%) patients had Pathological Complete Response (pCR). No MPR achieved in known EGFR mutated patients. The higher the tumor mutation burden, the greater is the response.

Of the patients analyzed, 178/181 patients had adverse events and 8% of patients discontinued treatment due to adverse events (AEs). MPR was associated with PDL1. Higher MPR as tumour proportion score (PDL1) increases.

The one-year disease-free survival was 85% for patients with stage I or II disease and 85% for those with stage III disease; overall survival rates were 92% and 95%, respectively. At 1.5 years, DFS and OS was 79% and 77%, and 91% and 87%, respectively.

The trial has met its primary endpoint and MPR is positively associated with PDL1 expression and negatively associated with EGFR /ALK (Anaplastic Lymphoma Kinase)fusion

Thoughts:

LCMC3 is the first largest study of immunotherapy as monotherapy in the neoadjuvant setting- a landmark for the later trials involving checkpoint inhibitors (CPI) in the neoadjuvant and adjuvant setting. It answered the major concern of using these molecules in this setting, showing that CPIs are at least as efficacious as chemotherapy and are safe before surgery, with minimal intra-operative and post-operative complications and a 92% rate of R0 resections. This trial again re-iterated the point that immunotherapy is most effective in the absence of driver mutations, with almost all the complete pathological responses and major pathological responses in mutation-negative patients.

Metastatic NSCLC
Targeted Therapies
1. CodeBreak 100[5]: Registrational Phase-II Trial of Sotorasib in KRAS p.G12C mutated Non-Small Cell Lung Cancer

This trial included 126 patients with locally advanced or metastatic NSCLC and a KRAS G12C mutation who had received three prior lines of treatment. Participants received oral sotorasib, highly selective and irreversible KRAS G12C inhibitor – at a dose of 960 mg/day until disease progression.

After a median follow-up of 12.2 months, the primary endpoint of objective response rate (ORR) was achieved by 37.1% of patients, with complete responses in 2.4% and partial responses in 34.7% and a disease control rate of 80.6%.

The median duration for response was 1.4 months and lasted for a median of 10.0 months. The ORR was 48% for patients with a PD-L1 tumour proportion score of less than 1%, 39% for those with a score of 1–49%, and 22% for those with a score of 50% or higher. The median progression-free survival in the overall cohort was 6.8 months.

Treatment-related adverse events (TRAEs) of grade-3 occurred in 19.8% of patients, with elevations in alanine aminotransferase and aspartate aminotransferase the most frequent events, at 6.3% and 5.6%, respectively. One patient experienced grade-4 pneumonitis and dyspnea. TRAEs resulted in discontinuations in 7.1%, but there were no deaths attributable to TRAEs.

Thoughts:

Kirsten rat sarcoma (KRAS), being one of the most common driver mutations in NSCLC, was only targeted after nearly 40 years of better understanding of the molecular biology of NSCLC and scientific efforts. This phase II trial showed the efficacy of Sotorasib (AMG 510) even in patients with prior two lines of therapies, and so was granted Breakthrough designation by United States Food and Drug Administration (USFDA), while results ongoing phase III trial are eagerly awaited.

2. CHRYSALIS [6] study

This is a Phase I dose-escalation/expansion trial of Amivantamab in Patients with unresectable/metastatic NSCLC with EGFR exon 20 insertion mutations who progressed on prior platinum-based chemotherapy.Amivantamab was given as infusion on day one and eight, two-weekly. Dose-escalation cohorts received 140-1750 mg and dose-expansion cohorts received 1400-1800 mg.

Primary endpoint ORR is 40% and median PFS is 8.3 months and OS of 22.4 months. 2% of patients discontinued treatment due to rash. 12% of patients experienced diarrhea (treatment-related in 10%). Infusion-related reactions primarily occurred during the first infusion (94% of cases) and did not impact the ability to receive subsequent treatments. 47% of patients (15/32) remained on treatment at data cutoff and 63% of patients (20/32) had responses ≥ 6 months. Overall amivantamab has an acceptable safety profile and shows activity in NSCLC harboring EGFR exon20ins

Thoughts:

With more and more emerging targeted therapies in NSCLC, not so uncommon EGFR EXON 20 insertions remained Achilles’ heel in the personalizing therapy, with only chemotherapy as an option and much poorer prognosis compared to other sensitizing EGFR aberrations. This newer fully human Bispecific antibody, acting both on EGFR mutations and mutations and amplifications of C-MET, is the first targeted therapy, acts by a novel mechanism of Trogocytosis and immune-stimulating mechanisms. With an objective response rate of 40% and median DOR of 11 months, this molecule raises hope in the patients with this difficult mutation.

3. DESTINY-Lung 01[7]:Novel ADC Trastuzumab Deruxtecan (T-Dxd) in HER2-Overexpressing Metastatic NSCLC

Multicenter, open-label phase II study in patients with non-squamous NSCLC overexpressing Human epidermal growth factor receptor-2 (HER2) or containing a HER2-activating mutation.
T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and topoisomerase I inhibitor.

