Virtual Library

Start Your Search

Alice T. Shaw

Moderator of

  • +

    ES10 - Oncology Drug Approval: Challenges and Opportunities (ID 13)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 5
    • Now Available
    • +

      ES10.01 - US Food and Drug Administration (Now Available) (ID 3205)

      13:30 - 15:00  |  Presenting Author(s): Gideon M Blumenthal

      • Abstract
      • Presentation
      • Slides

      Abstract

      Dr Blumenthal will provide the US FDA Oncology Center of Excellence perspective on Oncology Drug Approval: Challenges and Opportunity. With the recent influx of novel targeted therapies, immunotherapy and chemotherapy to treat patients with lung cancers, there are increased challenges to ensuring that safe and effective therapies are available to patients as efficiently as possible while ensuring that the evidence generated is robust and reliable. This talk will discuss FDA's perspective on global drug development.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      ES10.02 - Japan Pharmaceuticals and Medical Devices Agency  (Now Available) (ID 3206)

      13:30 - 15:00  |  Presenting Author(s): Sumimasa Nagai

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour and Welfare (MHLW) are responsible for reviewing applications and approving the marketing authorization of drugs, medical devices, and regenerative medicines in Japan. All applications for marketing authorization in Japan are submitted to the PMDA. The PMDA conducts scientific review. Review reports prepared by the PMDA are then submitted to MHLW. The MHLW approves the marketing authorization.

      Japanese regulation has two categories of regulatory review: standard review and priority review. Priority review is applied to orphan drugs and products designated by the MHLW. Other than orphan drugs, the MHLW designates medical products as priority review products based on the following criteria described: 1. Seriousness of the target disease and 2. Clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or the patient’s quality of life. The target total review time for standard review products and priority review products is 12 months and 9 months, respectively.

      The conditional and term-limited approval system has been first introduced for regenerative medical products since November, 2014. Regenerative medical products may be granted conditional and term-limited approval if their efficacy can be assumed and safety is confirmed in early-phase (phase I and/or II) registration trials. In the approval system, sponsors of the products must confirm their efficacy and safety after marketing authorization in postmarketing clinical studies etc and by resubmitting applications for regular approval within a predetermined period (not more than 7 years). The conditional and term-limited approval for regenerative medical products is similar to the accelerated approval in the US.

      In addition, the conditional approval system for drugs has been newly instituted since October, 2017 in Japan. This may be granted if all of the following requirements are met: 1. seriousness of the target disease, 2. clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or quality of life, 3. it is difficult or it takes too long time to conduct a confirmatory study, 4. exploratory clinical studies can show efficacy and safety, and 5. surveillance or clinical studies must be conducted as post-marketing requirement. Because these requirements include the requirements for priority review (seriousness of the target disease and clinical usefulness of the drug), drugs granted conditional approval can automatically enjoy priority review. Moreover, the requirement for conditional approval “it is difficult or it takes too long time to conduct a confirmatory study” in Japan is totally different from accelerated approval based on surrogate endpoint in the US. The requirement is similar to the requirement for marketing authorization under exceptional circumstances “companies cannot provide comprehensive clinical data because of the rarity of the disease” in the EU. Although the requirements for conditional approval for drugs in Japan include “surveillance or clinical studies must be conducted as post-marketing requirement”, the term of validity for conditional approval of drugs in Japan is not established, which is different from the conditional and term-limited approval for regenerative medical products in Japan. As of May 31, 2019, only lorlatinib for ALK fusion-positive non-small cell lung cancer and pembrolizumab for MSI-high solid cancer have been granted conditional approval for drugs in Japan. Conducting confirmatory comparative studies is not included in postmarketing requirements for the both drugs.

