Dr Reckamp on Emerging EGFR TKIs in EGFR Exon 20 Insertion+ NSCLC

Karen L. Reckamp, MD, MS, director, Division of Medical Oncology, associate director, Clinical Research, medical oncology director, Lung Institute, Cedars-Sinai, discusses emerging data for next-generation EGFR TKIs in the treatment of patients with non–small cell lung cancer (NSCLC) harboring 

Reckamp highlights recent data for 2 novel EGFR TKIs presented, emphasizing their potential in this patient population.

First, the phase 2 WU-KONG1 study (NCT03974022) investigated sunvozertinib (DZD9008) in patients with locally advanced or metastatic NSCLC harboring 

 exon 20 insertion mutations who received prior treatment with platinum-based chemotherapy. Findings presented at 

 showed that at the data cutoff of March 22, 2024, the best objective response rate (ORR) was 53.3% (95% CI, 42.0%-64.3%) in patients treated with sunvozertinib at 300 mg once per day (n = 107). The confirmed ORR was 44.9% (97.5% CI, 34.0%-56.1%). Two patients (1.9%) achieved a confirmed complete response (CR), and a third CR was unconfirmed. The median duration of response (DOR) was not been reached, and the 9-month DOR rate was 57%. Notably, responses were observed regardless of prior amivantamab-vmjw (Rybrevant) treatment. The best ORR in patients previously treated with amivantamab was 50%, and those naive to amivantamab had a best ORR of 53.8%.

Second, a global phase 1/2a study (NCT04036682) investigated zipalertinib (CLN-081; TAS6417) in patients with recurrent or metastatic 

 exon 20 insertion–mutated NSCLC previously treated with platinum-based chemotherapy. Results published in the 

 showed that responses occurred across all dose levels of zipalertinib, which ranged from 30 mg to 150 mg twice per day. Among all response-evaluable patients (n = 73), the confirmed partial response (PR) rate was in 38.4% (95% CI, 27%-49%). At the 100-mg dose level (n = 39), the confirmed PR rate was 41% (95% CI, 25%-56%).

Reckamp emphasizes the importance of understanding the differing mechanisms of action among these new-generation TKIs compared with other therapies, such as amivantamab. This distinction is crucial, suggesting the potential for sequencing these agents without the risk of cross-resistance, potentially expanding treatment options and improving outcomes for patients with 

 exon 20 insertion–mutated NSCLC, Reckamp concludes

Videos

Karen L. Reckamp, MD, MS, discusses emerging EGFR TKIs in EGFR Exon 20–Mutated NSCLC.

Dr Reckamp on Amivantamab in EGFR Exon 20–Mutated NSCLC

Karen L. Reckamp, MD, MS, professor of medicine, director, Division of Medical Oncology and Lung Institute, Cedars-Sinai Medical Center, associate director, Clinical Research, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, discusses the role of amivantamab-vmjw (Rybrevant) in the treatment of patients with non–small cell lung cancer (NSCLC) harboring 

the FDA approved amivantamab plus carboplatin and pemetrexed

 for the frontline treatment of patients with locally advanced or metastatic NSCLC harboring 

 exon 20 insertion mutations, as detected by an FDA-approved test. The agent 

 in May 2021 as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with 

 exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.

In the phase 3 PAPILLON study (NCT04538664), which supported the frontline approval of amivantamab plus chemotherapy, those treated with the combination (n = 153) experienced a median progression-free survival (PFS) of 11.4 months (95% CI, 9.8-13.7) vs 6.7 months (95% CI, 5.6-7.3) for those given chemotherapy alone (n = 155; HR, 0.40; 95% CI, 0.30-0.53; 

Reckamp explains that amivantamab has become the primary targeted therapy considered for the treatment of patients with advanced NSCLC harboring EGFR exon 20 insertion mutations. The EGFR- and MET-targeted antibody has demonstrated significant efficacy in previously treated patients, as well as in the frontline setting when combined with chemotherapy, she says. This dual-targeted approach has resulted in notable improvements in response rates and progression-free survival (PFS), she adds.

