Keytruda Poised for Another Knockout as Chemotherapy Combination Expands Its Reach to Squamous Histology in First-Line NSCLC

by Stephanie Amato | Jun 4, 2018
Co-Authored by Stephanie Hawthorne, Ph.D.

As 2018 rolls on, the battle for dominance in first-line metastatic non-small cell lung cancer (NSCLC) continues. Since the inception of checkpoint inhibitors in metastatic NSCLC in 2015, the immunotherapies Keytruda® (pembrolizumab, Merck & Co / MSD), Opdivo® (nivolumab, Bristol Myers Squibb / Ono Pharmaceuticals), and Tecentriq® (atezolizumab, Genentech / Roche / Chugai) have engaged in a fierce competition to capture the title of immunotherapy champion in this all important NSCLC space.

The fight for first-line began with a face-off between Keytruda and Opdivo monotherapy, which first reported at the European Society of Medical Oncology (ESMO) 2016 annual meeting. Keytruda came out the winner with positive results from its Phase III KEYNOTE-024 trial exhibiting significant progression-free survival (PFS) and overall survival (OS) benefit in patients who are PD-L1 positive (Tumor Proportion Score (TPS) ≥50%) regardless of histology (non-squamous or squamous)1. Opdivo was unable to match Keytruda’s results with a failed Phase III CheckMate-026 trial that did not meet its primary endpoint in patients with PD-L1 positivity at ≥5% based on their own PD-L1 assay2.  Keytruda was adopted as standard of care for those patients with TPS ≥50% PD-L1 expression, being utilized in approximately 50% of PD-L1 positive patients in the first-line as a monotherapy regardless of histology3. Patients with no or minimal PD-L1 expression were unable to join the immunotherapy bandwagon, and physicians continued treating these patients with platinum-based chemotherapy.

Keytruda struck another blow in May 2017 when it gained accelerated approval from the FDA for use in combination with Alimta® (pemetrexed, Eli Lilly) and carboplatin in non-squamous NSCLC patients based on the results from the randomized cohort G from the Phase II KEYNOTE-021 trial, irrespective of PD-L1 expression4. Results were validated at the American Association of Cancer Research (AACR) meeting in April 2018, as results of the Phase III KEYNOTE-189 trial evaluating Keytruda in combination with Alimta and platinum reported that the combination provides a significant increase in PFS and OS5. The combination offers non-squamous patients with any PD-L1 expression an immunotherapeutic option. The results also support the growing shift toward combining immunotherapy with chemotherapy, a combination rooted in the scientific rationale that the cytotoxic release of tumor antigens can enhance the anti-tumor immune response activated by checkpoint inhibitors6.  While Keytruda was the winner at AACR, Opdivo and Tecentriq each presented positive combination data keeping them in contention for first-line NSCLC (read a synopsis of those results here),  and the competition shows no signs of slowing down at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. All three of the major players - the reigning champion Keytruda, and the contenders Opdivo and Tecentriq – are still brawling to take a larger piece of the coveted first-line NSCLC immunotherapy pie.

At ASCO 2018, Keytruda entered the ring first with the presentation of the second-interim analysis of KEYNOTE-407 (NCT02775435), an international, placebo-controlled Phase III trial of 559 first-line patients with metastatic, wild-type squamous NSCLC patients randomized 1:1 to receive chemotherapy (carboplatin and paclitaxel or nab-paclitaxel) with either Keytruda (n=278) or placebo (n=281)9. In the intent-to-treat population, Keytruda plus chemotherapy demonstrated an OS benefit of 15.9 months compared to 11.3 months for chemotherapy alone (HR 0.64, p=0.0008). OS benefit was consistent across PD-L1 subgroups with 15.9 months (HR 0.61) for TPS <1%, 14.0 months (HR 0.57) for TPS 1-49% and not reached (HR 0.64) for TPS ≥50%. PFS for the treatment population was 5.4 months in the combination arm compared to 4.8 months in the chemotherapy arm (HR 0.56, p<0.0001); however, unlike OS, PFS benefit decreased with decreasing PD-L1 expression (PFS Hazard Ratio 0.37 for TPS≥50% cohort, HR 0.56 for TPS 1-49% cohort, and HR 0.68 for TPS <1% cohort), although significantly favored Keytruda for all expression levels. The ORR was 57.9% in the combination arm versus 38.4% in the chemotherapy arm. However, it remains unknown if the benefit of the combination is due to additive effects or synergistic immunogenicity that will ultimately improve the tail of the survival curve. Patients in the combination arm experienced comparable rates as people in the control arm for Grade ≥3 adverse events (69.8% vs 68.2%), most common of which were neutropenia and anemia. As expected, the addition of Keytruda increased immune-related adverse events; the most common Grade ≥3 included pneumonitis, colitis, and hepatitis. The combination had a marginally higher treatment discontinuation rate than chemotherapy alone (13.3% vs 6.4%). Results from KEYNOTE-407 complement the results previously presented at AACR 2018 for KEYNOTE-189 for patients with non-squamous histology, solidifying Keytruda plus Alimta and carboplatin as the new benchmark for first-line NSCLC regardless of histology or PD-L1 status and now allowing squamous patients with low or no PD-L1 expression level an immunotherapeutic option as well.