      The MHLW instituted in 2015 the SAKIGAKE (meaning pioneer or forerunner in Japanese) designation system for medical products for diseases in urgent medical need of innovative therapy and that may satisfying the following two conditions: 1. The medical product has been first developed in Japan, and a sponsor is planning to submit a marketing authorization application; and 2. Prominent effectiveness can be expected based on data from the mechanism of action, non-clinical studies, and early-phase clinical studies. Advantages of sponsors who have medical products granted SAKIGAKE designation are as follows: prioritized consultation (reduced waiting time), substantial pre-application consultation, prioritized review (target total review time of 6 months only for drugs, devices, and IVDs), assigning a PMDA manager as a concierge, and an extension of the reexamination period. Total review time for SAKIGAKE-designated regenerative medical products is not established. Although the SAKIGAKE designation is similar to a breakthrough therapy designation in the US and PRIME in the EU, the requirement “the medical product has been first developed in Japan” and the advantage of specific shortened total review time are unique to the SAKIGAKE.

      Companion diagnostics (CDx) are important for oncology drug development. Current regulatory considerations regarding CDx and tumor profiling test in Japan are similar to those in the US. As of May 31, 2019, three next generation sequencing-based oncology panel tests have been approved as CDx and/or tumor profiling test in Japan. However, more flexible regulations regarding CDx are necessary for efficient clinical practice and drug development.

      I will give an overview of regulatory frameworks and challenges regarding oncology drugs and companion diagnostics in Japan.

      References:

      Nagai S, Ozawa K. Regulatory approval pathways for anticancer drugs in Japan, the EU and the US. Int J Hematol. 2016;104:73-84.

      Nagai S, et al. Evolving Japanese regulations on companion diagnostics. Nat Biotechnol. 2016;34:141-144.

      Salgado R, Solit DB, Rimm DL, Bogaerts J, Canetta R, Lively T, Lyerly K, Span PN, Bateman-House A, Makady A, Bergmann L, Nagai S, et al.; IBCD-Faculty. Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology. Eur J Cancer. 2019;114:128-136.

      Lyerly HK, Ren J, Canetta R, Kim GH, Nagai S, et al. Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers. J Glob Oncol. 2018;4:1-11.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      ES10.03 - China National Medical Products Administration (Formerly CFDA)  (Now Available) (ID 3207)

      13:30 - 15:00  |  Presenting Author(s): Tony Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      ES10.04 - European Medicines Agency (Now Available) (ID 3208)

      13:30 - 15:00  |  Presenting Author(s): Jorge Camarero

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oncology Drugs Approval: Challenges and Opportunities

      In recent years, the development of new drugs in the oncology field has notably increased. This growth in oncology clinical trials appears to be mainly associated with the increasing knowledge in pathophysiology and molecular medicine in oncology. Targeted therapies have been approved, overall, on the basis of its ability to prolong progression free survival and/or life expectancy of patients. In addition, immunotherapy has arisen as a turning point in the treatment of cancer, opening a new era and setting up a milestone in the current armamentarium. However, the regulatory decision making process behind some of the approvals for these products have proven difficult and lead to important uncertainties still to be addressed. Such unanswered questions relate, among others, to the target population, subgroups of patients partially covered by authorized indications and limitations on important aspects such as duration and combination of treatments. Likewise, this increase in new molecules development poses a remarkable pressure on regulators, clinicians and payers, who albeit from different perspectives, face the very same problem of how to ensure (timely) access to patients of new authorized products. From a regulatory perspective, randomized clinical trials remain the gold standard for adequate assessment of both efficacy and safety. Nevertheless, conducting single arm studies is becoming a commonly approach for companies to speed up regulatory approval in those situations where there is an unmet medical need. The latter cast important doubts on when, where and how this strategy can be accepted.

      Last but not least, new clinical trials designs and the proposal of using Real Word Evidence/Real World Data to complement non-compelling clinical development, are creating a new parading when it comes to making a decision upon the benefit-risk balance

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

    • +

      ES10.05 - Brazilian Health Regulatory Agency - Agência Nacional de Vigilância Sanitária (Now Available) (ID 3209)

      13:30 - 15:00  |  Presenting Author(s): Carlos Gil Ferreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. Its hallmarks are administrative independence, financial autonomy, and the stability of its directors. Within the federal public regulatory structure, the agency is linked to the Ministry of Health [1].