Reckamp emphasizes that the integration of amivantamab into treatment protocols represents a major shift in the treatment of patients with EGFR exon 20–mutated NSCLC. With improved outcomes over chemotherapy alone, amivantamab offers a valuable option for patients, potentially leading to better overall survival and disease control, she concludes.

Karen L. Reckamp, MD, MS, discusses the role of amivantamab in the treatment of advanced non–small cell lung cancer.

During the 2023 International Lung Cancer Congress, 

® asked experts from the lung cancer field to discuss the challenges of the ongoing cisplatin and carboplatin shortages in the United States and detail how they are adapting in their practices.

Karen L. Reckamp, MD, MS, professor of medicine, director, Division of Medical Oncology and Lung Institute at Cedars-Sinai Medical Center and associate director at Clinical Research, Cedars-Sinai Cancer Institute

Edward Kim, MD, MBA, physician-in-chief at City of Hope Orange County and vice physician-in-chief at City of Hope National Medical Center

Heather Wakelee, MD, professor of medicine and chief of the Division of Oncology at Stanford University School of Medicine; deputy director and division chief of Medical Oncology at Stanford Cancer Institute; and president of the International Association for the Study of Lung Cancer

Edgardo Santos MD, FACP, FCCP, clinical affiliate associate professor at Florida Atlantic University and treasurer of the Florida Society of Clinical Oncology

Lyudmila Bazhenova, MD, medical oncologist and professor of clinical medicine at the University of California San Diego Moores Cancer Center

A survey conducted by the National Comprehensive Cancer Network Best Practices Committee published in June 2023 showed that 93% of the 27 United States cancer centers polled were experiencing a shortage of carboplatin, and 70% were facing a shortage of cisplatin. The survey showed that 100% of cancer centers were still able to treat patients who need cisplatin without any delays or claim denials; however, only 64% of centers reported being able to keep all patients who were receiving carboplatin on their current regimen. Additionally, 20% of surveyed institutions shared that they could continue this prescription for some but not all patients.

In April 2023, the Society of Gynecologic Oncology (SGO) recommended that clinical practices minimize ordering non-essential platinum chemotherapy, increase the interval between cycles, and reduce the total platinum dose when clinically acceptable. They also recommended that practices consider minimizing or omitting cisplatin or carboplatin for patients with recurrent platinum-resistant ovarian and other cancers and round doses down to the nearest vial size to ensure efficient use. Lastly, it was stated that platinum-based chemotherapy be reserved for curative-intent treatment or for patients in whom prolonged clinical benefit is anticipated.

Experts discuss the challenges of the ongoing cisplatin and carboplatin shortages in the United States and detail how they are adapting in their practices.

Lung Cancer Experts Detail Challenges of Cisplatin/Carboplatin Shortages

Karen L. Reckamp, MD, MS, professor of medicine, director, Division of Medical Oncology and Lung Institute, Cedars-Sinai Medical Center, associate director, Clinical Research, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, discusses current and emerging antibody-drug conjugates (ADCs) in lung cancer in addition to highlighting the development of patritumab deruxtecan (HER3-DXd) and telisotuzumab vedotin (ABBV-399; Teliso-V).

The body of evidence favoring the use of ADCs in lung cancer continues to expand with the addition of new agents to the landscape, Reckamp begins. The HER2-targeted agent fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) is currently the only ADC approved by the FDA for adult patients with unresectable or metastatic, 

-mutated non-small cell lung cancer (NSCLC) that was previously treated in the first line, Reckamp states.

The agent gained accelerated approval in August, 2022, based on findings from the phase 3 DESTINY-Lung02 study (NCT04644237)

, in which the confirmed overall response rate with T-DXd was 58% and the median duration of response was 8.7 months, Reckamp reports. T-DXd has been evaluated across multiple trials within lung cancer, and produced consistent response rates across dose levels.

In addition to T-DXd, there are 2 ADCs with breakthrough designation in NSCLC: patritumab deruxtecan (HER3-DXd) and telisotuzumab vedotin (ABBV-399; Teliso-V), Reckamp continues, noting that both agents continue to be investigated.

