Challenges and Unmet Needs in Squamous Non-Small Cell Lung Cancer

Written by Dr. Irfan A. Mirza
This article is sponsored and developed by Boehringer Ingelheim Pharmaceuticals

Significant strides have been made in the last decade for systemic treatment options for stage IV non-small cell lung cancer (NSCLC), including those tailored for squamous and non-squamous histology.1,2 While non-squamous NSCLC has benefited from advances such as the introduction of personalized, genotyped-directed therapies, and immunotherapy drugs, the treatment options for squamous cell NSCLC remain limited.1,2

Historically, the NCCN guidelines recommended the use of platinum-based chemotherapy in the first line setting, followed by immunotherapy in the second-line.3 However, following the results of the KEYNOTE-407 study, immunotherapy together with platinum doublet chemotherapy is now recommended in the first-line setting.4,5 This leaves an unmet need for patients with metastatic squamous NSCLC who have progressed, where most treatments consist of chemotherapy.2,6

Afatinib is an oral, non-chemotherapy option for patients with metastatic squamous NSCLC who have progressed on platinum-based chemotherapy.7 Afatinib is an irreversible second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor that selectively inhibits homo- and hetero-dimers of the ErbB receptor family (EGFR, ErbB2, and ErbB4).7

LUX-Lung 8 was a multicenter, open label, phase 3, randomized, controlled trial across 23 countries that enrolled 795 patients with advanced (stage III B and stage IV) squamous NSCLC, progressing after at least 4 cycles of platinum-based chemotherapy.8 Patients were randomized (1:1) to either afatinib 40 mg daily or erlotinib 150 mg daily until disease progression.8 The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC), using RECIST v1.1 and secondary endpoints included overall survival (OS) and objective response rates as assessed by an IRC.8

In LUX-Lung 8, significant improvement in PFS and overall survival was observed for afatinib compared with erlotinib.8 The median PFS was reported as 2.4 months with afatinib and 1.9 months with erlotinib [HR, 0.82 (95% CI 0.68-0.99)] (Figure 1).8
LUX-Lung-8-Median-Progression-Free-Survival
After a median follow up of 18.4 months, median OS was 7.9 months in the afatinib group and 6.8 months in the erlotinib group [HR 0.81 (95% CI 0.69-0.95), p = 0.0077].8 Estimates of OS among patients treated with afatinib were 64% at 6 months, 36% at 1 year, and 22% at 18 months (Figure 2).8

LUX-Lung-8-K-M-Estimates-of-Survival
More than half (51%) of patients treated with afatinib were able to achieve disease control (defined as complete response, partial response, stable disease, or non-complete response and non-progressive disease) compared with 40% with erlotinib.8 Excluding patients with non-complete response and non-progressive disease, disease control with afatinib was 37%, vs 29% with erlotinib, in a post hoc analysis.8 The median duration of objective response was 7.3 months with afatinib and 3.7 months with erlotinib.8

The most common adverse effects associated with afatinib were diarrhea, rash/acneiform dermatitis, stomatitis, decreased appetite, nausea, vomiting, paronychia, and pruritus.8,9 Twenty percent of patients discontinued afatinib treatment due to adverse reactions, with the most frequent adverse reactions leading to discontinuation being diarrhea in 4.1% of patients and rash/acne in 2.6%.9 Serious adverse reactions occurred in 44% of patients, with pneumonia (6.6%), diarrhea (4.6%), dehydration, and dyspnea (3.1% each) being the most frequent.9 Fatal adverse reactions in afatinib-treated patients included interstitial lung disease, pneumonia, respiratory failure, acute renal failure, and general physical health deterioration, all occurring in less than 1% of patients.9

Adverse Reactions (ARs) Reported in ≥10% of GILOTRIF-Treated Patients in LUX-Lung 89*:
GILOTRIF (n=392), erlotinib (n=395) – All Grades & Grades 3-4 ARs
Gastrointestinal Disorders
Diarrhea – GILOTRIF all grades: 75%; grades 3-4: 11%; erlotinib all grades: 41%, grades 3-4: 3%
Stomatitis – GILOTRIF all grades: 30%; grades 3-4: 4%; erlotinib all grades: 11%, grades 3-4: 1%
Nausea – GILOTRIF all grades: 21%; grades 3-4: 2%; erlotinib all grades: 16%, grades 3-4: 1%
Vomiting – GILOTRIF all grades: 13%; grades 3-4: 1%; erlotinib all grades: 10%, grades 3-4: 1%
Skin and Subcutaneous tissue disorders
Rash/acneform dermatitis – GILOTRIF all grades: 70%; grades 3-4: 7%; erlotinib all grades: 70%, grades 3-4: 11%
Pruritus – GILOTRIF all grades: 10%; grades 3-4: 0%; erlotinib all grades: 13%, grades 3-4: 0%
Metabolism and nutrition disorders
Decreased appetite – GILOTRIF all grades: 25%; grades 3-4: 3%; erlotinib all grades: 13%, grades 3-4: 0%
Infections
Paronychia§ – GILOTRIF all grades: 11%; grades 3-4: 1%; erlotinib all grades: 5%, grades 3-4: 0%
*NCI CTCAE v 3.0
Includes stomatitis, aphthous stomatitis, mucosal inflammation, mouth ulceration, oral mucosa erosion, mucosal erosion, mucosal ulceration
Includes acne, dermatitis, acneiform dermatitis, eczema, erythema, exfoliative rash, folliculitis, rash, rash generalized, rash macular, rash maculo-papular,