      Despite major advances in the regulatory process in Brazil, it is important to highlight that a major delay in cancer drugs approval over the last decade has had a negative impact on patient access to novel medications in Brazil. According to Barrios et al., [2] well-established and adequately functional drug approval legislation is indispensable to guarantee a country’s population health. Any malfunctions or delay in such a crucial process have serious consequences. As an example, the drug Crizotinib (Xalcori®Pfizer, NY, USA), which had its approval denied by ANVISA in June 2014 may be seen as a landmark. Assuming different premises, Barrios et al. [2] calculated 1.367 years of life lost over 34 months due to lack of access to Crizotinib between August 2011 (FDA approval) to June 2014 (refusal by ANVISA). Of note, Crizotinib was not approved in Brazil until Feb 2016, what may have added additional 804 years of life lost to final numbers due to this delay. Other example of unexplained delay in drug approval in lenalidomide. The gap between the drug approval in the US and Brazil was 12 years.

      Regarding drugs that do require a companion diagnostic, the situation may become more complicated since, unlike the US Food and Drug Administration, no clear mechanism is in place with ANVISA for the simultaneous linking of most companion diagnostic tests with their respective targeted therapeutic drug [3].

      In trying to understand the reasons behind this delayed drug approval process, methodological, cultural, political and ideologic reasons may account. At odds with other regulatory agencies such the FDA that allow conditioned approval based on non randomized data for drugs addressing unmet medical needs. For many years ANVISA authorities mandated randomized phase 3 data for a definitive approval, since no conditioned approval was allowed. In this context, having a specific oncology area or committee, such as the FDA Oncology Drug Advisory Committee [4], may be crucial. Fast track approval, breakthrough designation, companion diagnostics, different surrogate endpoints, integration of real world evidence (RWE) into the regulatory process are very specific topics from the oncology field and do require to be analyzed under the perspective of cancer specialists. From a political, cultural and ideologic perspective, althoughit is notorious that Brazil has invested substantially in expanding access to health care for all of its citizens, the country has, essentially, two clear distinct and dissimilar health systems [3]. The public system allows drugs to become commercially available through processes that are different from those in place in the private health-care system. Although difficult to measure those disparities and difficulties to reimburse expensive drugs in the public system, may have influenced the delayed process during the last decade.

      Over the last decade, delays at ANVISA’s approval process have been considered the only reason for the inequitable access to oncology care between the USA and Brazil. Yet, this may be a biased conclusion and a more comprehensive analysis in needed. By analyzinga basket of twenty-three oncology products approved by ANVISA after 2002 Bustamante et al. [5] identified that on average there was a difference of 8.6 months (449 X 186 days). However on average, a delay in the manufacturers’ submission for regulatory approval of 1.1 years (393 days between Brazil and the USA) was also identified.

      More recently, a trend toward improvements in the drug approval process has been identified (ex. Osimertinib and Durvalumab). Osimertinib was firstly approved by ANVISA in 2017 as a second line treatment in patients who did not respond well to the initial drug. With the new determination, in 2018 ANVISA approved its use as a first therapy to treat locally advanced non-small cell lung cancer. Durvalumab was approved by ANVISA in 2017. Nevertheless there is clear room for a continuous improvement. Increase in the number of ANVISA technicians, continuous training and collaboration with academic institutions and other regulatory agencies elsewhere are mandatory. Close scientific collaboration and open and transparent dialogue between ANVISA and pharmaceutical companies are required. In sum, if we are to have a continuous improvement in the oncology drug approval process, all the stakeholders (ANVISA, drug manufactures, patient advocacy, players at the private and public health systems) must act together.

      References

      1. Ba KH andSassi AB. ANVISA: an introduction to a new regulatory agency with many challenges. AAPS Open2018; 12 Dec 2018; 4:9.

      2. Barrios PM, Debiasi M, Lopes G, Barrios CH. P1.51: Impact of Regulatory Delays in Drug Approval: Mortality and Morbidity Due to With Lack of Access to Crizotinib in Brazil: Track: Supportive Care and Others. IASLC 7th Latin American Conference on Lung Cancer, 25-27 August 2016 • Panama City, Panama; Volume 11, Issue 10, Page S215.

      3. Ferreira CG, Achatz MI, Ashton-Prolla P, Begnami MD, Marchini FK, Stefani SD. Brazilian health-care policy for targeted oncology therapies and companion diagnostic testing. Lancet Oncol. 2016 Aug;17(8):e363-e370.

