Disease Analysis: Non-Small Cell Lung Cancer (NSCLC)
Publisher: Datamonitor Healthcare
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Disease Overview
Lung cancer is generally categorized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Of these, NSCLC is the most common type of lung cancer, accounting for roughly 85% of all cases. NSCLC can be further divided into non-squamous and squamous NSCLC histologies. Squamous NSCLC refers to patients with squamous cell carcinoma, whereas non-squamous NSCLC includes patients with adenocarcinoma, large cell carcinoma, and other less common subtypes. Incidence of adenocarcinoma and squamous cell carcinoma varies greatly by both geographic region and gender. In general, adenocarcinoma comprises approximately 30–50% of all lung cancer cases, while squamous cell carcinoma accounts for roughly 25–35%.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2021, there were 1.8 million incident cases of non-small cell lung cancer (NSCLC) worldwide, and expects that number to increase to 1.9 million incident cases by 2027. The majority of NSCLC diagnoses (65.4%) worldwide are in males, ranging from 52.9% to 72.1% across regions.
- In recent years, the number of therapies targeting specific sensitizing mutations in metastatic NSCLC has drastically increased, permanently altering the treatment landscape. Many of the new drugs have shown dramatically increased response rates over the previous standard-of-care therapies. However, given the relatively small percentage of metastatic NSCLC patients presenting with each oncogenic driver, competition is fierce and first-to-market advantage is critical.
- Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-targeted monoclonal antibodies for NSCLC are forecast to remain the best-selling class of drugs for this indication. Keytruda was the first PD-1/PD-L1 inhibitor to gain regulatory approval for first-line NSCLC patients without an oncogenic driver and has risen to dominance in this market as label expansions have broadened its target patient population and as late-phase trials have revealed consistently positive data. Furthermore, the commercial potential of this class of drugs will increase over the forecast period as the use of checkpoint inhibitors will likely soon extend beyond the metastatic patient population. Label expansions into earlier treatment settings may provide an opportunity for the other checkpoint inhibitors to differentiate themselves from Keytruda and carve out a niche in this lucrative market.
- PD-L1 inhibitor Imfinzi’s approval as sequential therapy for locally advanced patients following chemoradiation minimizes its direct competition with established immunotherapies, allowing the drug to secure a modest market share. Furthermore, its development program in combination with novel therapies monalizumab, oleclumab, and domvanalimab could potentially deter competition expected from other checkpoint inhibitors in development for the Stage III setting.
- Third-generation EGFR inhibitor Tagrisso is now the first-line standard-of-care treatment for NSCLC patients whose tumors harbor activating EGFR mutations (exon 19 deletion or L858R point mutation). Despite competition from Tarceva, Iressa, Gilotrif, Vizimpro, and Alunbrig, Tagrisso will continue to dominate the EGFR inhibitor market due to continued uptake and a label expansion into the adjuvant setting. However, Janssen’s ongoing Phase III MARIPOSA study of Rybrevant in combination with lazertinib is the first head-to-head trial against Tagrisso, and the combination could eventually threaten Tagrisso’s position in the first-line setting.
- Both Rybrevant and Exkivity have been approved for metastatic NSCLC patients whose tumors harbor an exon 20 insertion mutation in EGFR, a patient population where there were previously no approved targeted therapies. Although Exkivity has demonstrated more favorable overall survival data, Rybrevant won the first-to-market advantage and will likely dominate this setting. However, the relative rarity of this mutation limits the commercial potential of an approval in this patient population, and both therapies are also in development for the treatment of other actionable mutations.
- Alecensa has become the new first-line standard of care for ALK rearrangement-positive NSCLC. The Phase III ALEX study demonstrated superior progression-free survival when treated with Alecensa compared with previous standard of care Xalkori. Alecensa will likely remain the class leader even though it will face competition in the first-line setting from other ALK inhibitors such as Zykadia, Alunbrig, and Lorbrena. Dual ALK/ROS1 inhibitor Lorbrena is also approved in both the first- and second-line settings, but has experienced only modest uptake thus far.
- The ALK inhibitors Rozlytrek and Xalkori are both approved for the treatment of metastatic NSCLC patients whose tumors have a ROS1 rearrangement or fusion. Rozlytrek is also approved as a monotherapy for patients with NTRK+ gene fusions. The combined data from Rozlytrek’s development program compare favorably to the data for Xalkori, particularly in patients with CNS metastases at baseline. ROS1 gene rearrangements are present in 1–2% of NSCLC patients, while NTRK fusions are present in approximately 0.2% of cases.