Patients were treated with T-DXd 6.4 mg/kg every three weeks.

Primary endpoint: confirmed ORR by Independent Central Review (ICR). Additional endpoints were disease control rate, duration of response (DOR), progression-free survival (PFS), and safety.

Interim Analysis of DESTINY-Lung01 in HER2-Overexpressing Cohort-1

Trastuzumab deruxtecan showed promising early efficacy with ORR: 24.5% and similar ORR between HER2 expression of IHC3+ or 2+; DCR: 69.4% as of the data cutoff on May 30, 2020. Median PFS was 5.4 months. After a median follow-up of 6.1 months, the estimated median duration of response (DoR) was six months and the median overall survival (OS) was 11.3 months. The most common grade three or greater (>15%) Treatment Emergent Adverse Events (TEAE) was decreased neutrophil count (20.4%). There were eight cases of treatment-related interstitial lung disease, including two grade-1, three grade-2, and three deaths (grade-5).

The median treatment duration was 18 weeks (range, 3.0-57.1 weeks). As of the data cutoff on May 30, 2020, 22% of patients with HER2 overexpressing metastatic NSCLC remained on treatment.

Thoughts:

HER2 mutations became one of the commonly tested oncogenic drivers in the diagnostic workup of Metastatic NSCLC. However, with the disappointment of Trastuzumab in these subsets, testing of antibody-drug conjugates like TDM1 and Trastuzumab- Deruxtecan are underway. This trial with the latter drug is promising in this rare HER-2 mutant subset (2% of all NSCLC), with an ORR of 62% and median PFS of 14 months. The most prominent adverse events reported were neutropenia and interstitial lung disease.

Immunotherapy
1. KEYNOTE 598[8]:Pembrolizumab Plus Ipilimumab vs Pembrolizumab Plus Placebo as 1L Therapy for Metastatic NSCLC of PD-L1 TPS ≥50%

The randomized, double-blind phase III trial enrolled 568 metastatic non–small cell lung cancer (NSCLC) patients with high–PD-L1 to the combination of pembrolizumab at 200 mg every three weeks for up to 35 cycles plus ipilimumab at 1 mg/kg every six weeks or pembrolizumab and placebo as first-line therapy.

Primary endpoints: overall survival and progression-free survival in the intent-to-treat population.

Median overall survival was 21.4 months with ipilimumab plus pembrolizumab compared with 21.9 months with pembrolizumab alone (hazard ratio [HR] = 1.08; 95% confidence interval [CI] = 0.85–1.37; P = .74), Median progression-free survival was 8.2 months vs 8.4 months (HR = 1.06; 95% CI = 0.86–1.30; P = .72), and 45% of patients in each group responded, for a median duration of approximately 17 months.

Patients on the two drugs also had higher rates of treatment discontinuation due to adverse events This trial found no value in adding ipilimumab to pembrolizumab for the first-line treatment of metastatic NSCLC.

Thoughts:

Pembrolizumab still stands effective as monotherapy in indicated settings and adding one more checkpoint inhibitor doesn’t seem to add benefit, but toxicity.

Mesothelioma:
1. CONFIRM[9]: Nivolumab vs Placebo in Relapsed Malignant Mesothelioma(MM)

A total of 332 adult patients with previously treated, unresectable, histologically confirmed MM (pleural or peritoneal) mesothelioma and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned to nivolumab (n = 221) or placebo (n = 111)until Progressive Disease (PD), unacceptable toxicity, withdrawal, or 12 months

Participants were stratified by epithelioid vs non-epithelioid histology.

Co-primary endpoints: investigator-assessed PFS and OS

Secondary endpoints: best overall response and safety.

OS showed significantly longer survival with nivolumab median, 9.2 vs 6.6 months; HR, 0.72; 95% CI: 0.55-0.94; P=0.02).

Investigator-assessed PFS was longer for nivolumab vs placebo (3.0 vs 1.8 months; HR 0.61; 95% CI, 0.48-0.77; P < 0.001).

There was no statistically significant association between PD-L1 TPS > 1% (in 34% of included patients) and survival.

Grade 3-4 treatment-related adverse events were reported in 19% of patients who received nivolumab and in 6.3% who received placebo. Treatment discontinuation due to toxicity occurred in 13.1% (nivolumab) versus 2.7% (placebo).

Thoughts:

Phase III CONFIRM is an investigator-led trial in relapsed Mesothelioma, supported by cancer research UK. This is a ray of hope within patients with literally no options, who progressed on standard Pemetrexed- Platinum chemotherapy. Nivolumab is the only drug till now to show a survival benefit in this setting.

References
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  • Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
    Editor-in-Chief - Dr. Padmaj Kulkarni