      4. Vaccari L.A. The Role of the Oncology Drug Advisory Committee in the FDA Review Process for Oncologic Products. In: Teicher B.A., Andrews P.A. (eds) Anticancer Drug Development Guide. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ, 2004.

      5. Martin de Bustamante M, Martin de Bustamante M, Duttagupta S, Beckerman R, Smith NJ, Roitberg F, Lopes G.
Regulatory approval for oncology products in brazil: a comparison between the FDA and Anvisa approval timelines.
 Value in Health 18 (2015) a805–a881. Abstract PCN60.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.



Author of

  • +

    ES14 - What First Line in Oncogene Addicted NSCLC (ID 17)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • +

      ES14.02 - First Line in ALK Translocated Patients (Now Available) (ID 3231)

      15:15 - 16:45  |  Presenting Author(s): Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chromosomal rearrangement of ALK defines a distinct subset of non-small cell lung cancer (NSCLC) with marked sensitivity to small molecule ALK tyrosine kinase inhibitors (TKIs). Currently, five ALK TKIs are approved as standard therapies for advanced ALK-positive NSCLC, including the first generation ALK/ROS1/MET inhibitor crizotinib, the second generation ALK inhibitors ceritinib, alectinib and brigatinib, and most recently the third generation ALK/ROS1 inhibitor lorlatinib. In three randomized phase 3 studies (J-ALEX, global ALEX, and ALESIA), alectinib has demonstrated superior efficacy compared to crizotinib, and has replaced crizotinib as the standard first-line therapy for advanced ALK-positive NSCLC. Recently, in a planned interim analysis of the ALTA-1L phase 3 study, brigatinib has also shown superior efficacy to crizotinib as first ALK TKI in advanced ALK-positive NSCLC. In this talk, we will review all the available first-line data with ALK TKIs, with a focus on next-generation ALK inhibitors. In addition to discussing second-generation ALK TKIs, we will also highlight available data with lorlatinib in the first-line setting. The phase 3 study of lorlatinib vs crizotinib as first-line therapy (CROWN) has completed accrual, with results expected within the next year. Finally, we will discuss the potential role of investigational combinations as first-line therapy in advanced ALK-positive NSCLC. These investigational strategies hold the promise of further extending front-line progression-free survival as well as overall survival for this molecular subgroup of patients.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • +

      MA11.11 - STK11/LKB1 Genomic Alterations Are Associated with Inferior Clinical Outcomes with Chemo-Immunotherapy in Non-Squamous NSCLC (Now Available) (ID 2898)

      14:00 - 15:30  |  Author(s): Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Background

      Addition of pembrolizumab (P) to platinum-doublet chemotherapy [carboplatin (or cisplatin) and pemetrexed (CP)] prolongs overall survival and is a standard of care (SOC) for the 1st line treatment of metastatic EGFR/ALK wild-type (wt) non-squamous non-small cell lung cancer (mnsNSCLC). Despite widespread use of the CPP regimen, molecular determinants of clinical benefit from the addition of P to CP remain poorly defined. We previously identified genomic alterations in STK11/LKB1 as a major driver of primary resistance to PD-1/PD-L1 blockade in mnsNSCLC. Here, we present updated data on the impact of STK11/LKB1 alterations on clinical outcomes with CPP chemo-immunotherapy from a large retrospective multi-institution international study.

      Method

      620 pts with mnsNSCLC and tumor genomic profiling encompassing STK11/LKB1 from 21 academic institutions in the US and Europe were included in this study. Clinical outcomes were collected for two distinct patient cohorts: a) 468 pts treated with first-line CPP (or >1st line following FDA-approved TKIs) that were alive for 14 days thereafter and b) 152 STK11/LKB1-mt pts that received CP prior to regulatory approval of CPP.