- The combination of BRAF inhibitor Tafinlar and MEK inhibitor Mekinist has become the standard of care for advanced or metastatic NSCLC with BRAF V600E mutations. However, only 1–2% of NSCLC patients have a BRAF V600E mutation, which limits the combination’s commercial potential.
- Two MET inhibitors, Tabrecta and Tepmetko, have been approved in the US and Japan for NSCLC patients with a MET exon 14 skipping mutation. Both drugs are also in development for MET-amplified NSCLC and for patients with EGFR-mutated, c-MET-amplified NSCLC who have progressed after EGFR inhibitor treatment. Potential label expansions into these treatment settings represent a noteworthy market opportunity. Approximately 1–4% of NSCLC patients have a MET exon 14 skipping mutation. Furthermore, telisotuzumab vedotin is also in development for c-MET-amplified NSCLC.
- Retevmo was the first drug to be approved for the treatment of patients with RET fusion-positive NSCLC, and the confirmatory Phase III LIBRETTO-431 trial is ongoing. In its pivotal Phase I/II trial, Retevmo demonstrated efficacy in RET fusion-positive patients, as well as in a subgroup of patients with brain metastases. However, Retevmo will face competition from Gavreto, which has also been approved in the US and Europe.
- The approval of the first KRAS inhibitor, Lumakras, for previously treated patients with KRAS G12C-mutant NSCLC is an encouraging step forward for a patient population that was previously thought to be undruggable. This is a significant market opportunity for Lumakras, given that approximately 13% of NSCLC patients have KRAS p.G12C mutations. Adagrasib, another KRAS inhibitor, is in development for the second-line or later treatment of patients with KRAS G12C-mutant NSCLC.
- As checkpoint inhibitor regimens dominate in the first-line setting for patients without sensitizing mutations, effective treatments for the post-immunotherapy setting remain the largest unmet need within the indication. Treatment for these patients is largely palliative, and patients currently have very limited options. A number of therapies, including Cabometyx, Lenvima, sitravatinib, and tusamitamab ravtansine, are in development for this treatment setting.
- The overall likelihood of approval of a Phase I NSCLC asset is 8.6%, and the average probability a drug advances from Phase III is 38.3%. NSCLC drugs, on average, take 9.1 years from Phase I to approval, compared to 9.9 years in the overall oncology space.
- Key upcoming catalysts include an NDA filing for plinabulin, as well as PDUFA dates for Libtayo and Imfinzi in the first-line setting.
CONTENTS
10 OVERVIEW
10 Latest key takeaways
12 DISEASE BACKGROUND
12 Definition
12 Risk factors
13 Symptoms
14 Screening
14 Diagnosis
14 Prognosis
15 Patient segmentation
17 TREATMENT
17 Early-stage NSCLC (Stage I–II; all subtypes)
17 Advanced NSCLC (Stage IIIa–IIIc; all subtypes)
17 Metastatic NSCLC: molecular profiling
18 Metastatic NSCLC: EGFR+
19 Metastatic NSCLC: EGFR+, second line
20 Metastatic NSCLC: KRAS G12C mutation
20 Metastatic NSCLC: ALK+
21 Metastatic NSCLC: ROS1+
22 Metastatic NSCLC: BRAF V600E mutation
23 Metastatic NSCLC: MET exon 14 skipping
24 Metastatic NSCLC: RET+
25 Metastatic NSCLC: NTRK+
26 Metastatic NSCLC: HER2+
26 Metastatic NSCLC: PD-L1+ (≥50%)
27 Metastatic NSCLC: PD-L1+ (≥1–49%)
28 Metastatic NSCLC: all other
29 Metastatic NSCLC: maintenance therapy
30 Metastatic NSCLC: all other second line or later
32 EPIDEMIOLOGY
32 Incidence methodology