rash pruritic, rash pustular, skin exfoliation, skin fissures, skin lesion, skin reaction, skin toxicity, skin ulcer
§ Includes paronychia, nail infection, nail bed infection

In summary, LUX-Lung 8 met its primary and secondary endpoints and remains the largest prospective head-to-head trial that compares two TKIs for second-line treatment of patients with squamous NSCLC.8 Future studies should focus on understanding the clinical profile of afatinib within the context of other commonly-used treatment modalities, such as chemotherapy. In a disease setting with few treatment options, and a pandemic which can make delivery of infusions challenging, afatinib offers patients with metastatic squamous NSCLC an opportunity to receive a chemotherapy-free, oral option once they have progressed following treatment with standard, platinum based, first line treatment.8,9

INDICATIONS AND USAGE

GILOTRIF is indicated for the treatment of patients with metastatic squamous NSCLC progressing after platinum-based chemotherapy.

IMPORTANT SAFETY INFORMATION FOR GILOTRIF® (afatinib) TABLETS
WARNINGS AND PRECAUTIONS

Diarrhea
• GILOTRIF can cause diarrhea which may be severe and can result in dehydration with or without renal impairment. In clinical studies, some of these cases were fatal.
• For patients who develop Grade 2 diarrhea lasting more than 48 hours or Grade 3 or greater diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less, and then resume at a reduced dose.
• Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal until loose stools cease for 12 hours.

Bullous and Exfoliative Skin Disorders
• GILOTRIF can result in cutaneous reactions consisting of rash, erythema, and acneiform rash. In addition, palmar-plantar erythrodysesthesia syndrome was observed in clinical trials in patients taking GILOTRIF.
• Discontinue GILOTRIF in patients who develop life-threatening bullous, blistering, or exfoliating skin lesions. For patients who develop Grade 2 cutaneous adverse reactions lasting more than 7 days, intolerable Grade 2, or Grade 3 cutaneous reactions, withhold GILOTRIF. When the adverse reaction resolves to Grade 1 or less, resume GILOTRIF with appropriate dose reduction.
• Postmarketing cases of toxic epidermal necrolysis (TEN) and Stevens Johnson syndrome (SJS) have been reported in patients receiving GILOTRIF. Discontinue GILOTRIF if TEN or SJS is suspected.

Interstitial Lung Disease
• Interstitial Lung Disease (ILD) or ILD-like adverse reactions (e.g., lung infiltration, pneumonitis, acute respiratory distress syndrome, or alveolitis allergic) occurred in patients receiving GILOTRIF in clinical trials. In some cases, ILD was fatal. The incidence of ILD appeared to be higher in Asian patients as compared to white patients.
• Withhold GILOTRIF during evaluation of patients with suspected ILD, and discontinue GILOTRIF in patients with confirmed ILD.

Hepatic Toxicity
• Hepatic toxicity as evidenced by liver function tests abnormalities has been observed in patients taking GILOTRIF. In 4257 patients who received GILOTRIF across clinical trials, 9.7% had liver test abnormalities, of which 0.2% were fatal.
• Obtain periodic liver testing in patients during treatment with GILOTRIF. Withhold GILOTRIF in patients who develop worsening of liver function. Discontinue treatment in patients who develop severe hepatic impairment while taking GILOTRIF.

Gastrointestinal Perforation
• Gastrointestinal (GI) perforation, including fatal cases, has occurred with GILOTRIF. GI perforation has been reported in 0.2% of patients treated with GILOTRIF among 3213 patients across 17 randomized controlled clinical trials.
• Patients receiving concomitant corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or anti-angiogenic agents, or patients with increasing age or who have an underlying history of GI ulceration, underlying diverticular disease, or bowel metastases may be at an increased risk of perforation.
• Permanently discontinue GILOTRIF in patients who develop GI perforation.

Keratitis
• Keratitis has been reported in patients taking GILOTRIF.
• Withhold GILOTRIF during evaluation of patients with suspected keratitis. If diagnosis of ulcerative keratitis is confirmed, interrupt or discontinue GILOTRIF. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered. GILOTRIF should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Embryo-Fetal Toxicity
• GILOTRIF can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
• Advise females of reproductive potential to use effective contraception during treatment, and for at least 2 weeks after the last dose of GILOTRIF. Advise female patients to contact their healthcare provider with a known or suspected pregnancy.