      Result

      Among 468 CPP-treated pts, STK11/LKB1 genomic alterations (N=118) were associated with significantly shorter PFS (mPFS 5.0m vs 6.8m, HR 1.45, 95% CI 1.11 to 1.91; P=0.007) and shorter OS (mOS 10.6m vs 16.7m, HR 1.46, 95% CI 1.04 to 2.07; P=0.031) compared with STK11/LKB1-wt tumors (N=350). The likelihood of disease progression as BOR to CPP differed significantly between the two groups (29.5% vs 17%, P= 0.006). Similar results were obtained when limiting the analysis to EGFR and ALK-wt tumors (N=435) (mPFS 5.0m vs 6.9m, HR 1.48, 95% CI 1.12-1.95, P=0.006 and mOS 10.6m vs 16.7m, HR 1.45, 95% CI 1.02-2.05, P=0.036). Importantly, in pts with STK11/LKB1-mt mnsNSCLC, addition of pembrolizumab to CP did not result in significant improvement of PFS (mPFS 5.0m vs 3.9m, HR 0.82, 95% CI 0.63 to 1.07, P=0.14) or OS (mOS 10.6m vs 9.1m, HR 0.93, 95% CI 0.67 to 1.30, P=0.69) compared to CP alone.

      Conclusion

      In mnsNSCLC, STK11/LKB1 alterations define a subgroup of pts with inferior clinical outcomes with CPP and lack of benefit from the addition of pembrolizumab to CP chemotherapy. Novel therapeutic strategies are required to establish effective antitumor immunity in STK11/LKB1-mutant NSCLC.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    MA14 - The Adequate MTarget Is Still the Issue (ID 140)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
    • +

      MA14.02 - Entrectinib in Patients with ROS1-Positive NSCLC or NTRK Fusion-Positive Solid Tumors with CNS Metastases (Now Available) (ID 1631)

      15:45 - 17:15  |  Author(s): Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Background

      Entrectinib potently inhibits kinases encoded by NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated analysis data (31 May 2018 data cut-off) from three Phase 1/2 entrectinib trials (ALKA-372-001 [EudraCT 2012-000148-88]; STARTRK-1 [NCT02097810]; STARTRK-2 [NCT02568267]) for a large cohort of adult patients with NTRK fusion-positive solid tumors (NTRK+) or ROS1 fusion-positive NSCLC (ROS1+), with baseline CNS metastases.

      Method

      Patients had locally advanced/metastatic NTRK+ solid tumors or ROS1+ NSCLC by nucleic acid-based assays confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were performed at baseline, week 4, and then every 8 weeks by blinded independent central review (RECIST v1.1). Primary endpoints were overall response rate (ORR), duration of response (DOR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy in patients with CNS metastases, safety.

      Result

      Most patients were treated first-line or after one line of prior therapy; baseline characteristics relating to measurable CNS metastases for patients with NTRK+ solid tumors and ROS1+ NSCLC are presented (Table). Intracranial outcomes for the NTRK+ solid tumors (n=54; 18% NSCLC) and ROS1+ NSCLC (n=53) efficacy evaluable populations are reported (Table). Durability of treatment effect and potential delayed progression in the CNS was observed; time to CNS progression was 17.0 months (95% CI: 14.3–NE) for NTRK+ solid tumor patients and NE (95% CI: 15.1–NE) for ROS1+ NSCLC. In the subset of patients with NTRK+ NSCLC (n=10), 6 patients had CNS metastases at baseline (by BICR); IC-ORR was 66.7% (4/6), 2 CR; IC-DOR was NE. In both the NTRK+ and ROS1+ populations, entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2.

      Conclusion

      Entrectinib induced clinically meaningful durable responses in patients with NTRK+ solid tumors or ROS1+ NSCLC with CNS disease at baseline.

      Funding: This study was funded by F. Hoffmann-La Roche

      table.jpg

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 1
    • Now Available
    • +

      OA15.01 - Combination Olaparib and Temozolomide in Relapsed Small Cell Lung Cancer: Updated Results from Phase 1/2 Clinical Trial (Now Available) (ID 1394)

      14:30 - 16:00  |  Author(s): Alice T. Shaw

      • Abstract
      • Presentation
      • Slides

      Background

      DNA damage repair inhibition is an emerging strategy for treating small cell lung cancer (SCLC). Combining poly(ADP-ribose) polymerase (PARP) inhibition with the DNA alkylating agent temozolomide has shown activity in both preclinical models and early phase clinical trials.