HER3-DXd was granted breakthrough designation status by the FDA

-mutated NSCLC who developed resistance to EGFR TKIs in December, 2021. The regulatory decision was based on data from the dose escalation portion and 2 expansion cohorts of the phase 1 U31402-A-U102 study (NCT03260491). In this study, the agent produced a confirmed ORR of 39% in the heavily pretreated population, Reckamp notes.

In January, 2022, the FDA granted breakthrough designation to the MET-targeted ADC Teliso-V for patients with advanced or metastatic 

 wild-type NSCLC showing high levels of c-Met overexpression and disease progression on or after prior platinum-based chemotherapy. The agent has been shown to elicit responses in both patients with high 

Karen L. Reckamp, MD, MS, discusses current and emerging antibody-drug conjugates in lung cancer in addition to highlighting the development of patritumab deruxtecan and telisotuzumab vedotin.
 

Dr Reckamp on the Landscape of Current and Emerging ADCs in NSCLC

Karen L. Reckamp, MD, MS, professor of medicine, director, Division of Medical Oncology and Lung Institute, Cedars-Sinai Medical Center, associate director, Clinical Research, Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, discusses findings from an exploratory analysis of the added benefit of with adjuvant atezolizumab (Tecentriq) in the phase 2 LCMC3 trial (NCT02927301) in resectable stage IB to IIIB non–small cell lung cancer (NSCLC).

The single-arm, multicenter LCMC3 trial investigated the use of neoadjuvant atezolizumab followed by surgical resection and optional adjuvant atezolizumab in this population. Patients were required to have stage IB to IIIA NSCLC without 

 sensitizing alterations, and measurable disease.

All patients received 2 cycles of neoadjuvant atezolizumab prior to surgery. Individuals who experienced some clinical benefit from neoadjuvant therapy according to investigator assessment were provided with the option to receive up to 1 year of adjuvant atezolizumab after adjuvant chemotherapy with or without radiotherapy. The trial was previously reported to have met its primary end point of a major pathologic response (MPR) rate of more than 20% in patients who received neoadjuvant therapy. 

An exploratory analysis of LCMC3 compared outcomes in patients who received adjuvant atezolizumab after undergoing treatment with neoadjuvant atezolizumab and surgical resection vs those who did not, Reckamp says. At the time of data-cut off, the MPR-evaluable population consisted of 137 patients. Of these patients, 21% had an MPR. Patients in the MPR-evaluable group experienced a 3-year disease-control rate (DCR) of 72%, and a the 3-year overall survival (OS) rate of 82%. The median duration of follow-up for these data were 3.0 and 3.1 years, respectively.

Further analysis of patient outcomes according to those who received optional adjuvant atezolizumab or not, showed a survival benefit in the adjuvant atezolizumab group, Reckamp reports. The 3-year disease-free survival (DFS) rate in this group was 83% vs 64% in the non-adjuvant atezolizumab group. Similarly, 3-year OS rates were 89% and 77%, respectively. Regarding safety, 63% of patients in the adjuvant atezolizumab safety population (n = 57) experienced treatment-related adverse effects (AEs).

Although these data are encouraging, LCMC3 was not a randomized, controlled trial, Reckamp notes. Therefore, these outcomes may not be entirely attributable to the impact of adjuvant atezolizumab, Reckamp concludes.

Dr. Reckamp reports working as an independent contractor for Mirati, Genentech, Blueprint, Calithera, Daiichi Sankyo, Elevation Oncology, Janssen, Amgen, AstraZeneca, EMD Serano, GSK, Merck, Seattle Genetics, and Takeda; she reports receiving institutional support from Mirati, Genentech, Blueprint, Calithera, Daiichi Sankyo, Elevation Oncology, and Janssen.

Karen L. Reckamp, MD, MS, discusses updated findings from the phase 2 LCMC3 trial in resectable stage IB to IIIB non–small cell lung cancer. 


Dr Reckamp on the Effect of Adjuvant Atezolizumab on Patient Outcomes in Resectable Stage IB-IIIA NSCLC

Karen L. Reckamp, MD, MS, director of medical oncology, medical oncology director of the Women’s Guild Lung Institute, associate director for clinical research, Cedars-Sinai Cancer, discusses targeted therapy options for rare mutations in non—small cell lung cancer (NSCLC).

 mutations are the most prominent rare mutations in NSCLC, says Reckamp. They are common in patients with a history of smoking, she adds.

In June 2017, the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) gained FDA approval for the treatment of patients with metastatic NSCLC whose tumors express the 

 V600E mutation. The approval was based on findings from a single-arm, phase II trial (NCT01336634) that demonstrated a 2-year overall survival rate of 51% with the combination.

Less than 1% of patients with NSCLC harbor an 

 fusion, says Reckamp. Though it is an exceedingly rare mutation, larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) were granted accelerated approval in 2018 and 2019, respectively, for the treatment of patients with 

-positive solid tumors. The indications are specific to patients who have a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have progressed on therapy or have no alternative treatments.

Performing comprehensive genomic testing is critical to identifying these rare aberrations, concludes Reckamp.

Karen L. Reckamp, MD, MS, discusses targeted therapy options for rare mutations in non–small cell lung cancer.

Dr. Reckamp on Targeted Therapy Options for Rare Mutations in NSCLC

activating mutations were described in lung cancer over a decade ago, and in that time, targeted therapy with epidermal growth factor receptor (

) tyrosine kinase inhibitors (TKIs) have become the treatment of choice as first-line therapy. Targeted therapy improves responses and progression-free survival when compared with chemotherapy in these patients with advanced disease. Despite improvements in outcomes, resistance develops and the majority of patients expe- rience tumor progression and are not cured. The intro- duction of third-generation 

TKIs that effectively block activating mutations and the T790M resistance mutation while sparing wild-type 

has led to improved outcomes following the development of resis- tance. The future of 

therapy will explore the use  of these agents and combinations to potentially delay or eliminate resistance to increase efficacy and ultimately survival. This review will focus on current therapies used in the first-line setting for advanced 

mutation positive non—small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Lung cancer is the leading cause of cancer related mortality worldwide in both men and women.

 Patients with advanced epidermal growth factor receptor (EGFR) mutated non—small-  cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, show improved progression-free survival (PFS) compared with standard chemo- therapy as first-line therapy.

 Unfortunately, patients develop resistance through multiple routes, including acquired 

 In order to combat this resistance, second- and third-generation 

TKIs have been developed.  In order to prevent or delay the development of resistance, multiple strategies have been investigated, such as the  combina- tion of high-dose pulses with low-dose continuous 

TKI therapy or co-targeting bypass signaling pathways as in the com- bined inhibition of both 

 The development of third-generation TKIs has improved patient outcomes; however, therapeutic resistance still occurs. As the options for therapy increase, the available data should be considered in choosing a frontline treatment.

TKIs have been established as frontline therapy for patients with metastatic 

mutant lung. Differentiating between these treatment options requires an evaluation of the studies that have been performed.

The IPASS trial led the field, and was a randomized, phase 3 trial that compared gefitinib to carboplatin and paclitaxel  in 1217 previously untreated never or light ex-smokers  with advanced NSCLC, but did not require 

mutation. The pri- mary endpoint was PFS, and at 12 months, the PFS was 24.9% with gefitinib and 6.7% with carboplatin/paclitaxel. In the sub- group of patients with an 

mutation, PFS was significantly longer among those who received gefitinib.

mutation had improved PFS with chemotherapy, highlighting the importance of molecularly testing for activating 

A randomized, phase 3 trial compared gefitinib versus carboplatin/paclitaxel in previously untreated patients with 

 Analysis of the first 200 patients revealed that PFS was significantly longer in patients in the gefitinib group resulting in early termination. The gefitinib group had a median PFS of 10.8 versus 5.4 months in the chemotherapy group and a higher response rate of 73.7% versus 30.7%.

A third study comparing gefitinib and cisplatin plus docetaxel had similar results.

 This randomized, phase 3 study involved   177 previously untreated patients diagnosed with stage IIIB/IV NSCLC or postoperative recurrence with 

mutations and evaluated PFS as the primary endpoint. The gefitinib group had significantly longer median PFS compared with the cisplatin   plus docetaxel group (9.2 versus 6.3  months).

A randomized, phase 3 trial compared erlotinib with  carbo- platin/gemcitabine in 165 patients with stage IIIB/IV NSCLC and 

mutations.5 The analysis of PFS included 82 patients in the erlotinib group and 72 in the chemotherapy   group. Median PFS was significantly longer in the patients treated with erlotinib than those treated with chemotherapy (13.1 versus 4.6 months).

The EURTAC trial compared erlotinib versus platinum-based chemotherapy for first-line treatment of patients with advanced NSCLC with 

mutations in a randomized, phase 3 trial.

   In that study, 86 patients received erlotinib and 87 received standard chemotherapy. The preplanned interim analysis showed the study met its primary endpoint and enrollment was stopped. The median PFS in the erlotinib group was 9.7 months com-  pared with 5.2 months in the chemotherapy  group.

The LUX-Lung 3 study was a randomized, phase 3 trial  that compared afatinib to pemetrexed/cisplatin in  previously

untreated EGFR-positive stage IIIB/IV NSCLC patients.

 The study enrolled 345 patients who were randomly assigned in a  2:1 ratio and stratified by 

mutation (exon 19 deletion, L858R, or other). The median PFS was 11.1 months for the afatinib group and 6.9 months for the chemotherapy group. Median PFS among patients with exon 19 deletions and L858R deletions was 13.6 months for afatinib and 6.9 months for chemotherapy. The LUX-Lung 6 trial randomized 364 patients with previ- ously untreated 

mutation positive stage IIIB/IV NSCLC to receive either afatinib (242 patients) or gemcitabine-cisplatin (122 patients) a 2:1 ratio and stratified patients by 

muta- tion (exon 19 deletion, L858R, or other).4 Median PFS in the afatinib group was 11.0 months and 5.6 months in the gemcit- abine-cisplatin group.

A pooled analysis of LUX-Lung 33 and LUX-Lung 64 in- cluded 631 of the 709 patients randomized and evaluated overall survival (OS) in patients with exon 19 (n = 355) and exon 21 mutations (n = 276).

 OS was significantly longer in  the del19-positive tumors in the afatinib group than in the chemotherapy group (31.7 versus 20.7 months). There were   no significant differences by treatment group for patients with 

L858R-positive tumors. This study showed that OS was improved for patients with del19 

The LUX-Lung 7 trial was a randomized phase 2B trial that compared first-line treatment with either afatinib or gefitinib  in patients with 

 In the study, 160 patients received afatinib and 159 patients received gefitinib until disease progression. PFS was 11.0 months with afatinib and 10.9 months with gefitinib and median  time

to treatment failure was 13.7 months with afatinib and 11.5 months with gefitinib, and the results were statistically signifi- cant. Furthermore, survival was increased with afatinib at 27.9 versus 24.5 months, but the result was not   significant.

The current frontline options with afatinib, erlotinib, and ge- fitinib offer improved outcomes over standard chemotherapy in 

-mutant NSCLC patients. Toxicities are manageable and most commonly include rash, and skin toxicity, and diarrhea.

 Despite the benefit to patients, progression invariably occurs so we must consider novel strategies that might increase  survival.=

Enhancing outcomes for patients may require combination therapy or new generation inhibitors that can prevent or over- come resistance mechanisms. The strategies with early results include combination erlotinib and bevacizumab, afatinib and cetuximab, and osimertinib as first-line therapy for 

mu- tant NSCLC, and other agents and combinations are under investigation.

A randomized, phase 2 study in 154 patients with stage IIIB/ IV or recurrent non-squamous NSCLC with 

mutations  and no previous therapy for advanced disease compared erlo- tinib alone versus erlotinib plus bevacizumab.

 The median PFS was 16.0 months in the erlotinib plus bevacizumab group   and 9.7 months in the erlotinib alone group. Additional studies are ongoing to confirm these results and assess  toxicities.

Osimertinib, a third-generation EGFR TKI, is approved  as treatment for patients with 

TKI resistance due to emergence of the T790M mutation, and demonstrated  over 50% objective response rate (ORR).

 With the hypothesis that early treatment with osimertinib can prevent the emergence of T790M as a mechanism of resistance and improve PFS, cohorts were studied using osimertinib as first-line therapy. Sixty pa- tients from 2 phase 1 expansion cohorts of the original AURA trial received either 80 mg per day (n = 30) or 160 mg per day   (30 patients) of osimertinib as first-line therapy. The ORR was 77%. Median PFS was 19.3 months for the 160 mg dose, and  has not yet been reached for the 80 mg dose.

  This early data   are promising, and a phase 3 trial (FLAURA) is evaluating the efficacy of osimertinib in treatment-naïve 

mutation posi- tive NSCLC patients  (NCT02296125).

Afatinib plus cetuximab demonstrated clinical activity in 

-mutated lung cancers with acquired resistance compared with gefitinib or erlotinib, both with and without T790M mutations in a phase 1b study.

  This combination is now   being studied as a frontline therapy for 

Central nervous system (CNS) metastases, including leptome- ningeal carcinomatosis, are a challenge in patients with 

mutation positive lung cancer. Progression within the brain  often occurs in the absence of systemic tumor growth due to inadequate drug concentration in the CNS. Pulse dose erlotinib has been shown to be tolerated while increasing penetration   into the brain.

 A phase 1 study evaluated twice weekly pulse dose erlotinib at 1200-mg days 1 and 2 followed by 50 mg   on days 3 to 7 in treatment-naïve NSCLC patients with 

 The study demonstrated similar survival and responses seen in phase 3 trials, but of the 34 patients enrolled, none had progression in an untreated metastasis or developed new CNS metastases while on study. Additional trials evaluat-  ing activity of next-generation 

inhibitors in patients with CNS metastases are planned.

TKIs is effective, but patients develop resis- tance, most commonly due to T790M. Molecular analysis of cir- culating tumor cells or cell-free DNA may provide a strategy for monitoring changes in tumor genotypes and the development of drug resistant mutations during treatment. One study found  that the T790M was detectable in pretreatment tumor biopsies and circulating tumor cells during treatment and that T790M mutations were associated with reduced PFS (7.7 versus 16.5 months), and an increase in the number of cells with T790M mutations correlated with disease  progression.

TKIs in the frontline setting are ongoing and the results are forthcoming. These trials will help clarify the optimal use of TKIs in 

mutation positive NSCLC, and future studies will address the question of proper sequencing of therapy to provide the best outcomes for patients. The timing of third-generation EGFR inhibitors, such  as earlier use of osimertinib will likely lead to new mechanisms  of resistance, the emergence of the C797S 

 Additional studies to understand these mecha- nisms and therapies to overcome resistance will be  needed.

Emily A. Barber is with the University of California, Irvine, and Karen L. Reckamp is with the City of Hope Comprehensive Cancer Center.

Karen Reckamp discloses that she has provided consultant services to Amgen, Ariad, Astellas, Nektar, and received research support (to institution) from Ariad, Bris-   tol Myers Squibb, Boehringer Ingelheim, Clovis, Eisai, Novartis, Pfizer, Xcovery, Adaptimmune, Medimmune,  Stemcentrx.

: Karen L. Reckamp, MD, City of Hope City of Hope Comprehensive Cancer Center, 1500 E. Du- arte Road, Bldg 51, Duarte, CA 91010. phone: (626)   256-4673,

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Articles

This review will focus on current therapies used in the first-line setting for advanced EGFR mutation positive non–small cell lung cancer (NSCLC) followed by emerging data that may lead to a transition in the choice for initial therapy in these patients.

Karen L. Reckamp, MD, MS