ADVERSE REACTIONS

Adverse Reactions observed in clinical trials were as follows:

Previously Treated, Metastatic Squamous NSCLC
• In GILOTRIF-treated patients (n=392) the most common adverse reactions (≥20% all grades & vs erlotinib-treated patients (n=395)) were diarrhea (75% vs 41%), rash/acneiform dermatitis (70% vs 70%), stomatitis (30% vs 11%), decreased appetite (25% vs 26%), and nausea (21% vs 16%).
• Serious adverse reactions were reported in 44% of patients treated with GILOTRIF. The most frequent serious adverse reactions reported in patients treated with GILOTRIF were pneumonia (6.6%), diarrhea (4.6%), and dehydration and dyspnea (3.1% each). Fatal adverse reactions in GILOTRIF-treated patients included ILD (0.5%), pneumonia (0.3%), respiratory failure (0.3%), acute renal failure (0.3%), and general physical health deterioration (0.3%).

DRUG INTERACTIONS

Effect of P-glycoprotein (P-gp) Inhibitors and Inducers
• Concomitant use of P-gp inhibitors (including but not limited to ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, and amiodarone) with GILOTRIF can increase exposure to afatinib.
• Concomitant use of P-gp inducers (including but not limited to rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort) with GILOTRIF can decrease exposure to afatinib.

USE IN SPECIFIC POPULATIONS

Lactation
• Because of the potential for serious adverse reactions in breastfed infants from GILOTRIF, advise women not to breastfeed during treatment with GILOTRIF and for 2 weeks after the final dose.

Females and Males of Reproductive Potential
• GILOTRIF may reduce fertility in females and males of reproductive potential. It is not known if the effects on fertility are reversible.

Renal Impairment
• Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] 15 to 29 mL/min/1.73 m2) have a higher exposure to afatinib than patients with normal renal function. Administer GILOTRIF at a starting dose of 30 mg once daily in patients with severe renal impairment. GILOTRIF has not been studied in patients with eGFR <15 mL/min/1.73 m2 or who are on dialysis.

Hepatic Impairment
• GILOTRIF has not been studied in patients with severe (Child Pugh C) hepatic impairment. Closely monitor patients with severe hepatic impairment and adjust GILOTRIF dose if not tolerated.

REFERENCES
1. Baxevanos P, Mountzios G. Novel chemotherapy regimens for advanced lung cancer: have we reached a plateau? Ann Transl Med. 2018;6(8):139.
2. Santos ES, Hart L. Advanced Squamous Cell Carcinoma of the Lung: Current Treatment Approaches and the Role of Afatinib. Onco Targets Ther. 2020 Sep 22;13:9305-9321.
3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.1.2016. ©National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
4. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous NSCLC. N Engl J Med. 2018;379: 2040-2051; DOI:10.1056/NEJMoa1810865
5. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer. V.8.2020. ©National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed November 2, 2020. To view the most recent and complete version of the guidelines, go online to NCCN.org.
6. Paik PK, et al. New treatment options in advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book. 2019;39:e198-e206.
7. Hirsh V. Next-Generation Covalent Irreversible Kinase Inhibitors in NSCLC: Focus on Afatinib. BioDrugs. 2015;29(3):167 183.
8. Soria JC, et al. Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol. 2015;16(8):897 907.
9. GILOTRIF [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.

Please review the Full Prescribing Information and Patient Information at www.gilotrifhcp.com

Adjuvant TAGRISSO® in Resected EGFR-Mutated Non-Small Cell Lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.

TAGRISSO® (Osimertinib) is a highly selective third-generation Epidermal Growth Factor Receptor (EGFR) TKI presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, TAGRISSO® has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases. Among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with TAGRISSO® significantly improved median Overall Survival, compared with TARCEVA® and IRESSA®, and should therefore be considered the preferred regimen.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

ADAURA is a global, double-blind, randomized Phase III study, which assessed the efficacy and safety of TAGRISSO® versus placebo in patients with Stage IB–IIIA EGFR mutated NSCLC, after complete tumor resection and adjuvant chemotherapy, when indicated. In this study, 682 patients with completely resected Stage IB, II, IIIA NSCLC, with or without postoperative adjuvant chemotherapy, were randomly assigned 1:1 to receive either TAGRISSO® 80 mg orally once daily (N=339) or placebo (N=343) once daily, for up to 3 years. Eligible patients had an ECOG Performance Status of 0 or 1, with confirmed EGFR mutations (Exon 19del or L858R). Treatment groups were well balanced and patients were stratified by Stage (IB/II/IIIA), mutation type (Exon 19del/L858R), and race (Asian/non-Asian).
Most patients with Stage II to IIIA disease (76%) and approximately a quarter of the patients with Stage IB disease (26%) received adjuvant platinum-based chemotherapy. The Primary endpoint was Disease Free Survival (DFS) in Stage II–IIIA patients. Secondary endpoints included DFS in the overall population of patients with Stage IB to IIIA disease, Overall Survival (OS) and safety. Following Independent Data Monitoring Committee recommendation, the trial was unblinded early, due to efficacy. The authors reported the results from the unplanned interim analysis.

It was noted that in the patients with Stage II/IIIA disease, the DFS had not been reached with TAGRISSO® versus 19.6 months with placebo (HR=0.17; P<0.001). This was equal to an 83% reduction in the risk of recurrence or death, indicating a significantly longer DFS among patients in the TAGRISSO® group, compared to those in the placebo group. The 2-year DFS rate in this patient group with TAGRISSO® was 90% versus 44% with placebo.

In the overall population, which included Stage IB to IIIA disease, the median DFS was not reached with TAGRISSO® versus 27.5 months with placebo (HR=0.20; P<0.001). This Hazard Ratio equaled an 80% reduction in the risk of disease recurrence or death among patients in the TAGRISSO® group compared to those in the placebo group. The 2-year DFS rate in the overall population was 89% with TAGRISSO® versus 52% with placebo.

The benefit favoring TAGRISSO® with respect to DFS was observed consistently across all predefined subgroups including disease Stages IB, II, and IIIA and use or nonuse of adjuvant chemotherapy. The benefit with TAGRISSO® was greater at more advanced stages of disease (among patients with Stage IIIA disease, the overall HR was 0.12, among those with Stage II disease, the HR was 0.17, and among those with Stage IB disease, the HR was 0.39). At 2 years, 98% of the patients in the TAGRISSO® group and 85% of the patients in the placebo group were alive without CNS-related disease (HR for CNS disease recurrence or death=0.18). This indicated an 82% reduction in the risk of CNS disease recurrence or death with TAGRISSO®. The Overall Survival data were immature at the time of this interim analysis. Adverse Events were consistent with the known safety profile of TAGRISSO®.

The authors concluded that adjuvant TAGRISSO® is the first targeted agent in a global randomized trial, to show a statistically significant and clinically meaningful improvement in Disease Free Survival, among patients with Stage IB/II/IIIA EGFR mutation-positive NSCLC, and provides an effective new treatment strategy for this patient group.

Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. Wu Y-L, Tsuboi M, He J, et al. for the ADAURA Investigators. N Engl J Med 2020; 383:1711-1723.

GILOTRIF® in EGFR Positive Non Small Cell Lung Cancer Harboring Uncommon Mutations

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Approximately 10-15% of Caucasian patients, and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations. The majority of patients have classical EGFR mutations which are either Exon 19 deletions or L858R substitution mutation in Exon 21, and for those patients with EGFR mutation-positive NSCLC, EGFR-TKIs are the first choice of treatment. However, around 5-20% of tumors harbor Major uncommon mutations, such as G719X, L861Q and S768I, as well as other more rare mutations, and these uncommon EGFR mutations show heterogeneity in their response to EGFR-TKIs. Compared with other EGFR mutations, G719X, L861Q and S768I substitution mutations are associated with a poorer prognosis and have limited treatment options.

GILOTRIF® (Afatinib) is an oral, irreversible blocker of the ErbB family which includes EGFR (ErbB1), HER2 (ErbB2), ErbB3 and ErbB4. GILOTRIF® demonstrated clinical activity against Major uncommon EGFR mutations such as G719X, L861Q and S768I which is more often seen in Asian patients, and is FDA approved in this setting. There are however, few clinical data regarding the efficacy of the available EGFR-TKIs against other uncommon EGFR mutations, and there is no knowledge of ethnic differences in prevalence and outcomes.

This study investigated the efficacy of GILOTRIF® in EGFR mutation positive NSCLC among Asian and non-Asian patients with uncommon mutations. Uncommon mutations were classed into five categoriesMajor uncommon (G719X, L861Q and S768I), Compound, Exon 20 insertions, T790M Mutation, and Other. Patients may have more than uncommon mutation.

The researchers conducted a pooled analysis from randomized clinical trials and Real-World Studies and examined the activity of GILOTRIF® in Asian and non-Asian patients with NSCLC and uncommon EGFR mutations, who had not received prior treatment with EGFR TKIs. All identified patients included in this study had outcome data such as Time to Treatment failure (TTF) or Objective Response Rate (ORR) available. The total number of evaluable patients were 298 (N=298), of whom 60% were Asian (N=178) and 40% were Non-Asian (N=120). The median patient age ranged from 60-66 years across the different mutation groups. Approximately 40% of patients had Major uncommon mutations such as G719X, L861Q and S768I, 24% had Exon 20 insertions, 12% had T790M mutations and 24% had Compound and Other mutations. When broken by ethnicity, among Asian patients, approximately 62% had Major uncommon mutations, 14% had Compound mutations and 16% had Exon 20 insertions. Among non-Asian patients, 35% had Major uncommon mutations, approximately 7% had Compound mutations and 39% had Exon 20 insertions. The Endpoints included Objective Response Rate (ORR), Duration of Response (DoR) and Time to Treatment Failure (TTF), and outcomes were compared in Asian and non-Asian EGFR-TKI-naïve patients.

This analysis showed that the efficacy of GILOTRIF® was unaffected by ethnicity, and the Overall Response Rate (ORR) among tumors with Major uncommon mutations was 66% in Asian patients versus 59% in non-Asian patients, and the median Duration of Response (DoR) was 14.7 months compared with 15.9 months respectively. Among those with Major uncommon mutations, the ORR in tumors harboring G719X mutation was 62% in Asian patients and 65% in non-Asian patients. Among those tumors with a L861Q mutation, the ORRs were 60% versus 50%, respectively and among those with a S768I mutation, the ORRs were 80% versus 25%, respectively. The Overall Response Rate (ORR) among tumors with Compound mutations was 81% in Asian patients versus 100% in non-Asian patients and the median Duration of Response (DoR) was 11.5 months compared with 18.6 months respectively. Among patients who harbored Exon 20 insertions, the ORR with GILOTRIF® in Asian patients was 21% versus 23% in non-Asian patients, with a Duration of Response of 11 months and 10.7 months, respectively.

It was concluded that GILOTRIF® shows clinical activity against uncommon EGFR mutations in both Asian and non-Asian patients, with durable clinical responses, and should be considered as a first-line treatment option in Asian and non-Asian patients with Major uncommon (G719X, L861Q and S768I) and Compound EGFR mutations.

Afatinib in Asian and non-Asian patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC harboring major uncommon mutations. Yang JC-H, Schuler M, Popat S, et al. Presented at: 2020 IASLC North America Conference on Lung Cancer; October 16-17, 2020; Virtual. Abstract MO01.36.

GAVRETO® (Pralsetinib)

The FDA on September 4, 2020 granted accelerated approval to GAVRETO® for adult patients with metastatic RET fusion-positive Non-Small Cell Lung Cancer (NSCLC), as detected by an FDA approved test. GAVRETO® is a product of Blueprint Medicines Corporation.

KRAS G12C Inhibition with Sotorasib in Advanced Solid Tumors

SUMMARY: The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. The KRAS protein is a GTPase, and converts GTP into GDP. To transmit signals, the KRAS protein must be turned on, by binding to a molecule of GTP. When GTP is converted to GDP, the KRAS protein is turned off or inactivated, and when the KRAS protein is bound to GDP, it does not relay signals to the cell nucleus. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous.
KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of Colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, resulting in a predominantly GTP-bound KRAS oncoprotein, amplifying signaling pathways that lead to oncogenesis.Inhibiting-KRAS-G12C

Sotorasib (AMG 510) is a small molecule that specifically and irreversibly inhibits KRAS-G12C and traps KRAS-G12C in the inactive GDP-bound state. Preclinical studies in animal models showed that Sotorasib inhibited nearly all detectable phosphorylation of Extracellular signal-Regulated Kinase (ERK), a key downstream effector of KRAS, leading to durable complete regression of KRAS-G12C tumors.

The authors conducted a multicenter, open label Phase I trial of Sotorasib, in patients with advanced solid tumors harboring the KRAS-G12C mutation. This trial consisted of dose escalation and expansion cohorts and included a total of 129 patients, of whom 59 patients had NSCLC, 42 had Colorectal cancer, and 28 patients had other tumor types (Appendiceal, Endometrial, Pancreatic cancers and Melanoma). Sotorasib was administered orally once daily and each treatment cycle was 21 days. The planned dose levels for the escalation cohorts were 180, 360, 720, and 960 mg. Treatment was continued until disease progression or unacceptable toxicity. The median patient age was 62 years and most of the enrolled patients were heavily pretreated and had received a median of 3 previous lines of anticancer therapy for metastatic disease. Among the NSCLC patient cohort, approximately 90% of patients were current or former smokers and had received anti- Programmed cell Death protein-1 (PD-1) or PD-Ligand 1 (PD-L1) therapies. All patients had received previous platinum-based chemotherapy. The Primary endpoint was safety, including the incidence of dose-limiting toxicities and key Secondary end points were pharmacokinetics and Objective Response Rates. The Sotorasib dose of 960 mg daily was identified as the dose for the expansion cohort. The median follow up was 11.7 months and the median duration of treatment was 3.9 months, with 57% of patients having received treatment for 3 months or more, and 29% of patients, for 6 months or more.

Among those patients with NSCLC, 32.2% of the patients had a confirmed Objective Response (Complete or Partial Response at all dose levels, and 88% had disease control (Objective Response or Stable disease), with a median Progression Free Survival of 6.3 months. Responses were rapid and were seen at week 6, and these responses were durable and ongoing at a median follow up of nearly a year.

Among the colorectal cancer subgroup, at a median follow up of 12.8 months, 7% had a confirmed response, and 74% had disease control, with a median duration of stable disease of 5.4 months and median PFS of 4 months. Responses were also observed in patients with Pancreatic, Endometrial, and Appendiceal cancers and Melanoma. It has been postulated that the inconsistent tumor responses noted between NSCLC and Colorectal cancer suggests either that KRAS-G12C is not the dominant oncogenic driver for colorectal cancer or that other pathways such as Wnt or EGFR pathways may mediate oncogenic signaling beyond KRAS. The authors suggest that a viable option would be to combine Sotorasib with therapies that block additional pathways, as was shown by studies in BRAF V600E-mutant Colorectal cancer. Approximately 57% of patients had treatment-related Adverse Events, of whom, about 12% had Grade 3 or 4 events. These toxicities included abnormal liver function studies, anemia, lymphopenia and diarrhea.

It was concluded Sotorasib showed promising anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS-G12C mutation. Studies evaluating Sotorasib as monotherapy or in combination with various agents in patients with NSCLC or other solid tumors are under way

KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors. Hong DS, Fakih MG, Strickler JH, et al. N Engl J Med 2020; 383:1207-1217.

Optimal Duration of Immune Checkpoint Inhibitors in Advanced Non Small Cell Lung Cancer

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response. The optimal duration of treatment with checkpoint inhibitors across tumor types is currently unknown and finding the balance between efficacy, toxicity and cost of therapy remains an ongoing challenge. There are presently no adequately powered, prospective, checkpoint inhibitor trials, comparing different treatment durations.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response, and unleashing the T cells. The authors in this study explored the impact of duration of treatment with OPDIVO®, on outcomes, in patients with previously treated advanced NSCLC, in a randomized study.

CheckMate 153 is a largely community based, ongoing, Phase IIIb/IV study, reflecting a real-world population, designed to evaluate the efficacy and safety of OPDIVO® monotherapy treatment duration, in previously treated advanced NSCLC. In this study, patients with previously treated advanced or metastatic NSCLC received OPDIVO® 3 mg/kg IV every 2 weeks until disease progression, unacceptable toxicity, or for 1 year. Treatment beyond initial progressive disease was permitted for patients with investigator-assessed clinical benefit, no rapidly progressive disease, and stable ECOG performance status, who were tolerating treatment. Patients who continued to receive treatment at 1 year were randomly assigned, regardless of response status to continue OPDIVO®, or to stop treatment (1-year fixed duration group), with the option of receiving OPDIVO® retreatment on study after disease progression. The Primary end point of safety was previously reported. Exploratory post-random assignment end points were added. Safety and tolerability, Progression Free survival (PFS), Overall Survival (OS), and Objective Response Rate (ORR) were assessed from the time of random assignment of those patients who continued to receive treatment at 1 year. The comparison was between a fixed 1-year treatment regimen and continuous therapy.

Of the 1,428 patients who received OPDIVO® in this study, 252 patients were randomly assigned to continuous treatment (N=127) or 1-year fixed-duration treatment (N=125). With minimum post-random assignment follow up of 13.5 months, median PFS was longer with continuous treatment versus 1-year fixed duration treatment (24.7 months versus 9.4 months; HR=0.56). Median Overall Survival from random assignment was also longer with continuous treatment versus 1-year fixed duration treatment in the Progression-Free Survival population (Not Reached versus 32.5 months; HR, 0.61), as well as in the Intent To Treat population (Not reached versus 28.8 months; HR, 0.62). New onset treatment-related Adverse Events occurred in a few patients and no new safety signals were identified.

The authors concluded that the above findings from an exploratory analysis represent the first randomized data on continuous versus fixed-duration immunotherapy, in previously treated patients with advanced NSCLC, and suggest that continuing OPDIVO® beyond 1 year improves outcomes.

Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non–Small-Cell Lung Cancer: CheckMate 153. Waterhouse DM, Garon EB, Chandler J, et al. DOI: 10.1200/JCO.20.00131 Journal of Clinical Oncology. Published online September 10, 2020.

FDA Approves GAVRETO® for Metastatic RET Fusion-Positive Non Small Cell Lung Cancer

SUMMARY: The FDA on September 4, 2020, granted accelerated approval to GAVRETO® (Pralsetinib) for adult patients with metastatic RET fusion-positive Non Small Cell Lung Cancer (NSCLC), as detected by an FDA approved test. The FDA also approved the Oncomine Dx Target (ODxT) Test as a companion diagnostic for GAVRETO®. Lung cancer is the second most common cancer in both men and women MOA-of-GAVRETOand accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers.

In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors.

RET kinase is a transmembrane Receptor Tyrosine Kinase and plays an important role during the development and maintenance of a variety of tissues, including neural and genitourinary tissues. RET signaling activates downstream pathways such as JAK/STAT3 and RAS/RAF/MEK/ERK and leads to cellular proliferation, survival, invasion, and metastasis. Oncogenic alterations to the RET proto-oncogene results in uncontrolled cell growth and enhanced tumor invasiveness. RET alterations include RET rearrangements, leading to RET fusions, and activating point mutations occurring across multiple tumor types. RET fusions have been identified in approximately 2% of NSCLCs, 10-20% of non-medullary thyroid cancers. Activating RET point mutations account for approximately 60% of sporadic Medullary Thyroid Cancers (MTC) and more than 90% of inherited MTCs. Other cancers with documented RET alterations include colorectal, breast, and several hematologic malignancies.

GAVRETO® is an oral, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations, including fusions and mutations, regardless of the tissue of origin. The efficacy of GAVRETO® was investigated in a multicenter, open-label, multi-cohort, Phase I/II basket clinical trial (ARROW), in patients with tumors showing RET alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either Next Generation Sequencing (NGS), Fluorescence In Situ Hybridization (FISH), or other tests. (In a basket trial, tumors with different histologies and single biomarker are placed in different baskets and receive a single treatment). The main efficacy outcome measures were Overall Response Rate (ORR) and response duration, as determined by a blinded Independent Review Committee, using RECIST criteria.

The efficacy for RET fusion-positive NSCLC was evaluated in 87 patients previously treated with platinum-based chemotherapy. Patients received GAVRETO® 400 mg orally once daily. The ORR was 57%, with a Complete Response (CR) rate of 5.7% and 80% of responding patients had responses lasting 6 months or longer. The median Duration of Response was not reached. Efficacy was also evaluated in 27 patients who never received systemic treatment and the ORR in this patient group was 70% with 11% CR rate and 58% of responding patients had responses lasting 6 months or longer. The most common adverse reactions (25% or more) were fatigue, constipation, musculoskeletal pain and hypertension.

It was concluded that patients treated with GAVRETO® had a rapid, potent, and durable clinical response, in patients with advanced RET fusion positive NSCLC, regardless of RET fusion partner, presence of brain metastases, or prior therapies.

Gainor JF, Curigliano G, Kim D-W, et al. DOI: 10.1200/JCO.2020.38.15_suppl.9515 Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020) 9515-9515.

Immunotherapy Benefits All Patient Groups with Advanced Cancer

SUMMARY: The American Cancer Society estimates that in 2020, there will be an estimated 1.8 million new cancer cases diagnosed and 606,520 cancer deaths in the United States. Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options by improving Overall Response Rate and prolongation of survival across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Biomarkers predicting responses to ICI’s include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. Other biomarkers such as Tumor Infiltrating Lymphocytes (TILs), TIL‐derived Interferon‐γ, Neutrophil‐to‐Lymphocyte ratio, and peripheral cytokines, have also been proposed as predictors of response.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

Immune Checkpoint Inhibitors enhance antitumor immunity by unleashing the T cells. However, this benefit may vary among patients and tumor types. Sex is a biological variable that affects immune responses. Women tend to mount stronger innate as well as adaptive immune responses, than men. (Innate immunity is inherently present in the body, whereas Adaptive immunity occurs in response to exposure to a foreign substance). This can translate into greater efficacy with vaccines and more rapid clearance of pathogens. Aging alters immune responses and adaptive immunity becomes less functional. Altered ECOG Performance Status has also been associated with poor immune response. Several other studies have been published looking at these variables, with conflicting results.

To address these discordant results, the authors performed a meta-analysis to examine the potential association of sex, age, and ECOG PS with immunotherapy survival benefit in patients with advanced cancer. This study was limited to randomized clinical trials that compared Overall Survival (OS) in patients with advanced cancer treated with ICI immunotherapy versus non-ICI control therapy. Data sources such as PubMed, Web of Science, Embase, and Scopus were searched and a total of 37 Phase II or III randomized clinical trials involving 23,760 patients were included in the analysis. Of these, 13 trials evaluated ICIs as first-line therapy. The most common cancer types studied were Non-Small Cell Lung Cancer (N= 14). The most common immune checkpoint inhibitors used were PD-1/PD-L1 inhibitors (N=25). The main Outcomes and Measures were the difference in survival benefit of ICIs between sex, age (less than 65 versus 65 years or more), ECOG PS (0 versus 1 or more), as well as the outcomes stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy (ICI alone or ICI combined with non-ICI) in the intervention arm.

The authors noted that Overall Survival benefit with ICI immunotherapy treatment was found for both men (HR=0.75) and women (HR=0.79), for both younger and less than 65 years (HR=0.77) and 65 years or older (HR=0.78) patients, and for both, patients with ECOG Performance Status 0 (HR=0.81) and PS greater than or equal to 1 (HR=0.79). There was no significant difference of relative benefit from immunotherapy over control therapy in patients of different sex (P=0 .25), age (P=0.94), or ECOG PS (P=0.74). Further, there was no significant difference found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

It was concluded that the results of this meta-analysis suggest that immunotherapy with ICIs may confer a survival benefit in the treatment of advanced cancer, regardless of patient sex, age, and performance status, and should not be restricted based on these characteristics.

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials. A Systematic Review and Meta-analysis. Yang F, Markovic SN, Molina JR, et al. JAMA Netw Open. 2020;3(8):e2012534. doi:10.1001/jamanetworkopen.2020.12534

Next-Generation Sequencing Superior to Single Gene Testing in Advanced NSCLC

SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2020, about 228, 820 new cases of lung cancer will be diagnosed and 135,720 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
In addition to the well characterized gene fusions involving ALK and ROS1 in NSCLC, genetic alterations involving other kinases including EGFR, BRAF, RET, NTRK, MET, HER2 are all additional established targetable drivers. These genetic alterations are generally mutually exclusive, with no more than one predominant driver in any given cancer. The hallmark of all of these genetic alterations is oncogene addiction, in which cancers are driven primarily, or even exclusively, by aberrant oncogene signaling, and are highly susceptible to small molecule inhibitors. Patients with nonsquamous NSCLC should therefore be tested for Actionable Driver Oncogenes, as highly effective treatments may be available for these patients. Nonetheless, Single Gene Testing for EGFR and ALK is more common in the US rather than broad multigene panel testing with Next-Generation Sequencing.Overview-of-Next-Generation-Sequencing

Next-Generation Sequencing (NGS) platforms or second-generation sequencing, unlike the first-generation sequencing, known as Sanger sequencing, perform massively parallel sequencing, which allows sequencing of millions of fragments of DNA from a single sample. With this high-throughput sequencing, the entire genome can be sequenced in less than 24 hours. There are a number of different NGS platforms using different sequencing technologies and NGS can be used to sequence and systematically study the cancer genomes in their entirety or specific areas of interest in the genome or small numbers of individual genes. Recently reported genomic profiling studies, performed in patients with advanced cancer suggest that actionable mutations are found in 20-40% of patients’ tumors.

The authors in this study used a decision analytic model they had developed, and compared the value of broad NGS-based testing, to Single Gene Testing (SGT), in patients with nonsquamous NSCLC, and discussed their implications for the US population. The authors noted that Single Gene Testing for EGFR and ALK is relatively common (>80%) in the US, whereas testing for less common Actionable Driver Oncogenes is rare. The broader NGS Actionable Driver Oncogene panel includes EGFR, ALK, ROS1, BRAF, RET, MET, NTRK. The authors took into consideration reimbursement by CMS for broad NGS-based testing ($627.50), reimbursement for Single Gene testing (EGFR+ALK $732.30), and the cost of treatment for 2 years at $10K/year ($20,000). The expected prevalence of Actionable Driver Oncogenes among non squamous NSCLC patients, as well as survival outcomes of patients, in the presence versus absence of an Actionable Driver Oncogenes treatment strategy, was calculated based on current literature. The number of eligible patients with nonsquamous NSCLC, for testing in the US, were 89,000 (N=89,000). The estimated number of patients with Actionable Driver Oncogenes (EGFR, ALK, ROS1, BRAF, RET, MET, NTRK) was 26,300 (N=26,300). The goal of this study was to measure the cost and value differences when one chose to run a Single Gene Testing (narrow genomics panel), which included interrogation for either EGFR or ALK, versus a broader NGS panel. The potential value of each testing approach was measured based on Life Years Gained (LYG) and the cost per LYG. (Life Years gained is a modified mortality measure where remaining life expectancy is taken into account).

It was noted that a broad NGS approach to test for genetic alterations resulted in additional Life Year Gains with cost savings, compared to Single Gene Testing for EGFR or ALK. This analytical model suggested that at the current 80% testing rate, replacing Single Gene Testing with NGS would result in an additional 21,019 Life Year Gained, with reduced cost per LYG of $599. Increasing testing from 80% to 100% of eligible patients would further increase the Life Year Gained by 15,017. If 100% of eligible patients were tested with NGS and every identified patient received treatment, the cost per Life Year Gained with this strategy would be $16,641.57.

According to this decision model, the estimated median survival and 5-year survival for a patient who was tested with NGS, followed by a highly effective therapy selected on the basis of that alteration, would be 39 months and 25%, respectively. For a patient who had an Actionable Driver Oncogene that was not identified by Single Gene Testing, the estimated median survival would be 14 months and 5-year survival would be 5%. This analysis suggested that not running broad multigene NGS panel routinely for eligible patients, and only using Single Gene Testing could be a missed opportunity, as actionable mutations would be missed and patients may not get the most effective therapy for their disease.

The authors concluded that based on their decision analytic model, when highly effective therapy is available to all identified patients with Actionable Driver Oncogenes, broad NGS testing, compared to Single Gene Testing for EGFR or ALK, leads to large gains in Life Years, at reduced cost per Life Year Gained, compared to Single Gene Testing. This model supports universal NGS testing of all patients with advanced nonsquamous NSCLC.

A model comparing the value of broad next-gen sequencing (NGS)-based testing to single gene testing (SGT) in patients with nonsquamous non-small cell lung cancer (NSCLC) in the United States. Pennell NA, Zhou J, Hobbs B. J Clin Oncol 38: 2020 (suppl; abstr 9529)