      Method

      This is a single-arm phase 1/2 study combining the PARP inhibitior olaparib (tablet formulation) with temozolomide in patients with SCLC. Key eligibility criteria include histologically or cytologically confirmed incurable SCLC which progressed following ≥ 1 platinum-based chemotherapy. In cohort 1, olaparib and temozolomide are administered orally on days 1-7 of 21-day cycles. After cohort 1 completed enrollment, cohort 2 was added in a protocol amendment, in which olaparib is administered continuously days 1-21 and temozolomide is administered days 1-7 of 21-day cycles. For each cohort, the phase 1 portion is a conventional 3+3 design, with the primary objective to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). The primary objective of the phase 2 dose expansion portion is to determine the objective response rate (ORR). Response assessments are performed every 6 weeks, with treatment continued until progression, unacceptable toxicity, or investigator’s discretion. Treatment post-progression is allowed for patients with ongoing clinical benefit.

      Result

      Between October 2015 and April 2018, 50 patients were enrolled to cohort 1. The median age was 63 (range 39-85), median number of prior therapies was 2 (range 1-7), and 72% were platinum sensitive. The RP2D was olaparib 200 mg PO BID d1-7 and T 75 mg/m2 QD d1-7. The confirmed ORR was 41.7%. After a median follow-up of 7.1 months among 22 surviving patients, the median progression-free survival (mPFS) was 4.2 months, median overall survival (mOS) was 8.5 months, and median duration of response (mDoR) was 4.3 months. The ORR among platinum-sensitive and platinum-resistant patients was 47.1% and 28.6%, respectively, with no significant differences in mPFS, mOS or mDOR. The most common grade 3/4 treatment related adverse events were neutropenia (38%), anemia (28%) and thrombocytopenia (26%). Among 41 pts treated at the RP2D, dose reductions occurred in 44% overall and 64% of those who received at least 3 cycles. Enrollment to the phase 1 portion of cohort 2 began in November 2018 and is ongoing. Updated results from cohorts 1 and 2 will be presented at the meeting.

      Conclusion

      Combination olaparib and temozolomide has an acceptable tolerability profile and shows promising clinical activity in relapsed SCLC. Clinical trials identifier NCT02446704.

      Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
    • +

      P1.01-84 - Interaction of Lorlatinib with CYP2B6, CYP2C9, UGT, and P-gp Probe Drugs in Patients with Advanced Non-Small Cell Lung Cancer (ID 293)

      09:45 - 18:00  |  Author(s): Alice T. Shaw

      • Abstract
      • Slides

      Background

      Lorlatinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC). Because lorlatinib is an inducer and inhibitor of various cytochrome P450 (CYP) enzymes and transporters, an evaluation of its effect on these substrates at steady state is warranted. A drug-drug interaction (DDI) sub-study was conducted in patients with advanced NSCLC to evaluate the net effect of these interactions.

      Method

      Probe drugs utilized included bupropion for CYP2B6, tolbutamide for CYP2C9, acetaminophen for uridine 5'-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase, UGT), and fexofenadine for P-glycoprotein-1 (P-gp). Thirty-two patients (to have at least 6 evaluable patients per probe drug) were administered a single dose of a probe drug alone on Day −2 to determine plasma exposure of the probe drug alone. Starting on Cycle 1 Day 1, patients began lorlatinib tablets 100 mg daily. On Cycle 1 Day 15, another single dose of the same probe drug was administered concurrently with lorlatinib.

      Result

      Co-administration of lorlatinib 100 mg with bupropion, a sensitive CYP2B6 probe drug, decreased bupropion geometric mean plasma AUCinf and Cmax by 25% and 27%, respectively. For tolbutamide, a sensitive CYP2C9 probe drug, lorlatinib decreased tolbutamide AUCinf and Cmax by 43% and 15%, respectively. Likewise, for acetaminophen, a sensitive UGT substrate, lorlatinib decreased acetaminophen AUCinf and Cmax by 45% and 28%, respectively. Finally, for fexofenadine, a sensitive P-gp substrate, lorlatinib decreased fexofenadine AUCinf and Cmax by 67% and 63%, respectively.