35 Prevalence of common non-small cell lung cancer biomarkers
37 MARKETED DRUGS
48 PIPELINE DRUGS
75 KEY REGULATORY EVENTS
75 Pemetrexed Baxter Wins EMA Thumbs Up
75 Celltrion’s Vegzelma Becomes Fourth US-Approved Bevacizumab
75 Amneal Makes First Biosimilar Launch With US Bevacizumab
75 LIBRETTO Trial Scores Two More Retevmo Approvals
76 Poziotinib Fails To Get FDA Panel Support Though Members Not As Dubious As Agency
76 First-Of-Kind Treatments Win Funding In England & Wales
77 Celltrion To Jostle For Space In Crowded EU Bevacizumab Market
77 Daiichi Sankyo/AstraZeneca Get Two Lucky Breaks For Enhertu
78 EQRx Revises Plans To Get Chinese Licensed Drugs To US Market
78 Roche Disappointed By English Funding Rejection For Gavreto But Will Not Appeal
79 Exkivity 2L EU Filing Pulled
79 Novartis/BeiGene Opt For PD-1/TIGIT Combo For NSCLC In US
79 FDA Accepts Merck’s sBLA For Keytruda
80 Celltrion Gets Ready To Face The Competition After European Bevacizumab Nod
80 EMA Begins Evaluating MAA For Adagrasib
81 Innovent And Etana Get Indonesian Bevacizumab Nod
81 Merck KGaA’s Tepmetko Secures English Funding For NSCLC
81 Tislelizumab & Tremelimumab Among Latest Filings In EU
81 Tabrecta Among Four Drugs To Receive Thumbs Up From EMA
82 Lilly To Decide Next Steps After Formal FDA ‘Nay’ For First Chinese PD-1
82 Novartis Due For Oral Explanation At EMA For Capmatinib
82 Pricing Deals Spell Good News For Exkivity & Vimizin In England
83 Scotland Okays First ILAP Drugs For Reimbursement
83 BMS Gets First Immunotherapy Approval In Neoadjuvant Lung Cancer, Quickly
83 US Poziotinib Approval Expected
84 US FDA Puts Mirati’s KRAS Challenger To Amgen In The Slow Lane
84 Foreign Data: Sintilimab’s Development Shows What Not To Do When Pursuing US Approval
84 Casualty Of Change? Innovent/Lilly’s Chinese PD-1 Inhibitor Sintilimab Falls Hard At US FDA Panel
85 New Submissions Under FDA Review
85 Tremelimumab Filed In EU For NSCLC
85 Keeping Track: Breakthrough Designations Fuel Expansion Of Genomically-Defined NSCLC Therapy
85 Pfizer, CStone Score China’s Seventh Immuno-Oncology Approval
86 13 New Drugs On Track For EU Approval
86 Rx For Immuno-Oncology Excess? Top US FDA Cancer Officials Take On Development ‘Wild West’
86 Spectrum Eyes Niche NSCLC Market With Poziotinib NDA
87 Evrysdi & Tagrisso Among Myriad Products To Win English Funding
87 Sotorasib Gets Green Light From EMA For KRAS G12C Mutated NSCLC
87 Scotland’s HTA Body OKs New Indications For Tagrisso And Tecentriq
88 EMA Schedules Oral Explanation Meetings For Four Sponsors
88 Tyvyt Regulatory Setback
89 PROBABILITY OF SUCCESS
90 LICENSING AND ASSET ACQUISITION DEALS
90 Boryung Enters Into Agreement With Eli Lilly
90 Sareum’s Lead Asset Hangs In Balance As GSK Withdraws From Oncology Pact
90 Erasca Five-Year Collaboration With MD Anderson Focused On MAPKlamp Combo
91 GSK Makes ADC Pipeline Comeback With Mersana Deal
91 Sanofi, Innovent Link On China Oncology Ambitions As ADCs Surge
92 Merck And Sichuan Kelun Enter Licensing Agreement
92 Royalty Pharma Acquires Ex-US Royalty Interest In Blueprint’s Gavreto
92 BMS Hopes Turning Point Buyout Will Fare Better Than Roche’s Ignyta Acquisition
92 Regeneron Takes Full Libtayo Rights As March Into Oncology Progresses
93 Bayer Shuffles Atara’s CAR-Ts Out Of Its Cell Therapy Deck
93 Taiho To Pay $275m Up Front For CLN-081/TAS6417
93 Gilead Gets 5T4-Targeted NK Cell Therapy Candidate From Dragonfly
94 Lilly/Innovent Deal Follows FDA’s Rejection Of Tyvyt In Lung Cancer
94 Tianjin Tasly Inks $40m Licensing Deal With Sutro For ADC Cancer Treatment
94 Novartis Expands BeiGene Tie-Up To TIGIT Inhibitor In $1bn-Plus Option Deal
95 Taiho Takes Up Japan/Asia Option For Arcus Oncology Antibodies
95 Blueprint May Corner EGFR Exon Mutated Lung Cancer Market With Lengo Buyout
95 Deal Watch: Sanofi To Tap Owkin’s AI, Machine Learning In Oncology
96 Zai Lab Licenses Two Blueprint Medicines EGFR Inhibitors
97 CLINICAL TRIAL LANDSCAPE
98 Sponsors by status
99 Sponsors by phase
100 Recent events
113 DRUG ASSESSMENT MODEL
113 EGFR inhibitors
115 ROS1 and NTRK gene fusions
116 ALK inhibitors
117 KRAS inhibitors
117 RET inhibitors
118 BRAF inhibitors
118 PARP inhibitors
119 MET inhibitors
119 PD-1/PD-L1 inhibitors
121 CD73 inhibitor
122 TIGIT inhibitors
122 Natural killer cell therapy
123 Microtubule inhibitors
123 Folate analog metabolic inhibitor
124 VEGF inhibitors
124 Interleukin 1β antagonist
124 Post-immunotherapy
126 HER2 inhibitors
127 MARKET DYNAMICS
128 FUTURE TRENDS
128 Keytruda is forecast to remain the leading immunotherapy approved for NSCLC
128 Checkpoint inhibitors are expected to move into earlier stages of NSCLC
129 Approvals and subsequent uptake of new therapies in the post-immunotherapy setting will contribute significantly to growth in the NSCLC market
129 Alecensa is expected to continue leading the ALK inhibitor class due to strong results in the first-line setting, despite potential competition
130 Tagrisso will remain the best-selling EGFR inhibitor due to continued uptake in the first-line setting and a label expansion into the adjuvant setting
130 New EGFR inhibitors will address the EGFR exon 20 insertion mutation, which is associated with poor response to current treatments
131 The approval and uptake of MET inhibitors is expected to address unmet needs in patients with exon 14 skipping mutations
131 Recent approvals and subsequent uptake of therapies targeting new mutational drivers will support growth in the NSCLC market over the forecast period
131 Generic or biosimilar erosion of key brands will have minimal impact on growth
133 CONSENSUS FORECASTS
140 RECENT EVENTS AND ANALYST OPINION
140 Poziotinib for NSCLC (September 22, 2022)
141 Lumakras for NSCLC (September 12, 2022)
143 Enhertu for NSCLC (September 11, 2022)
145 Opdualag for NSCLC (September 9, 2022)
147 Lumakras for NSCLC (August 30, 2022)
148 Ilaris for NSCLC (August 15, 2022)
150 Rybrevant for NSCLC (June 3, 2022)
152 Rybrevant for NSCLC (June 3, 2022)
153 CLN-081 for NSCLC (May 31, 2022)
155 Adagrasib for NSCLC (May 26, 2022)
156 CAN-2409 for NSCLC (May 26, 2022)
157 Multiple Drugs for NSCLC (May 11, 2022)
158 Sintilimab for NSCLC (February 10, 2022)
159 Bavencio for NSCLC (February 8, 2022)
161 KEY UPCOMING EVENTS
164 KEY OPINION LEADER INSIGHTS
165 UNMET NEEDS
166 BIBLIOGRAPHY
169 APPENDIX
LIST OF FIGURES
34 Figure 1: Trends in incident cases of NSCLC, 2018–27
48 Figure 2: Overview of pipeline drugs for NSCLC in the US
48 Figure 3: Pipeline drugs for NSCLC, by company
49 Figure 4: Pipeline drugs for NSCLC, by drug type
49 Figure 5: Pipeline drugs for NSCLC, by classification
89 Figure 6: Probability of success in the NSCLC pipeline
97 Figure 7: Clinical trials in NSCLC
97 Figure 8: Top 10 drugs for clinical trials in NSCLC
98 Figure 9: Top 10 companies for clinical trials in NSCLC
98 Figure 10: Trial locations in NSCLC
99 Figure 11: NSCLC trials status
100 Figure 12: NSCLC trials sponsors, by phase
113 Figure 13: Datamonitor Healthcare’s drug assessment summary for NSCLC
127 Figure 14: Market dynamics in NSCLC
128 Figure 15: Future trends in NSCLC
143 Figure 16: Lumakras for NSCLC (September 12, 2022): Phase III – CodeBreak 200
145 Figure 17: Enhertu for NSCLC (September 11, 2022): Phase II – DESTINY-LUNG02
148 Figure 18: Lumakras for NSCLC (August 30, 2022): Phase III – CodeBreak 200
150 Figure 19: Ilaris for NSCLC (August 15, 2022): Phase III – CANOPY-A (Adjuvant)
152 Figure 20: Rybrevant for NSCLC (June 3, 2022): Phase I – CHRYSALIS (Advanced NSCLC)
153 Figure 21: Rybrevant for NSCLC (June 3, 2022): Phase I – CHRYSALIS-2 (w/Lazertinib)
158 Figure 22: Tiragolumab and Tecentriq for NSCLC (May 11, 2022): Phase III – SKYSCRAPER-01
160 Figure 23: Bavencio for NSCLC (February 8, 2022): Phase III – JAVELIN Lung 100
161 Figure 24: Key upcoming events in NSCLC (one of five)
162 Figure 25: Key upcoming events in NSCLC (two of five)
162 Figure 26: Key upcoming events in NSCLC (three of five)
163 Figure 27: Key upcoming events in NSCLC (four of five)
163 Figure 28: Key upcoming events in NSCLC (five of five)
LIST OF TABLES
15 Table 1: Five-year survival rates of lung cancer, by stage at diagnosis
16 Table 2: Non-small cell lung cancer staging and corresponding TNM classifications
19 Table 3: Preferred branded first-line treatment regimens for patients with Stage IV EGFR+ NSCLC
20 Table 4: Preferred branded treatment regimens for patients who progress on first- and second-generation EGFR TKIs
21 Table 5: Preferred branded first- and second-line treatment regimens for patients with Stage IV ALK+ NSCLC
22 Table 6: Preferred treatment regimens for patients with Stage IV ROS1+ NSCLC
23 Table 7: Preferred treatment regimens for patients with Stage IV BRAF V600E mutated NSCLC
24 Table 8: Preferred treatment regimens for patients with Stage IV NSCLC and a MET exon 14 skipping mutation
25 Table 9: Preferred treatment regimens for patients with Stage IV RET+ NSCLC
26 Table 10: Preferred treatment regimens for patients with Stage IV NTRK+ NSCLC
27 Table 11: Preferred branded first-line treatment regimens for patients with advanced NSCLC and PD-L1+ TPS ≥50%
28 Table 12: Preferred branded first-line treatment regimens for patients with advanced NSCLC and PD-L1+ TPS ≥1–49%
29 Table 13: Preferred branded first-line treatment regimens for patients with advanced NSCLC
31 Table 14: Preferred branded second-line or later treatment regimens for patients with metastatic NSCLC
33 Table 15: Incident cases of NSCLC, 2018–27
35 Table 16: Incident cases of NSCLC, by gender, 2018
38 Table 17: Marketed drugs for NSCLC
50 Table 18: Pipeline drugs for NSCLC in the US
134 Table 19: Historical global sales, by drug ($m), 2017–21
137 Table 20: Forecasted global sales, by drug ($m), 2022–26
140 Table 21: Poziotinib for NSCLC (September 22, 2022)
142 Table 22: Lumakras for NSCLC (September 12, 2022)
144 Table 23: Enhertu for NSCLC (September 11, 2022)
146 Table 24: Opdualag for NSCLC (September 9, 2022)
147 Table 25: Lumakras for NSCLC (August 30, 2022)
149 Table 26: Ilaris for NSCLC (August 15, 2022)
151 Table 27: Rybrevant for NSCLC (June 3, 2022)
152 Table 28: Rybrevant for NSCLC (June 3, 2022)
154 Table 29: CLN-081 for NSCLC (May 31, 2022)
155 Table 30: Adagrasib for NSCLC (May 26, 2022)
156 Table 31: CAN-2409 for NSCLC (May 26, 2022)
157 Table 32: Multiple Drugs for NSCLC (May 11, 2022)
158 Table 33: Sintilimab for NSCLC (February 10, 2022)
159 Table 34: Bavencio for NSCLC (February 8, 2022)
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