The Plenary Session on Sunday followed with the presentation of KEYNOTE-042 (NCT02220894) evaluating Keytruda as a monotherapy in a broader PD-L1 patient population for both non-squamous and squamous histologies10. This trial was initially designed as a confirmatory trial for KEYNOTE-042 to evaluate overall survival in patients with PD-L1 TPS ≥50%. However, the trial design was modified to include efficacy assessment not only in those patients who have high PD-L1 expression but also lower PD-L1 thresholds (TPS ≥20% and ≥1%). The trial included patients of any histology and TPS ≥1%, randomizing patients 1:1 to receive Keytruda monotherapy (n=637) or chemotherapy (carboplatin plus paclitaxel or pemetrexed; n=637). No crossover was permitted. The primary endpoint of OS in each of the three PD-L1 expression groups were met - in patients with PD-L1 TPS ≥50%, 20.0 vs 12.2 months (HR 0.69, p=0.0003); in patients with PD-L1 TPS ≥20%, 17.7 versus 13.0 months (HR 0.77, p=0.0020); and for the entire study population of patients with PD-L1 TPS ≥1%, 16.7 versus 12.1 months (HR 0.81, p=0.0018). In a sub-group analysis, squamous patients demonstrated a greater survival benefit than non-squamous patients (HR 0.75 vs 0.86). OS results suggest survival benefit in the whole population is driven by the benefit experienced by the high PD-L1 expressers (TPS ≥50%) given the relatively high hazard ratio when considering TPS ≥1%. This hypothesis was confirmed in an exploratory analysis of the TPS 1-49% subgroup, in which Keytruda failed to show OS benefit over chemotherapy (HR 0.92). Interestingly, across all PD-L1 expression groups, crossing of the survival curves was shown at about 6 months, where more patients initially died on Keytruda compared to chemotherapy and the durable responders accounted for the improved OS over time. Keytruda also failed to show an improvement in PFS or ORR compared to chemotherapy in the high PD-L1 group, with only a 0.7 month increase in median PFS [HR 0.81, p=0.0170 (not significant)] and 7.5% increase in ORR (39.5% vs 32.0%).  Safety data for Keytruda was in line with previous studies of Keytruda monotherapy with fewer patients experiencing Grade ≥3 adverse events than on chemotherapy (17.8% vs 41.0%), but discontinuation rates due to adverse events were similar (9.0% vs 9.4%) which was attributed to a longer treatment duration in the Keytruda arm. Although positive OS data is primarily driven by high PD-L1 expressers, data in the intent-to-treat (TPS≥1%) trial population could still support an expanded FDA label for Keytruda that allows its use as a monotherapy in a broader population than its current indication (PD-L1 TPS≥50%).   

With data from Sunday, Keytruda is poised to remain champion of the NSCLC first-line competition. The more pertinent question then becomes which patients should receive Keytruda monotherapy versus those that should receive Keytruda in combination with chemotherapy?

For patients with minimal or no PD-L1 expression (TPS <1%), the clear choice will be Keytruda plus chemotherapy, which demonstrated an OS benefit over chemotherapy for both non-squamous and squamous patients. No data is available for Keytruda monotherapy for these patients for either histology. Another potential option for these patients could be Opdivo plus Yervoy® (ipilimumab, Bristol-Myers Squibb / Ono Pharmaceuticals) based on CheckMate-227 preliminary results11, especially if the patient has a high tumor mutational burden.

For patients with moderate PD-L1 expression (TPS between 1%-49%), the cross-trial comparison is difficult as each trial evaluated patients with different histologies and used different TPS buckets for its survival analysis. KEYNOTE-042 reported OS for those ≥20% and ≥1% and for both non-squamous and squamous histologies. Despite statistical significance, the OS benefit is biased by the inclusion of a high proportion of patients with TPS ≥50% and exploratory analysis states that patients who fall into this moderate range of PD-L1 expression do not benefit from Keytruda monotherapy compared to chemotherapy alone. The OS benefit is clearer for Keytruda plus chemotherapy in this PD-L1 subtype. In non-squamous patients, the median OS has not been reached compared to 12.9 months for chemotherapy (HR 0.55)5 and in squamous patients, the median OS is 14.0 months versus 11.6 months for chemotherapy (HR 0.57)9. Given the statistically significant survival benefit, the Keytruda and chemotherapy combination will likely be the winner for patients who can tolerate chemotherapy, although the combination of Tecentriq plus Avastin® (bevacizumab, Genentech / Roche / Chugai) and carboplatin/paclitaxel could also be a future treatment option based on the results of IMpower 1508.

For patients with high PD-L1 expression (TPS ≥50%), both Keytruda alone and in combination with chemotherapy show a survival benefit over chemotherapy alone, but the choice between the two comes down to a cross-trial comparison of outcomes in the absence of a head-to-head comparison of these treatment options. Based on cross-trial comparisons, Keytruda plus chemotherapy has stronger data in each histology subgroup (NSq: not reached vs 10.0 months, HR 0.42, p=0.0001; Sq: 15.9 vs 11.3 months, HR 0.64, p=0.0008) than Keytruda histology agnostic data (NSq/Sq: 20.0 vs 12.2 months, HR 0.69, p=0.0003). However, other factors beyond efficacy data will influence the decision on how to treat these patients. Keytruda monotherapy will likely still be widely adopted given previous experience in this setting and its more tolerable or “chemo-free” profile for those who are too elderly/unfit to receive a platinum doublet or unwilling to receive chemotherapy (Grade ≥3 adverse events: 17.8% NSq/Sq Keytruda; 67.2% NSq Keytruda + chemo; 69.8% Sq Keytruda + chemo)10,5,9. Keytruda plus chemotherapy may be reserved for patients who need to achieve a quick response given symptomatic, aggressive, and/or high burden of disease, since it offers a higher response rate than monotherapy Keytruda (ORR: 39.5% NSq/Sq Keytruda vs 47.6% NSq Keytruda, chemo vs 57.9% Sq Keytruda, chemo)10,5,9.

Tecentriq and Opdivo are eagerly awaiting round two at ASCO 2018, with positive data reporting out for their chemotherapy combinations on Monday June 4th in the NSCLC Oral Abstract session.  Follow-up data from the Phase III IMpower150 trial (NCT02366143) report an OS benefit for the combination of Tecentriq plus Avastin/carboplatin/paclitaxel compared to Avastin/carboplatin/paclitaxel in patients with non-squamous NSCLC (19.2 vs. 14.7 months, HR 0.78, p=0.016)12. Survival benefit was also demonstrated in all sub-groups analyzed, including ALK/EGFR sensitizing mutations after progression on a tyrosine kinase inhibitor, and patients with liver metastasis, which can be potential opportunities for this combination since data for Keytruda is not available in these subsets. This data also comes shortly after Roche / Genentech announced that the IMpower130 trial (NCT02367781; investigating Tecentriq in combination with Abraxane® (nab-paclitaxel, Celgene) and carboplatin versus Abraxane plus carboplatin) met its co-primary endpoints of OS and PFS as first-line therapy for patients with non-squamous wild-type NSCLC (Roche press release, May 29, 2018; full data to be reported at a future medical meeting). Despite these positive results for Tecentriq in non-squamous patients, Keytruda plus chemotherapy is a formidable opponent that may be difficult to beat.

Tecentriq also expects to keep itself in contention for patients with squamous NSCLC, with preliminary PFS and safety data reporting at ASCO 2018 for IMpower131 (NCT02367794), a Phase III study evaluating Tecentriq in combination with carboplatin and paclitaxel or nab-paclitaxel versus chemotherapy alone13. The trial met its co-primary endpoint of improving PFS, but with only a 0.7 month benefit favoring the Tecentriq arm (6.3 vs 5.6 months, HR 0.71, p=0.0001, as reported in a Genentech press release on June 2, 2018). At the interim analysis, an OS benefit was not observed, but data to be presented on Monday June 4, 2018 may provide further guidance. If a lack of OS benefit holds, Tecentriq may not have what it takes to defeat Keytruda in the squamous chemotherapy combination fight.

The third competitor, Opdivo, is also expected to present positive data on Monday from Part 2 of its Phase III, multi-arm, CheckMate-227 trial (NCT02477826) evaluating Opdivo plus platinum doublet chemotherapy versus platinum doublet chemotherapy in both non-squamous and squamous wild-type NSCLC patients with <1% PD-L1 expression14.  According to the abstract ahead of presentation, PFS was higher in the Opdivo plus chemotherapy arm compared to chemotherapy alone in the entire population (HR 0.74) though non-squamous patients demonstrated a stronger benefit (HR 0.68) compared to squamous patients (HR 0.92).  When comparing across low PD-L1 expressers, the Opdivo combination does have a stronger PFS hazard ratio in non-squamous than the Keytruda combination (HR 0.755), but lacks positive OS data.

These data from ASCO 2018, and more to come as other ongoing clinical trials read out in the near future, are sure to continue the competition in first-line NSCLC, as both Tecentriq and Opdivo look to defeat the reigning champion, Keytruda.



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  10. Lopes G, Wu YL, Kudaba I, et al; “Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study;” J Clinical Oncol, Abstract LBA4, ASCO 2018.
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  13.  Jotte RM, Cappuzzo F, Vynnychenko I, et al; “IMpower131: Primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel vs carboplatin + nab-paclitaxel as 1L therapy in advanced squamous NSCLC;” J Clinical Oncol, Abstract LBA9000, ASCO 2018.
  14. Borghaei H, Hellmann MD, Paz-Ares LG, et al; “Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: Results from CheckMate 227;” J Clinical Oncol, Abstract 9001, ASCO 2018.


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