      Conclusion

      Critical steady-state–based DDI evaluations can be conducted in patients with cancer in carefully designed studies. Per FDA guidance, strong, moderate, and weak inducers are drugs that decrease the AUC of sensitive index substrates by ≥80%, ≥50% to <80%, and ≥20% to <50%, respectively. Based on these criteria, lorlatinib behaved as a net weak inducer of CYP2B6, CYP2C9, and UGT; and a net moderate inducer of P-gp. The results of this sub-study can help guide recommendations for dose modifications when lorlatinib is given concomitantly with drugs that are metabolized by these enzymes or transporters. Based on the current results, only drugs that are P-gp substrates of narrow therapeutic index may require dose adjustments when used concomitantly with lorlatinib.

      Only Active Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login or select "Add to Cart" and proceed to checkout.

  • +

    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
    • +

      P2.01-04 - NCI-NRG Oncology ALK PROTOCOL (NRG-LU003): A Biomarker-Driven Protocol for Previously Treated ALK-Positive Non-Squamous NSCLC Patients      (ID 2021)

      10:15 - 18:15  |  Author(s): Alice T. Shaw

      • Abstract

      Background

      Currently, the 1stgeneration ALK inhibitor crizotinib and 2ndgeneration ALK inhibitors ceritinib, alectinib and brigatinib are FDA-approved for the treatment of advanced ALK-positive NSCLC. The 3rdgeneration ALK inhibitor lorlatinibrecentlyreceived accelerated approval for patients after failure of a 2ndgeneration inhibitor.

      2ndgeneration ALK inhibitors are widely used in crizotinib-resistant patients and have recently replaced crizotinib as first-line therapy for newly diagnosed patients. There is an urgent need to define the optimal therapy for patients who have become resistant to a second-generation ALK inhibitor. Pre-clinical data and small case series suggest that the presence/absence of ALK resistance mutations or the specigic ALK mutation may serve as a critical biomarker to guide selection of therapy, particularly in the setting of relapse on a 2ndgeneration ALK inhibitor when ALK resistance mutations are more common,

      Method

      NRG-LU003 proposes to study ALK-positive non-squamous NSCLC patients who develop resistance to a second-generation ALK inhibitor, in order to establish a treatment algorithm for these patients based on resistance mechanisms.Patients will undergo tissue biopsy along with blood sampling for cfDNA analysis. One of the aims of the study is to establish the concordance between tissue and liquid biopsies; liquid biopsy may replace tissue biopsy after the first 200 patients enrolled, depending on the concordance and in consultation with CDRH/FDA. Treatments will be selected based on preclinical and clinical data demonstrating activity of treatment particular inhibitor against the specific ALK mutation or resistance mechanism identified. If no ALK resistance mutations are identified, patients will be randomized to receive either a next-generation ALK inhibitor they have not previously received or pemetrexed-based therapy with cisplatin or carboplatin.

      Target accrual is 660 patients and primary objective is to assess whether ALK kinase domain mutations (e.g., G1202/C1156/I1171/L1196/V1180/F1174 mutations) associated with drug resistance are predictive of objective response to subsequent ALK inhibitor therapy, to assess whether subsequent pemetrexed based chemotherapy improves objective response compared to ALK inhibitor therapy for patients with no ALK resistance mutations, and to evaluate objective responses of patients with specific genetic alterations (e.g., ALK L1198F, compound mutations, or high-level MET amplification) treated with crizotinib.

      Mutation

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      STUDY DRUG

      G1202, G1202del, G1202R

      lorlatinib

      brigatinib

      C1156Y

      lorlatinib

      alectinib

      brigatinib

      I1171

      lorlatinib

      ceritinib

      brigatinib

      L1196, L1196M

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      V1180

      lorlatinib

      ceritinib

      brigatinib

      F1174

      lorlatinib

      alectinib

      brigatinib

      Compound mutation

      lorlatinib

      ALK L1198F (alone/ in combination with another ALK mutation)

      crizotinib

      MET amplification

      crizotinib

      No ALK-resistance mutations*

      lorlatinib

      ceritinib

      alectinib

      brigatinib

      ensartinib

      Pemetrexed

      +

      Cisplatin or Carboplatin

      Result

      "Section not applicable"

      Conclusion

      This study has been approved and is open for enrollment through the National Clinical Trials Network (NCTN).

      This project is supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI)